This Podcast Will Kill You - Ep 210 Histoplasmosis: Bats, birds, and budding yeast

Episode Date: May 19, 2026

Once thought to be a rare, always fatal disease, histoplasmosis is now recognized as one of the most prevalent fungal infections in North America. It infects hundreds of thousands of people every year, and its distribution is growing. In this episode, we dissect this abundant fungus, examining how it makes us sick, who tends to get sick, and what we can do about it. We also take you through the history of this fungus, a story that features a surprise discovery, more evidence that everything is tuberculosis, and a spotlight on an extinct bird. Curious to know how all the pieces fit together? Tune in for the full picture. Support this podcast by shopping our latest sponsor deals and promotions at this link: https://bit.ly/3WwtIAuSee omnystudio.com/listener for privacy information.

This is exactly right. Say hello to your new favorite drinks. Introducing new Mick Cafe refreshers. I see cool, undeniably refreshing, and available in three flavors. Strawberry watermelon, mango pineapple, and blackberry passion fruit. Only at McDonald's. I'm Michelle McPhee, and I've been unraveling the strangest criminal alliance I've ever reported on. A Mormon polygamist and an Armenian businessman.

Multi-million dollar house. Ferraris and Lamborghinis, private jets, a billion dollar fraud. But how long can this alliance last? Tell me what you know. Is somebody coming after me? Listen to Kingdom of Fraud on the IHart Radio app, Apple Podcasts, or wherever you get your podcasts. Your 20s can be so exciting, but they can also be really overwhelming, confusing, and honestly, just kind of lonely. May is Mental Health Awareness Month, and the psychology of your 20s.

is breaking down the science behind the biggest roadblocks we face. I was six years into my career, the 80-hour weeks, and just the first one in, the last one out, and I ended up burning out. There was a large chunk of my 20s that I, like, was just so wanting to, like, be out of that phase out of my skin, and I just, like, really regret not living in the present more. You don't need to have everything figured out right now.

You just need to understand yourself a little bit better. Listen to the psychology of your 20s on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. My name is Macy, and I'm a 25-year-old from Southern Indiana. During my senior year of college, I started feeling pretty tired and chilly just a couple of days after I returned to campus after Thanksgiving break. I had a lot of final projects and studying to do, but I was feeling really exhausted, so I decided to give myself a break and lie down for a short nap. Not long after that, I realized that I might be running a fever. I took my temperature to find that it was just over 100 degrees.

It was 22, so I took a quick at-home COVID test, but it was negative. I figured I would keep an eye on it and see how things progressed over the next few days. But over the next week, my temperature steadily increased to just over 101 degrees. I wasn't experiencing a runny nose, cough, body aches, or anything else you would expect with a cold. I had been feeling more tired and had started taking a nap each day after class, but I was still able to function almost like any other college student. By day 12, my fever was reaching over 103 at times, and I was much more fatigued and sleeping even more. but now I was starting to notice some shortness of breath just walking from my apartment door to the elevators in my building.

It was also getting a little uncomfortable to breathe deeply. At that point, I decided I should go to the doctor, but with as busy as urgent cares are in a big college town during flu season, I wasn't able to get in anywhere for a few days. I went into my urgent care appointment on day 16 of this fever, expecting to be tested for a few infections, get an answer, and be sent home with some antibiotics. Instead, when the nurse practitioner came in to tell me about my results, She said that everything had come back negative. I do have a history of immunosuppression, though.

So she chose to send me to the emergency department for further workup, just to be sure that she wasn't missing anything big. In the ED, the doctors told me that my chest x-ray and CT showed some sort of pneumonia covering both lungs top to bottom. I was admitted, and over the next few days, I was treated with empiric antibiotics while they tried to figure out what was causing this. In the meantime, I continued to run a fever and got more and more fatigued. Around day four in the hospital, they started treating me with oral antifungal.

as they began to suspect that it was more likely to be a fungal infection. On day seven, I was told definitively that I had pulmonary histoplasmosis. My doctors were somewhat stumped as we could not pinpoint any likely exposure event. They chalked it up to me being immunocompromised and living in the Ohio River Valley. That evening, I was given ampheteris and B. They were planning to put in a pickline for continued infusions on discharge if I tolerated it well. But during that infusion, I experienced severe nausea, headache, and I spiked a fever for the first time that day.

On my eighth morning in the hospital, they chose to go ahead and give me a second ampheterosin B infusion before switching me to oral itchoconazil and sending me home. I was kept on intraconazole for a full year after that. I followed up with pulmonology for about three months and had to follow up with infectious disease for a couple of years. It has now been over three years since I was diagnosed with histoplasmosis, and I'm fully recovered. I just have a few small pulmonary calcifications on my chest x-ray to show for it. Macy, thank you so much for sharing your story with us. We really appreciate it.

Yeah. It really does mean a lot. Thank you. Yeah, thank you. Hi, I'm Erin Welsh. And I'm Aaron O'Mant Updike. And this is, this podcast will kill you. Welcome to histoplasmosis. Histoplasmosis. It's taken us a while to do this despite getting requests for it. And also this being one of the more abundant, prevalent. Much more common than other fungal pathogens that we've covered on the podcast, which I didn't really realize, honestly. I didn't either. I mean, I think when I saw the first time I read about how people in the Ohio River Valley, like 90% have been exposed, I'm like, oh, I've lived there. Yes. That's where I grew up. Correct. I have been exposed to Histo. It never occurred to me. Yeah. No. It's same. Same. Yeah. I'm excited to learn more about the biology because I'm like, when does somebody find out? Anyway, there's so much to cover. I'm so excited for this episode. So, so we got to get through some things first. We do, as always. It's quarantine time.

Yeah. What do we drink in this week? We're drinking the fungus among us, which we're pretty sure was the title of our blastomycosis episode. But it's a great, it's a great title. This is truly the fungus that is among us. Way more so than. Blasto. At least for, you know, the eastern half of the United States, but also other places, and it's also more broadly spread. Exactly. I know. I know. It's everywhere. It's everywhere. Well, what's in the fungus among us there? It is, it's going, we modeled it to look like, maybe I shouldn't say that. I'll say the ingredients first. It has coconut cream, pineapple juice, lime juice. It's really good. And we did, we used coconut cream because, of the way that a lot of exposures to histoplasmosis occur,

which is through bat, guano, and bird excrement. So we wanted it to look a little bit poopy, like bird poopy. A little bit bird and bat poopy. Yeah, in the spirit of histo. Yeah. You can find the full recipe for that delicious quarantini on our website, this podcast will kill you.com, and all of our social medias. Are you following us on the socials because we're there?

We are there. Make sure you follow, review, subscribe, rate, et cetera. And our website, things that you can discover on there include transcripts, links to our bookshop.org affiliate page, our Goodreads list, music by Bloodmobile, a firsthand account form, a contact us form, and links to merch, Patreon. Wow. So much. So much. That's it. I think that's it. Yeah. Check it out. Sources. Because I have a lot of more sources than I anticipated for this and some really great ones that I am encouraging people to read. I am so excited. Also, apologies because my cat is being very loud in the other room right now. Is he hungry? Is it the day?

It can't be. He's always hungry and he's always been fed. So I don't know what it is. Anyways. He's just making himself known. Yep. Yeah. Well, Aaron, should we get into this?

Let's do it. Let's take a quick break and get started. Say hello to your new favorite drinks. Introducing new Mick Cafe refreshers. I see cool, undeniably refreshing and available in three flavors. Strawberry watermelon, mango pineapple, and blackberry passion fruit. Only at McDonald's. Jacob Kingston grew up in an isolated polygamous sect.

