Ep 210 Histoplasmosis: Bats, birds, and budding yeast

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/3WwtIAu See omnystudio.com/listener https://omnystudio.com/listener for privacy information.

• 0:01Speaker 00

  This is exactly right.

• 0:06Speaker 01

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• 0:51Speaker 01

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• 1:03Speaker 02

  Hey, I'm Niall Rogers. This fall, I'll be driving across the country, meeting some of today's coolest and most fascinating artists. We'll explore the stories before the moments that changed everything. Because every musician remembers the moment where it all began. Experience Before the Moment, a Lincoln original series on the iHeartRadio app, YouTube, or wherever you get your podcasts.

• 1:35Speaker 03

  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 2022, 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 one hundred one degrees. I wasn't experiencing a runny nose, cough, body aches, or anything else you would expect with a cold.

• 2:19Speaker 03

  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 twelve, my fever was reaching over one hundred three 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 sixteen 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.

• 3:04Speaker 03

  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 antifungals, 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 Amphotericin B.

• 3:50Speaker 03

  They were planning to put in a pick line 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 Amphotericin B infusion before switching me to oral intracranial and sending me home. I was kept on intracranial 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.

• 5:10Speaker 04

  Macy, thank you so much for sharing your story with us. We really appreciate it.

• 5:15Speaker 03

  Yeah, it really does mean a lot. Thank you.

• 5:17Speaker 04

  Yeah, thank you. Hi, I'm Erin Welsh.

• 5:21Speaker 03

  And I'm Erin Omen Updike.

• 5:22Speaker 04

  And this is This Podcast Will Kill You.

• 5:24Speaker 03

  Welcome to histoplasmosis.

• 5:27Speaker 04

  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.

• 5:39Speaker 03

  Much more common than other fungal pathogens that we've covered on the podcast, which I didn't really realize, honestly.

• 5:47Speaker 04

  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. That's where I grew up. I have been exposed to histo. It never occurred to me.

• 6:05Speaker 03

  Yeah, no, it's a same.

• 6:07Speaker 01

  Same.

• 6:08Speaker 04

  Yeah. I'm excited to learn more about the biology because I'm like, when does somebody find out? Anyway, there, there's so much to cover. There's, I'm so excited for this episode. So, uh, but so we got to get to through some things first.

• 6:20Speaker 01

  We do, as always.

• 6:22Speaker 04

  Quarantini.

• 6:23Speaker 01

  Quarantini time.

• 6:23Speaker 04

  Yeah. What are we drinking this week?

• 6:25Speaker 01

  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.

• 6:34Speaker 04

  This is truly the fungus that is among us.

• 6:36Speaker 01

  Way more so than blasto.

• 6:38Speaker 04

  At least for, you know, the eastern half of the United States, but also other places. And it's also more broadly spread.

• 6:44Speaker 01

  Exactly.

• 6:44Speaker 04

  I know, I know. Yeah.

• 6:45Speaker 01

  It's everywhere.

• 6:45Speaker 04

  It's everywhere.

• 6:47Speaker 01

  Well, what's in the fungus among us, Erin?

• 6:50Speaker 04

  It is, um, it's going, we modeled it to look like, maybe I shouldn't say that. I'll say the ingredients first.

• 7:00Speaker 04

  It has coconut cream, pineapple juice, uh, 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.

• 7:19Speaker 01

  A little bit bird and bat poopy.

• 7:20Speaker 04

  Yeah. In the spirit of histo.

• 7:24Speaker 04

  Yeah.

• 7:25Speaker 01

  You can find the full recipe for that delicious quarantini on our website, thispodcastwillkillyou.com and all of our social medias. Are you following us on the socials? Because we're there.

• 7:36Speaker 04

  We are there. Make sure you follow, review, subscribe.

• 7:42Speaker 01

  Nailed it.

• 7:42Speaker 04

  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, uh, links to merch, Patreon.

• 8:02Speaker 01

  Wow. So much.

• 8:03Speaker 04

  So much. 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.

• 8:15Speaker 01

  I am so excited. Also apologies because my cat is being very loud in the other room right now.

• 8:22Speaker 04

  Is he hungry? Or is it the day? It could be, it could be.

• 8:25Speaker 01

  He's, he's always hungry and he's always been fed. So I don't know what it is. Anyway.

• 8:30Speaker 04

  He's just, he's just making himself known.

• 8:32Speaker 01

  Yep.

• 8:33Speaker 04

  Yeah.

• 8:35Speaker 01

  Well, Erin, should we get into this?

• 8:37Speaker 04

  Let's do it.

• 8:38Speaker 01

  Okay.

• 8:38Speaker 04

  Let's take a quick break and get started.

• 8:42Speaker 01

  What is one thing many of us deal with every single day but rarely talk about? Dry hands. Whether you frequently wash your hands or deal with harsh weather, your hands can be left feeling dry, rough, cracked, and even uncomfortable. That's where O'Keefe's Working Hands Hand Cream comes in to help. The fast-absorbing formula goes on smoothly, and it won't leave behind a greasy residue, so you can get back to your busy day without ever missing a beat. And because a little will go a long way, O'Keefe's Working Hands Hand Cream is effective, dependable, and economical, too. Whether you're dealing with harsh weather outside, demanding work, or everyday wear and tear, O'Keefe's Working Hands works just as hard as you do. So keep your hands hydrated, smooth, and feeling comfortable all season long.

• 9:27Speaker 01

  Visit okeefescompany.com today. That's O-K-E-E-F-F-E-S company.com for guaranteed relief. O'Keefe's Working Hands. Yeah, it works.

• 9:39Speaker 02

  Hey, I'm Nile Rodgers, producer, songwriter, guitarist, and co-founder of the group Sheik. A great song has a way of defining a moment, a moment of joy, heartbreak, or anything in between.

• 9:56Speaker 02

  This fall