We were God's chosen kingdom on earth. He felt destined for greatness. So when a swaggering Armenian businessman catapults Jacob into an extraordinary world, he doesn't look back. Ferraris and Lamborghinis, private jets, meeting the president of Turkey. I'm Michelle McPhee, and this is one of the most shocking criminal conspiracies I've ever come across. When Jacob met Levant, this went to a billion-dollar fraud. But with two kings from entirely different worlds,

just how long can their empire survive? The largest tax investigation in American history. You need to tell me what you know. Is somebody coming after me? Jacob told Levan, you're ruining my life. Listen to Kingdom of Fraud on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. May is Mental Health Awareness Month, and your 20s, they can feel like a lot. On the psychology of your 20s podcast, we unpack the anxiety, the overthinking, the heartbreak, the identity crisis, all of it that comes with being in your 20s.

Because if you've ever thought, is anybody else feeling this way, they definitely are. I feel like my 20s was a process of checking off everything that I was not good at to get to what I was good at. Oftentimes we take everything a little bit too seriously and we get lost in things. that we later on decide weren't even important to us to begin when. There was a large chunk of my 20s that I like was just so wanting to like be out of that phase out of my skin. And I just like really regret not living in the present more. Each week we break down the science behind what you're going through and give you real tools to navigate it. Your 20s aren't about having it all figured out.

They're about understanding yourself just a little bit better. Listen to the psychology of your 20s on the IHeart Radio app, Apple Podcasts, or wherever you get your podcast. costs. Histoplasmosis is the name for a disease caused by a fungus called histoplasma capsulotum. And it turns out that there's actually quite a lot of genetic diversity in this particular fungal species. Yeah. There's probably, I don't know, they might even be split into multiple species at some point. I don't know how fungal species differentiation works. Me neither. So I'm not. I'm not going to get deep into it today. We're just going to kind of focus on the histoplasma capsulotum group, okay? Right. And we have covered a relatively

similar fungus, at least in the kind of pathophysiology of how it works in our bodies earlier, and that is blastomycosis caused by blastomyses. But don't worry if you didn't listen to that episode or if you don't remember anything from it, because neither did I. So. Although it's a good episode. It is a really good episode. It's a really good episode. Because there's deep time and dinosaurs and, yeah, it's a really good episode. But unlike Blastomyses, the fungus that is the focus of today's episode, histoplasma, is extremely abundant in the environment, it turns out. Extraordinarily so.

You mentioned, Aaron, that classically in the U.S., we associate histoplasmosis with the Mississippi and Ohio River valleys. That's like what we learned in med school. And I did look this up this time because I kind of knew exactly where those were geographically, but let's be real. Not everybody does. So the Mississippi River runs north-south from like Minnesota all the way down and exits in the Gulf of Mexico. The Ohio River is one of its many tributaries that runs sort of east-west-ish from Pennsylvania to where it lets out in the Mississippi River. And so classically, this is where most. Most cases of histoplasmosis were seen.

And so that is the kind of association in a lot of people's minds. And it's true that today, the vast majority of cases in the U.S. are centered in these regions. But it is not only these regions where this fungus can be found. Nope. This fungus exists in the soil as a mold. And it can be found on every continent except Antarctica. Yep. It loves humid, nitrogen and phosphorus-rich soils, which means that it tends to grow very well where there's a lot of poop, bird poop and bat poop specifically.

Yeah. Oh, I was trying to get deep into like what makes a bird poop different amounts of nitrogen and phosphorus. I mean, I don't know the answer. I love that. But I was, there was a period of time. There was like a few hours where I was like. like bird poop composition. Different birds, different. I'm sure the composition's quite different. Right.

Right. And which one does histoplasma like? You know, you do know some of that. Exactly. I was going to say there are some papers with that. And it also seems like bats are a particularly important component of the histoplasmosis cycle. Right. Especially because the fungus itself can also be found in the bats.

And so then bat poop not only is good fodder in the soil for this multivism. grow, but can actually contain the histoplasma so they can spread it as they poop around the world. Right. Yeah. So lovely. Although I did also hear, so birds can't be infected, it seems. Yeah. But their feathers might be able to carry it because they're all poopy.

Yes, because they're covered in spores and things. That's so lovely. But, okay, if this fungus was just a mold living in the soil, then we wouldn't be talking about it on this podcast will kill you. Okay. Well, we might at some point. Maybe. but realistically, we probably wouldn't.

So what makes it pathogenic? What makes it pathogenic is that this fungus, like Lastomyses that we've covered before, is what's called thermally dimorphic, which means it can exist in two different forms depending on the temperature largely of the environment in which it exists in. So in the environment in the soil, which is going to be a cooler temperature, like let's say ideally 25 to 30 Celsius, which is like 70s to 80s. That's their sweet spot. That's when we see this fungus existing as a fungus, as a mold in this filamentous, branchy form. But it can also exist as a yeast, which is a single-celled fungus when it is exposed to higher temperatures around 37 degrees

Celsius, aka human body temperature 98.6 Fahrenheit. Okay, so tell me how does that work? Like, if you are exposed to the mold, will it turn into a yeast? Yeah, tell me about that. I would love to tell you about it. The answer is yes. So this is an example of an environmentally transmitted pathogen. So this is not something that's transmitted person to person. If I have histoplasmosis, I cannot give it to you, Aaron, especially not over the internet.

And there aren't any, like, vectors directly involved. So, yes, a human gets exposed via. exposure to the mold form of this fungus that thrives in the soil. Okay. So little bits of these heify, this filamentous branching mold, can break off in the soil. And the way that this form of the mold reproduces is it forms these spores called conidia. And those are what get dispersed into the environment so that this mold can continue to, you know, grow and move around the environment. So those spores, as well as little bits of the filaments themselves, get mixed up in the soil, and they can end up blown by the wind directly into our noses, or many mammals' noses, where we're going to breathe them in.

And once they are inside our warm human body, they're actually gobbled up almost immediately by our immune cells. They're gobbled up by cells like macrophages, which are kind of like one of the bouncers of our immune system, that gobble things up that don't belong. And histoplasma is, like, well adapted to this process. Once it is engulfed by a macrophage in this warm environment, it switches. That is, I know. Oh, my gosh. They completely transform.

They rearrange the entirety of their cell walls and how they exist and how they reproduce and turn into this yeast form. Now, yeasts, which are single-celled fungi, they don't reproduce by making spores. They reproduce by a process of budding, which basically just is like if you have one yeast cell, they kind of bloop pinch off, and now there's two of them and so on and so forth.

Histoplasma does this inside of our macrophages. So it's like a virus-ish. Yes. It's an intracellular pathogen. Okay, I did not know it was an intracellular. cellular pathogen. That is, so, okay, so then it, it, it buds and buds and buds inside this macrophage, and then to the point where the macrophage bursts, like, does it wait for the macrophage to burst, or does it go anywhere? Where does it go in your body? Yeah, eventually, it will kill this macrophage,

right? Eventually, it will, it will reproduce so much and so many times that these macrophages burst open, and then now these yeasts are free to be gobbled up by other macrophages and continue this process. And so it's all macrophages is the intracellular part of it? There's other cells too, but macrophages are one of like the main ones. Okay. Now, where this is happening is primarily in our lungs. Because we are exposed, yeah, by breathing it in. And so these tiny little spores that we've been exposed to get down into our lungs and that's where they are transforming into this yeast form. As our macrophages are gobbling them up, they're trying to mount a typical immune response.

And that means that they are flagging and telling other immune cells like our T cells to come in and get rid of this pathogen. And for the vast majority of us, that is the end of the story. Okay. Okay. So exposure, we have not gotten to infection yet. This is still like what an exposure would look like that could potentially lead to infection. You're breathing in these spores. They turn into yeast. They start to replicate. And then at some point throughout this process, as more and more macrophages are infected, your two cells are like, we're shutting this down. Absolutely.

Unless it progresses. Unless they can't. Exactly. So for the vast majority of us, we will have exposure, some kind of immune response. And it's our whole entire immune system that's involved. And then goodbye fungus, the end. we do a really good job of clearing this fungus. Classically. However, also classically, fungi are really good at flying under the radar and can find ways to avoid being completely eradicated.

So for some people, whether because they're immunocompromised or just because they were exposed to a really high dose, right? Like they inhaled a whole face full of these spores. They could end up with a symptomatic infomerized. So let's talk about what that looks like, shall we? Yeah. If someone is going to have symptoms from exposure to histoplasma, the most common thing they're going to have is a pneumonia, which is unsurprising because, again, this is all happening in our lungs. Usually, this is only happening if you're exposed to a really high concentration of spores.

And it's going to take some time because these yeast aren't like really fast at reproducing, you know, take some time. Okay. So after an incubation period of usually a couple of weeks or so. but anywhere from like three to 21 days, some of the papers I read said, you will start to have kind of nonspecific flu-like symptoms, fever, headache, cough, maybe some chills, muscle aches. It'll look like a pneumonia. Okay.

Many people might go to the doctor, be treated for bacterial pneumonia, and then they might get better all on their own. And the antibiotics absolutely were not the thing that made them get better. But most people who have even an acute pneumonia from histoplasmosis are going to recover all on their own and get over this infection. Okay. For others that maybe had a really even higher exposure or just are susceptible for one reason or another, they might have a more severe course. They might have increased inflammation. They might end up having like difficulty breathing, shortness of breast. or if you actually checked, you know, their oxygen concentration, it might actually be low.

And so in those cases, people might actually get the diagnosis of histoplasmosis, and then they might actually need treatment with antifungals. But that's not necessarily like a majority of people who are even having symptomatic acute pulmonary histoplasmosis. But that is not the end of the story. for some people. Okay, real quick, though. Yeah, give it to me. How long, on average, does this last if it is a self, self, what do you call it? A self-limiting infection? It's a good question. I don't have like a perfect timeline. I would expect it to be like within the, within what would be a typical course of pneumonia for a lot of people. So maybe a couple of weeks, max or so. But it all is just going to depend on what your immune response to it is, whether or not you get severely sick. and things like that. So it's very person dependent. And so most of these people are diagnosed based on symptoms and it is, and they're diagnosed as having bacterial pneumonia. Yeah, it's very, like we probably drastically underestimate the actual incidence of acute pulmonary histoplasmosis

because so many cases are either never seen by a healthcare professional because they think it's just some other cold or flu. Right. Or, yes, they're misdiagnosed as community-acquired pneumonia, treated with antibiotics, and they get better, but not because of the antibiotics, and it was actually histoplasmosmosis. Okay. I have two questions. Okay.

The first is, at what point does exposure become infection? Like, in order for an infection to count as infection, do there have to be symptoms? Yes. I don't know. It's a great question. I'm nodding because it's such a good question, but I don't have an answer for you. Okay. And then the other question is at what point does, you know, you said these diagnoses are often bacterial,

at what point does histoplasma become the horse and not the zebra, I guess? Yeah. Like at what point do people start to say this is, it's not resolving with antibiotics or like it's still, yeah. That's a really great question, Aaron. I don't have any answer for that either. Because it's going to so depend, right, on like, what hospital you end up in, who you are, how sick you are. Like, how much people are looking into this? Are you getting worse and worse and worse? Or are you getting kind of better? Like, do you have access to diagnostics? Do you not? Like, right. There's so much that's going to play into that.

Do you have risk factors that would suggest this is an opportunistic? Yeah. Like, I will say, I mean, having worked in hospitals, like, but not in a region that is common for histoplasmosis. I mean, in med school I was, but I don't remember thinking that much about histoplasmos as a med school. But like whenever there was someone who's not getting better, then one of the things, at least that we would do, would be to talk to the infectious disease folks. And this is often one of the first things that they would think of. And that's why it's so valuable to have access to infectious disease experts because they're going to think of things that other physicians might not remember as often or might not be top of mind when the symptoms are hard to kind of pinpoint. Or if you're not in the geographic region where. This is classically a histo zone. But as we know, as we'll talk about, it happens outside of histo zones all the time.

So those are great questions, though. And I like how, when does it consider an infection versus not is such an interesting question because we don't know. Most of the literature says that like less than 1% of people will have symptoms. But like that other 99% do we consider them having been infected? Right. I mean, if they mounted immune response, then yes, you do consider. or that, right, even if you were totally asymptomatic. So I think a lot of people have been infected, but just really very few of them end up actually having symptoms. And you can become re-exposed and

reinfected? Absolutely. Yes. Yeah. Yeah. And along those lines, Aaron, this acute, like, limited infection is not the end of the story for a lot of people because this fungus can continue to grow. even as we are mounting an immune response to it. And if that happens, there's kind of like two main ways that it can go in the long term. Or not even the long term, but there's two kind of ways that it can grow. One is that this yeast can continue to replicate, but our immune system can be kind of fighting back at the same time. Okay. And so it can do this thing that we do with a lot of.

lot of infections that are really hard to eradicate where our immune system kind of decides, look, we can't really get rid of this thing entirely. So let's wall it off. And so that results in the formation of these things called granulomas. And that's these like inflammatory little pockets of fungus and immune cells that kind of can just like sit there. This is, we've, we've, we've encountered this before because I feel like I made some bad, a cask of a Monteado, Edgar Alan Poe joke about walling off. Probably. That sounds familiar. Yeah.

No idea what episode that was. I mean, it could have been blastomachosis. Could have been TB. Yeah. But that was so long ago. I don't know. But you can see things like this in tuberculosis, absolutely. And histoplasmosis is easy to conflate with tuberculosis in a lot of cases.

And what's interesting is that this can happen, this process of this granuloma formation, can happen even without any clinically apparent disease. So even without having had any known symptoms, you can end up with these granulomas in your lungs that you might find on, say, a CT scan decades later. Decades later. It's actually quite a common cause of pulmonary nodules, like asymptomatic pulmonary nodules. What? And so that would just be like a random finding or would you be going in for something else?

No, it's really common that we have just incidental pulmonary. Nodular Nodules. They're like, oh, like, whoops, did you know that was there? Yeah. Okay. Okay. So these, these granulomas can do two sorts of things. One is they can just sit there and be an incidental nodule that never causes a problem or they could result in a chronic sort of disease that may or may not have symptoms and that may or may not be able to reactivate. We see this chronic pulmonary histoplasmosis much more commonly in people that have pre-existing lung conditions like COPD. And it can really mimic tuberculosis because it tends to be in the upper lobes of the lungs where we see these granulomas. And they can really progress with time to where eventually they

kind of really cause significant damage throughout the lungs. But it's usually only in lungs that already have underlying structural damage. Gotcha. So that's one way that this disease or that this can kind of proliferate in our lungs sort of low level. But the second way is that this fungus, this yeast, could continue to grow unchecked and can invade our lymphatic system or our bloodstream and then end up causing a disseminated infection where it can spread because it's inside of our blood cells, inside of our white blood cells to literally any organ in our body. Our eyes, our spleen, our liver, our bones, our skin, our nervous system, almost any organ, really any organ. Our colon is actually a really big

one. And this disseminated histoplasmosis is what we tend to see in people with immunocompromise, like uncontrolled HIV, or like a solid organ transplant who's on immunosuppressive medications, or a congenital immune deficiency, or especially today, people who are on medications like TNF alpha inhibitors, which are a class of medications that's used to treat a really wide variety of autoimmune conditions like rheumatoid arthritis or ulcerative colitis and things like that. So there can be these nodules and there can be disseminated disease. How long does it take for disseminated disease to develop and can it kind of bypass these

other stages and just sort of be disseminated? Yes. Those are really great questions. So to answer the first question, I don't have an exact timeline. Because we don't really have, at least from what I read. And so if I missed it, someone please let me know. But there's not like really great like, oh, here's an exposure versus here's disseminated disease like timelines out there, if that makes sense. So it's going to really depend on who the person is and how sick they were or how compromised their immune system was to begin with. But then yes, they absolutely could. have disseminated disease without having like a pneumonia type infection first, if that makes sense. And then what are the symptoms of disseminated disease? Great question. They can be really nonspecific, which can make them really hard to identify. What you end up seeing are these same kind of granulomatous lesions wherever this yeast has disseminated to, the lungs, the liver, the brain, the colon. And so it really depends on how far, this has progressed and what organs it has invaded to know what the symptoms are going to be.

But often what we see are fevers and especially fevers that don't respond to antibiotics, right, or that we can't find a source of a bacterial infection. We can find weight loss because this tends to be like a really progressive disease. When you look at people's blood, like when, you know, they're in the hospital because they're sick and you're checking their blood, we see that all of their blood counts. So like white blood cells, red blood cells, platelets tend to go down, down and down. And that's what we call pancytopenia. That's a pretty bad prognosis in histoplasmosis. I don't know the exact mechanism of it. Okay. And yeah, beyond that, the symptoms can be just really nonspecific. If someone has a lot of lung involvement,

they might have symptoms that look like pneumonia, but again, they're not getting better with antibiotics. We can often see, and this is when it gets really extreme, like colon perforations and things, which of course, is like a surgical emergency, and that's if the colon is very involved. If it's in the brain, then you might have symptoms similar to meningitis. If it's in the eye, then you might have damage to the eye, including vision loss. So it really just, it's so, so varied and it really just depends on where it has disseminated to. Yeah, that makes sense. Yeah. Is there, okay, too, sorry. I feel like I'm like just preempting you. I love it. I love it. Keep going. What is the breakdown of, let's say, you know, a hundred people

are become infected with histoplasma every year. What proportion of those are, like, asymptomatic, what proportion are symptomatic and self-resolved? What are the ones that are nodules? What are the ones that are disseminated? Yeah. Yeah. This is such a great question. I don't have, I wanted to find, like, exact stats on that. But the best that I got is that a lot of the papers say that one percent of people, so one percent, one out of that 100, would have a symptomatic infection. So we're going to have to go bigger. We'll go like a thousand. Okay. And then 60 percent of people who have a symptomatic infection will have respiratory symptoms. So that's more that like acute pulmonary infection. Of the rest of the 40 percent, I don't know what that breakdown is. How much of that

40 percent is like a chronic pulmonary histoplasmosis. versus a disseminated someone with immunocompromise having a disseminated infection. I don't have a breakdown on that other 40% of the 1%. Of the 1%. Of the 1%. Okay. And treatment. Yeah.

So before I talk about treatment, I want to just mention that one of the big problems, and we kind of have alluded to this, but one of the big issues with histoplasmosis is being able to diagnose it to begin with. Okay. Because if it's an acute infection, then it looks a lot like a bacterial pneumonia, right? Maybe an x-ray would look a little bit different or a little bit more patchy rather than like, you know, a low bar that we would see with a bacterial infection. But really, it's not super different in those early stages for acute infections. And so in those cases, it can be hard to diagnose because you're not thinking about it. like you said horses not zebras right but when it becomes chronic it can just be so nonspecific that it's hard to think of and then even when you think of it the gold standard for diagnosis is always culture but it can take six weeks to culture this fungus at which point at which point you needed to do something already right yeah so there is a lot of work being done and there are a lot of other tests out there to look at things like antigen detection, including in like urine, which is really great because that makes it cheap and easy. It's like very easy, obviously,

to collect urine compared to like cerebrospinal fluid from people. And then there's also PCR-based methods, but those are not available everywhere. So especially in places where histoplasmosis historically has been thought to be less common, there's a lot of issues with even having the tools in place to be able to detect this. pathogen, which is a huge problem because if you can't diagnose it, then you can't treat it. Yeah. Now, when it comes to treatment, not everyone ends up needing treatment, right? If this resolves on its own, then people don't need to be treated. And in fact, the guidelines from the Infectious Disease Society of America, which I think are under revision because they haven't been

updated since 2007, really emphasize like trying to not treat it unless you really have to. So unless somebody is really getting sick. And that's because fungal pathogens are really difficult to treat. And the antifungal medications that we use tend to be pretty hard on our bodies and cause quite a lot of side effects. So the two main medicines that are used are amphotericin B, which like pokes holes in the fungus and then kills them. But also pokes holes in our own cell membranes because it binds to cholesterol in our cells. And so it can cause pretty severe kidney and liver damage in some cases. And then the other medicine that's used is itrichonazole, which is another antifungal medication that also can have a lot of damage to the liver because of the

way that it's metabolized. And in either case, people often need at least six to 12 weeks of therapy and sometimes six to 12 months of therapy. Okay. That's a long time to be with those side effects. Exactly. Exactly. So it requires quite. a lot of close monitoring and everything. When it comes to the like big, big picture of mortality from histoplasmosis, the mortality rates are actually quite high. They're 5 to 8 percent. And that's in the U.S., like that's based on U.S. statistics.

And even those statistics are really generalized across the board. Like that's from the symptomatic infections that we know of. But in certain subpopulations or in certain geographical regions, this mortality rate can be substantially higher. So, for example, in people with HIV who end up with disseminated histoplasmosis, the U.S. mortality rate is closer to 10 percent is what I saw. But in some places, like in some areas of Brazil, it's up to 40 percent. Oh, my God.

And a lot of that is due to delays in diagnosis and treatment and access and things like that. So it is not a minor disease when it becomes disseminated. Yeah. Yeah. And that is histoplasmosis, Erin. Oh. It's a, I mean, fungal infections in general are just harder. They're so much harder.

Our body doesn't do as well, recognizing them often. Yeah. We have a harder time treating them. And then once they kind of. establish a foothold, it seems really difficult to knock them out. They're really good at just sort of like resisting our clearance. Yeah. You know? So yeah. Tell me, Erin, how did we get to here? Where did this fungus among us come from? Great, great questions. Say hello to your new favorite drinks. Introducing new Mick Cafe refreshers. I see cool, undeniable.

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May is Mental Health Awareness Month, and your 20s, they can feel like a lot. On the psychology of your 20s podcast, we unpack the anxiety, the overthinking, the heartbreak, the identity crisis, all of it that comes with being in your 20s. Because if you've ever thought, is anybody else feeling this way, they'd be. definitely are. I feel like my 20s was a process of checking off everything that I was not good at to get to what I was good at. Oftentimes we take everything a little bit too seriously and we get lost in things that we later on decide weren't even important to us to begin when. There was a large chunk of my 20s that I like was just so wanting to like be out of that phase out of my skin and I just like really regret not living in the present more. Each week we break down the science behind

what you're going through and give you real tools to navigate it. Your 20s aren't about having it all figured out. They're about understanding yourself just a little bit better. Listen to the psychology of your 20s on the IHeart radio app, Apple Podcasts, or wherever you get your podcasts. Our picture of histoplasmosis has taken shape over the past century and change. In fact, 2026 marks 120 years since it was first described. Oh, wow. Yeah.

Okay. And over that time, it has transformed from a rare disease to one of abundance, not just in terms of the number of annual exposures, which is numbering in the hundreds of thousands, millions, potentially, but also in terms of where it thrives. It loves nutrient-rich soils like those that have been enriched by bat guano or bird excrement. I won't say contaminated. did. This theme of abundance is something that I'm going to come back to later on. But for now, let me take you through the history of this fungus, which, oddly enough, started out not as a fungus, but as a protozoan, according to the guy who first observed it. Oh, what? Yeah. Yeah. Okay. Tell me. In December 1905, Samuel Taylor Darling had freshly arrived in Panama in the canal zone, where he acted as a pathologist in the hospital.

where he was working. On December 5th, 1905, a 27-year-old man, a carpenter, checked himself into the hospital when his illness, which had started a few months earlier as fever and vomiting, it took a turn for the worse. He was described as, quote, mildly delirious and incoherent with an enlarged spleen, but his lungs were clear and his blood did not contain any malaria parasites. Over the next 24 hours, he steadily declined and he died on the evening of the 6th of December. A preliminary diagnosis of milliary tuberculosis was given, which is when the tuberculosis bacteria have spread throughout the body forming nodules and leading to these systemic symptoms. And initially, the autopsy seemed to confirm this diagnosis.

Quote, the odor on opening thorax was suggestive of pulmonary tuberculosis, end quote. Interesting. I don't know. But he, I mean, the way he wrote about that is just sort of like everyone knows what this. Everyone knows what this smells like. Yeah. I mean, I guess that makes sense in that if you do something very often and you are exposed to, I am, I am not surprised that the formation of a bunch of caseating granulomas has a specific smell to it. Totally. Totally. Yeah. That's so interesting, though. Wow. Yeah. I just have never encountered that. Yeah. Yeah, I know that like C. diff has a particular smell. but like I didn't anyway. But also, quote, the lungs on section were found studded with pale gray milliary tubercles, tubercles, from two to three millimeters in diameter, end quote. But as Darling continued with the autopsy, he noticed several findings that contradicted

the initial tuberculosis diagnosis. Things like, quote, the tubercles were not as closely packed or so numerous as is often found in miliary tuberculosis and the general color of the lungerosis. and the general color of the lungs was quite red, end quote. Interesting. Yeah. And his suspicions were confirmed when he took a look at some blood smears under the microscope and found no tuberculosis bacteria, but instead, quote, enormous numbers of small bodies, generally oval or round. Most of them were intracellular in alveolar epithelial cells, while others appeared to be free in the plasma of the spleen and rib marrow, end quote.

I love that description. Erin. And to Darling's eye, which admittedly was limited by crude microscope equipment, these round bodies resembled protozoan parasites, like those that cause Leishmaniasis. Right. Yeah. And so he concluded that this was a new species of a pathogenic species of protozoan distinct enough to warrant a new name, histoplasma capsulotum. Huh. That's how it got its name. That's how it got its name. How interesting, Aaron. Yeah. Yeah. And this incorrect categorization as a protozoan, it didn't last all that long. It was just like five years later in 1912 after he published this paper, or after he first saw it, rather, another famous pathologist, Enrique de Rochalima, published a report where he was like, are you sure it's a protozoan? Because I just compared with what histoplasma looks like next to Leishmania and yeast. And it looks a lot more like yeast than a protozoan parasite. All right. So, like, it was corrected pretty shortly after, confirmed a number, you know, years later.

But, but like. I just love that your description of that made it sound like he was so polite about it. I mean, I'm so sorry, dude, but like, I just, I wanted you know, like. Make sure, like, can we just double check this again? Really cute. That's how I'm imagining. Very gentlemanly about the whole thing. That's making me cry.

Wow, your bar for jokes is way too well. I don't know what's going on with me. This correction was ultimately, of course, necessary. Like, it was, it had to happen. But it was kind of inevitable, like someone was going to come to this conclusion sooner or later. And it didn't exactly, like, shake the mycology world to its core, right? Histoplasma was not widely known at all. And those who had heard of it thought of it as a rare tropical disease, so of limited interest, I would say.

More of like a medical curiosity than something of like major, major importance. Okay. Yeah. The first inkling that it might be more than that, though, came in 1932. And this is when Dr. Catherine Dodd asked another physician at her university, Dr. Edna Tompkins, to take a look at a blood smear that she had just taken from a child with an unusual form of anemia. A few years earlier, Dr. Tomkin, so the one that she had asked to look at the slide, had just so happened to attend a demonstration on histoplasmosis given by a researcher who had visited Dr. Samuel Darling to learn about the fungus. And so he came to this hospital and was like,

here's this presentation, here's how you look at it or here's what it looks like. And so when she saw the blood smear, she was like, I've seen this before. Right? Like this looks familiar. And so she reached out to this researcher who had presented this demonstration to confirm her suspicions. And yes, it was histoplasmosis. Huh. And so why this was a landmark moment in histoplasmosis history is because this was the first time that someone had been diagnosed while they were still alive. Oh, wow. Every case prior to this, which was not very many cases, had been diagnosed at autopsy.

Okay. And so this gave researchers an opportunity to better culture and characterize the organism. And also just to describe like symptoms while someone was still alive. Wow. And the work that was done on just this one case tied up many loose ends, at least in terms of the fungus itself. It fulfilled Cox postulates. It identified the best medium for growth, led to the development of a test, and hinted at a more widespread distribution of this organism in nature, like in the environment.

something that would be confirmed in the following decades. Up until the 1940s, those who had heard of histoblasmosis considered it a rare, almost uniformly fatal disease. Huh. Very different than the pathogen. You described, Aaron, where it was, you know, 1% actually is symptomatic. Yeah. Yeah.

So what did it take to change that perception? Tuberculosis. Everything. Everything. is tuberculosis. Still happening. Yeah. Okay. And so what was going on is that increasingly doctors were finding that some patients that

seemed like they had tuberculosis had a negative TB skin test. Health exams during World War II laid the groundwork for this. Okay. X-rays had become part of the screening process to see whether someone could enlist, and physicians began to notice these calcified regions, these nodules in the lungs on x-ray. without an accompanying positive TB test. Mapping out where this happened showed Kentucky, Tennessee, Ohio, North Carolina, West Virginia, Mississippi, Missouri, Indiana, and Illinois as the hotspots for this phenomenon. And this is where just, I think I mentioned it earlier, but up to 90% of residents are estimated to be exposed during their lifetime.

Yeah. Yeah. Yeah. Yeah. Yeah. And, like, have evidence of prior, like, antibody response, meaning that they had an infection. even though it was asymptomatic most likely. Yep.

Yep. And so a few years after this, so World War II, once these draft screenings were over, a few years later, by which point a histobloidosis test was available, the same phenomenon was observed in tuberculosis sanatoriums. And it pointed not towards an unusual form of tuberculosis, but a separate disease entirely. Wow. Okay. Yeah. A paper from 1962 looked at 81 sanatoriums across the U.S., Canada and Cuba, and found that 7.5% of the 45,000 patients screened were positive for histoplasmosis. So, like, they were in there being treated for tuberculosis, but they actually had histoplasmosis. Yeah.

Fascinating, Aaron. Yep. Yep. At least one quarter of those had active histoplasmosis. Wow. And few were also positive for tuberculosis. Wow. So how many people in sanatoriums actually had histo and not tuberculosis or and then developed TB during their time there? Right.

Of course. No idea. No idea. But more than zero. Interesting. Yeah. Especially in the areas that we tend to think of as the classic histoplasmosis region. Yeah.

So for instance, more on that paper from 1962, the percentage of people who are. who were positive for histoplasmosis in Indiana, Kentucky, and Tennessee, respectively, was 15%, 14% and 13%. Oh, so like much higher than just the baseline. Oh, wow. Much higher than the 7.5%. Yeah. So this definitely pointed towards a tip of the iceberg situation. Mm-hmm.

Far from being a rare tropical disease, histoplasma probably led to millions of exposures every year and thousands of active cases in certain regions of the United States. But how were they getting it? A number of outbreaks throughout the 1950s and the 1960s helped to shed light on that question. And a pattern gradually emerged. Exposure to disturbed soil, like through construction or tornadoes. I saw a paper that was like tornadoes as a spreader of histoplasmosis. That totally makes sense. Totally makes sense. 100%. And that is tornado zone. Like it's not quite all of tornadoes. alley, but like there are tornadoes that absolutely happen there. Yeah, yeah. But even just like walking around, right, can disturb soil. And it's not just any soil. Soils enriched by bat guano or

bird excrement seemed particularly prone to harboring the fungus. Research demonstrated that like we talked about many bats can be, or while while many bats can become infected, birds cannot, but the poop of both animals is just stupendous for histo growth. And bird's, and birds, might be able to carry it in their feathers. Right. Outbreak investigation often led to like a chicken coop or a roof where pigeons roosted or a cave where bats lived. So, for instance, the 1970 Earth Day outbreak where nearly, ironically, where nearly 300 students in faculty at a junior high school in Delaware, which was 40% of the entire staff and students there,

they were symptomatic. after cleaning up Blackbird and pigeon roosting sites. They all were trying to clean up for Earth Day and then they all got histo. It's not funny. It's not funny, but it is just like, of course. Of course. You try to do something good. But yeah, histoplasma capsulatum was later isolated from the soil where they were doing the cleanup.

That tracks. A paper from 2016 by Benedict and Modi examines. histoplasmoses outbreaks in the United States and Puerto Rico since 1938 and found that in the 105 outbreaks that they examined, 77% were associated with bird or bat poop. Yep. And while earlier outbreaks tended to be rural and more limited, later outbreaks grew to be more urban and occasionally enormous. So for instance, a couple of outbreaks in Indianapolis in the late 1970s and early 1980s resulted in an estimated 200,000 people becoming infected 100K in each outbreak, roughly. What?

Yeah. Yeah. That's what the estimates are. But that's not all symptomatic. That's like how many people total because of, like, based on the symptomatic cases. This question of, yeah, exposure versus infection. And the epidemics, both of these were associated with construction. So, like, there was the tearing down of an old amusement park along with construction.

of a new tennis stadium and then the construction of like a swimming gym, swimming pool, gym thing on a university campus. So you got all that soil being disturbed and then winds carrying it throughout the city, which is densely populated and boom, like everyone is just breathing in histo. Histo. Yep. And then the 1980s and the AIDS pandemic ushered in the next era of histoplasmosis. Histoplasmosis is a disease that you mentioned air and disproportionately affects people with weakened immune systems. And over the course of the next few decades, it proved to be devastating, like truly devastating for so many people infected with HIV, especially those living in endemic regions, with case fatality rates up to 60 percent in some situations. And effective

treatments for histo back then were few and far between. And still relatively little was known about it. And so this period led to a big push for more research. research to better understand this infection and just growing awareness of the disease overall. As you might expect, these years of research led to histo turning out to be much more prevalent and widespread than expected, not just restricted to the Mississippi, Ohio River valleys, but elsewhere in North America, South America, parts of Africa and Eastern Asia, and its range is shifting currently, just as it once did. histoplasma likely originated in South America and began its spread to these other regions about

13 million to 3.5 million years ago, something like that. Just a casual 10 million year rain just of it. I mean, that's how it goes. But that is when the global climate was warmer. And it experienced a pause and kind of range contraction during the Pleistocene about like 100, or sorry, about 1.8 million years ago when the climate cooled. And then as it warmed again, it reestablished itself, flourishing in warmer and wetter areas. Oh, really? Aaron, warmer and wetter.

As always, well, wetter in some places. Yeah. As always, we can look towards the past to better predict our future. Yeah. Ongoing human-induced climate change is altering where this fungus can live and how we interact with it. Yeah. As temperatures have risen, histoplasma has expanded northwards in North America and to other temperate regions where it historically has not really occurred or has not been that prevalent,

such as northern Italy, parts of Argentina, and Turkey. This global warming might not only impact the range of this pathogen, but also how deadly it is. It might be selecting for more virulent and heat-tolerant strains, meaning it could better infect us. It might be more infectious in humans or also animals like our pets or bats enabling greater spread, or, in the case of bats more harm on top of another fungal pathogen that they're currently dealing with, the white nose syndrome. So what will the impact be? We don't know. Time will tell. Time will tell. Will increasing construction and land use change affect exposure to this pathogen? Seems pretty likely. I'm going to go, yes. That's where my money is. Yep. What we do

know is that histoplasma will continue to change in the coming years due to human. intervention. And I want to wrap up today by talking about this change, not in terms of a hypothetical future, but as a hypothetical past. What might histoplasmosis have looked like 150 or 200 years ago, particularly in the region that we think of as classic histocountry, the Ohio and Mississippi River valleys? Why would it have been any different than today? My answer. Okay. The passenger pigeon. Stop it.

Also known as ectopistus migratorious. Okay. What? Do you know about the passenger pigeon? I mean, I know that they were a thing that people used to send messages and things. Different pigeon. Oh, that's a different pigeon? I think that's the carrier pigeon.

Okay. So what the heck is the passenger pigeon then? Okay. The passenger pigeon. This might be my first tattoo ever. Okay. The passenger pigeon was once the most numerous bird in North America. Okay.

With an estimated population of 5 to 10 billion with a bee, before European invasion, 3 to 5 billion after. Which means that at one point, there were more passenger pigeons than humans on the planet. Wow. Wow. Okay. Over the 18th and 19th centuries, the passenger pigeon steadily declined until the sole remaining member of the species.

Martha, died in the Cincinnati Zoo on September 1st, 1914. She was 29 years old. Oh, wow. Her passing marked the end of an era. Never again would flocks of these birds tens of millions strong blot out the sun as they flew in search of food. This extinction served as a wake-up call and inspiration for the modern conservation movement. And while researching for this episode, I saw a. a passing reference to the passenger pigeon in a textbook called One Health and Micology,

where the author just kind of almost in a throwaway line, suggests that this bird drastically impacted histoplasmosis distribution across the United States. And I was like, uh, what? So, okay, so since most histo outbreaks are associated with exposure to bird or bat excrement, the presence of billions of birds and the untold amounts of their poop could have driven the spread of histoplasmosis across the landscape, or at least provided the nutrients necessary for their growth. Yeah. I've always had a soft spot for the passenger pigeon. Growing up in northern Kentucky, we would often go to the Cincinnati Zoo where there's a statue of Martha and an exhibit on the passenger pigeon. And it always struck me as horribly said. And also somehow like another era,

like it is another era. And it, yeah, I've always had a soft spot, I guess. So when I saw that in that book, I had to pull in that thread. And I was like, okay, where do we go from here? So just to prepare you, I did not find any conclusive evidence linking the passenger pigeon to histoplasmosis. But I did find plenty that is suggestive of a connection. And so if it's all right with you, I thought I'd spend the last bit of time just going through some of these observations and really just like, this is my time to pay tribute to this amazing species.

Yes. Me too. I'm so glad. We'll get tattoos together. Okay. I've been trying to get you to do that for a long time. I know, I know. The first one won't be T.PWKY.

It'll be the passenger pigeon. I don't know if mine's going to be the passenger pigeon, but maybe you're going to convince me right now. Your favorite species driven to extinction by humans? Give it to me, Erin. Give it to me. Okay, okay. The passenger pigeon could be found throughout the eastern half of North America, basically east of the Mississippi River, halfway north into Canada, and halfway, or halfway, or, Halfway into Canada on the northern side and halfway down Florida.

Okay. But its breeding range was primarily across the Ohio River Valley and Great Lakes region. Okay. Indiana, Ohio, Michigan, Wisconsin, Kentucky. If you look at a map of histoplasmosis outbreaks and passenger pigeon distribution, it is almost spot on. Like the Venn diagram is a circle kind of thing. Okay. Yeah.

Correlation is not causation. And there could be many reasons for that overlap. Just like, hey, both things like the same environment here. It's warm and humid, yeah. But it is compelling nonetheless, especially when you consider the poop. The poop. John James Audubon described what he saw in the 1820s and 1830s, quote. The dung lay several inches deep, covering the whole extent of the roosting place, like a bed of snow.

Many trees, two feet in diameter, I observed, were broken off at no great. distance from the ground and the branches of many of the largest and tallest had given way, as if the forest had been swept by a tornado, end quote. Because of how many birds are sitting on there? Oh my gosh. Yeah. Yeah. It's like hard to fathom until you listen to some of these descriptions. Because there's another one, this is also from Audubon, quote, the air was literally filled with pigeons. The light of noon day was obscured as by an eclipse. The dung fell in spots, not unlike. like melting flakes of snow, end quote, to have the sun obscured. Yeah. These flocks were millions

strong. That's not a small amount of dung. No. Which also could have provided excellent substrate for histoplasmosis to grow. Yeah. Pistoplasmosis that could have been misdiagnosed as tuberculosis, especially since the diagnostic technology for TB, x-rays and tuberculine skin tests, was only developed in the last years of the bird's existence. Wow, Erin. Perhaps it's a coincidence that high tuberculosis mortality in the late 1800s was observed in the histoplasmosis corridor, which was also the passenger pigeon breeding grounds. Perhaps not. I wish I knew. I really wish I knew. And maybe if I had like another few weeks slash do a PhD on this, then I could. But yeah, I really do wish that the information was out there somewhere. Right. So, but I did find, again, going back to just a few compelling statistics.

So during World War I, so 1914, 19, 18, 23% of draftees in Kentucky were rejected due to tuberculosis. And that was compared to the national average of 9%. Oh, wow. Which is kind of interesting. Yeah. Could be for many different things. Could be, many different things. Could be, you know. But could be histo. Could be histo. Maybe. Alexander Wilson, the fact. founder of American ornithology described a breeding site in Kentucky that was several miles wide and nearly 40 miles long, by his estimate. Quote, in this tract, almost every tree was furnished with nest, wherever the branches could accommodate them. Several people informed me that the noise in the woods was so great as to terrify their horses and that it was difficult for one person

to hear another speak without bawling in his ear. It was dangerous to walk under these flying and fluttering millions from the frequent fall of large branches broken down by the weight of the multitudes above and which in their descent often destroyed numbers of the birds themselves, while the clothes of those engaged in traversing the woods were completely covered with the excrements of the pigeons. End quote. Wow. I cannot imagine this. Doesn't it seem like fantastical? Yes. But it was real. I mean. It was. I mean. It's real. Some of this was exaggerated, no doubt, but like you can't, not all of it.

No. Because this is also many, many, many, many, many different accounts. Right. Of how many birds there were. How many birds there were. Yeah. Interestingly, in August 1980, just I was like, oh, this sounds like similar settings to what happened in this 1980 histoplasmosis outbreak when a group of people were traveling through,

it was a cross-country wagon train. And in 1980, it was for like a trance. troubled youth camp thing. Yeah. And they were traveling through eastern Kentucky and 81% of the 85 people on the train

developed histoplasmosis after stopping on the site of a former blackbird roost. It is interesting. And it wasn't even that like they were doing a lot of digging. It was simply just like setting tents up. Oh, wow.

Yeah. Can you imagine traveling through a passenger pigeon roosting site tens of miles long? No. Or even just standing beneath a flock as it passed overhead. Right. I've got one last quote from Wilson, also in Kentucky. Quote, happening to go ashore one charming afternoon to purchase some milk at a house that stood near the river. And while talking with the people within doors, I was suddenly struck with astonishment at a loud, rushing roar, succeeded by instant darkness, which on the first moment I took for a tornado about to overwhelm the house and everything around. round in destruction. The people, observing my surprise, coolly said, it is only the pigeons. And on running out, I beheld a flock 30 or 40 yards in width. These continued passing for more

than a quarter of an hour. And quote. Fifteen minutes of so many birds that they blocked out the sun. And he thought it was a tornado. Right. Birds numerous enough to be mistaken for a tornado, whose excrement was inches deep in roosting sites, where roosting sites left their mark on the forest for years, passenger pigeons were a force on this continent. And their decline in ultimate extinction was a shock, although it really shouldn't have been. Since Europeans landed in North America

and began to cut down enormous forests to make way for pasture land, the birds began to drop in abundance. By the early 1800s, they still numbered in the billions, but population growth and deforestation over that century contributed to their annihilation, along with the introduction of species that competed for resources like pigs and the free-for-all hunting in which, quote, wagon loads of the young birds could be easily obtained, end quote, tens of thousands, even over 100,000 killed at once, just for sport. For sport?

Many of them would just rot because people could only, a lot of people ate them for food. but this type of a thing was just like a free-for-all. It's just complete waste. Yeah. And it's possible that also as they declined and their strength in numbers could no longer protect them from predators, including humans,

they just couldn't recover year after year. Conservation as a concept was still in its infancy, and no one thought to create a captive breeding program, which could have preserved the species. but without adequate continuous forest, it's doubtful that they could have ever recovered to their billion strong numbers. And there is some talk from the Resurrection Company with all the dire wolf like overhype. But again, I feel like those resources could be better spent on actual conservation efforts rather than implying that like, oh, it's fine. If it goes extinct, we can always bring it back.

And guess what? Yeah, this technology is proprietary. So good luck. Yeah. No. Jeff Goldblum said it best. It's like, yeah, that's a whole, I could, that's a soapbox that I should probably just not at this point. That's exactly how I feel. But when passenger pigeons were made extinct, North America lost a major ecosystem engineer.

These birds preferentially fell on mast from red oaks and the forests where they roosted were filled. with broken branches and twigs and trees, leading to more intense and frequent forest fires. Part of the natural cycle. You know, like cycle of forest fires. These two things, favored white oaks, which are more fire resistant. And when the passenger pigeon went extinct, the forest of eastern North America shifted from white oak to red oak, which is just kind of an interesting component of this. I love, this makes me just love ecology so much like I used to, you know, like it's. like the story of the otters and the sea urchins and the kelp and the like it's the same oh keystone species

caseone species everything is connected it's everything is connected it is it is just amazing also how little people have heard like it's also amazing at all yeah and it was just over a hundred years ago yeah that that martha died um but also of interest forest forest's lost a major seed distributor and tree-mast consumer as well. So like acorns, like all of the stuff, the seeds and stuff that these trees produced. And that opened up a niche for competitors like deer and rodents. Oh, like Lyme disease? In their populations, which may have contributed to the rise of Lyme disease.

Passenger Pigeon extinction, man. Did the extinction of the passenger pigeon also reduce histoplasmosis across the landscape? it's possible, I don't know. I mean, all of this is the links between histo and the passenger pigeon is speculation on my part. I'm just trying to connect the dots across these historical accounts of a lost bird and our modern understanding of this fungal disease. The discovery of histoplasma capsulatum occurred just eight years before Martha's death and nine years after the last passenger pigeon in the wild was killed. histoplasmosis is a disease of abundance, and it's possible that some of this abundance can be attributed to this once abundant bird. I'm not sure we'll ever know the relationship between the two, but we can't afford to ignore the role that we humans play in the rise and fall of species.

So with that, Aaron, I'll turn it over to you to tell me where we are with histo today. Oh, and also I wanted to mention I wore this sweater that has birds on it. Can you see this bird over here too? I can. My little guy. So cute. Yeah. In honor of the passenger pigeon. Oh, Aaron. I don't even want to say anything. I just want to end it there. But I will. Only because I already wrote it down. So listen. Don't let good work go to waste. Right. We'll wrap this up real quick here. Oh gosh. That was so much. I'm like still reeling. So histoplasmosis has been described as the most common endemic mycosis in the Americas. And the fungus itself has been reported, like you mentioned, Darren, across the United States, especially in the eastern half, especially in the Mississippi, Ohio River valleys.

But also throughout a large portion of Latin America, including Central and South America, it has been found in Central. and Western Africa, though there, and this is what I said at the very beginning, there's like different sort of subspecies or like variants, and so there's a little confusion over there. And it's been found across a lot of Asia as well. Truly, this is a global pathogen. The more that we look for it, the more that we find it. In the U.S., which is where we have probably the most data on like incidents and prevalence, the estimated incidence overall is between one to two.

cases per 100,000 people. Okay. I don't know if that is the incidence of symptomatic infection, but I anticipate that it is. So that's how many symptomatic cases we expect. Because like we've said numerous times now, it's estimated that anywhere from 60 to 90% of people who live in areas of high histoplasma in the soil, they show evidence of prior infection. Yeah. And in the U.S., this disease is only reportable in, like, 14 states in those areas that we know histoplasmosis is more common. So our data isn't great across the rest of the country. Right. And that one to two cases per 100,000 is averaged across the whole country. So it is higher incidents in places like Kentucky, Ohio, etc., where this is more common, right? Right. Yeah, yeah. And so then how do we, like how many cases are there?

in the U.S. across like each year, we don't, we really don't have good numbers. There was a paper I found that looked at like Medicare data over a nine year period from 2007 to 2016 that said there were 79 or so thousand cases that were reported. These are all going to be symptomatic cases, of course. And those are just the ones that are reported. Wow. Because it's not, it's not reportable. Only in 14 states. Only in 14 states across. So. So this was a Looking at like Medicare data, like hospital data and things like that. So where there was like a histoplasmosis, you know, case documented. Yeah. But another paper suggested that there could be upwards of 500,000 new infections each year in the U.S. I saw that because, I mean, and that makes sense if you think about. If you think about the asymptomatic infections. Or the people who recover, even though they're in, they're diagnosed with bacterial pneumonia. Exactly. Exactly. 100%. So that's including all of that like, you know, self-limited disease or asymptomatic disease. So it's suggested that like over 40 million people in the U.S. at least have been infected.

And that's probably an underestimate. It's so common. So, so common. Oh, my gosh. And like I said, the more places that we look for it, the more places that we find it. In Central and South America, there are cases reported year after year. We're seeing more and more case reports across Asia, especially in the Yanksy River Valley in China.

River valleys, man. Apologies for my pronunciation there. Yeah, river valleys. But there's also been case reports in Thailand, in South Korea, in India, in Africa. It's been reported in Uganda, Tanzania, and South Africa. And one of the things that we talked about is the impact of this disease on people who are immunocompromised, especially in people living with HIV, especially in areas that lack access to either diagnosis and or treatment for HIV, especially in places where there's a lot of

stigma associated with HIV still. So there are a number of papers out there that are looking at histoplasmosis specifically in people living with HIV. And one of the places that they're doing a lot of research on this is in Brazil. And in some cases, not only is the case fatality rate of histoplasmosis so high in people living with HIV, but there's estimates that the mortality rates in people living with HIV with histoplasmosis are equivalent to, if not exceeding, the mortality due to tuberculosis. That's, oh my God. I know.

So this is a hugely impactful disease. Like, it is way more widespread and it is a much bigger concern, certainly than I realized. Totally. And with more and more people being put on medications like these TNF alpha inhibitors, and that's just one. example, but there's a lot of like strong association between those types of drugs and fungal infections like histoplasmosis specifically. But those among other drugs that cause immunocompromise and immune suppression, our understanding of histoplasmosis is like more important than ever, right? That we're able to diagnose it, that we have access to better treatments, which we don't right now.

Like our treatments are ancient and not great. Not great, yeah. And like you mentioned, we might not have a current day passenger pigeon situation. But given how much land use change is happening, how rapid land use change is happening in places, the effects of climate change on fungal pathogens broadly, including histoplasmosis, like this is very likely to only continue to increase histoplasmosis. Absolutely. So. That's what I got. We should be talking more about it. We should be talking more about it.

We should be talking more about it. And about the passenger pigeon, but that's my personal, my personal, like, obsession. I need to look up, like, images of the passenger pigeon. Does it look like a pigeon? I mean, it's certainly pigeon-like, but it's, I think it's quite beautiful. And there was a strong amount of sexual dimorphism, which not all pigeons have anyway. Oh, cute. I love, that's my favorite thing I've learned.

So, I'm glad. If you want to learn more, we'll tell you. We have, like I said, I really, because of the rabbit hole or pigeonhole, um, sorry. Again, you're showing how low your bar for jokes is, Aaron. I'm in a good mood, I guess. But the, I have so many sources because I was like, and what about this? What about this?

So anyway, let me take you through a couple on histo. There's a paper from 1957 by Schwartz and Baum called the Hibald. history of histoplasmosis 1906 to 1956. It was a great sort of primer on like what people have discovered and where are we from here. Then from 2022 by Taylor at all, considerations about the geographic

distribution of histoplasma species. Yep. Saw that one. And then if you would like to read about the passenger pigeon, I read a book called A Message from Martha by Mark Avery. But there's like a number of passenger pigeon books out there. And I have a couple papers about the genome.

Anyway, it's, and did I find one about its diet? I did find one about its diet. Yeah. Anyway, go ahead, Erin. So I had a number of papers as well. Just a few that I'm going to shout out here that were really good overviews of histoplasmosis itself. One was by Linder and Kaufman from 2019 in current fungal infection reports called histoplasmosis, Epidemiology, diagnosis, and clinical manifestations.

Another from 2024 by Gandhi at all that was called histoplasmosis around the world, a global perspective on the presentation, variance factors in treatment of histoplasmosis. There's too many, and they're all just like really long titles. There's a whole bunch there. I had an interesting one that was comparing histoplasmosis to blastomycosis. So if you want more details on those, the similarities and differences, we got them all. On our website, this podcast will kill you.com, right under the episodes tab. You can find the list of sources from this and every single one of our many episodes.

Many episodes. Yeah. Thank you again so much, Macy, for sharing your story with us. We really appreciate it. We do. Thank you. Thank you also to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to Leanna and Tom and Pete and Mark and everyone at exactly right for everything that you do.

Thank you, thank you. And thank you to you listeners. If you find more info about the passenger pigeon and histo or refuting the link or things you want to know more about or whatever, let us know what you think. We always like to know. If you already have a tattoo of a passenger pigeon, can you send it so that Aaron can get some inspo?

Please. Please. It's going to be that and the Tasmanian tiger. Oh, I love it. That's so cute. And as always, a special shout out to our patrons. Thank you so much for your support. It really does mean.

It really does mean a lot to us. It really does. It means so much to us. Thank you. Until next time, wash your hands. You filthy animals? I'm Michelle McPhee, and I've been unraveling the strangest criminal alliance I've ever reported on. A Mormon polygamist and an Armenian businessman. Multi-million dollar house, Ferraris and Lamborghinis, private jets, a billion dollar fraud. But how long can this alliance last? Tell me what you know. Is somebody coming off?

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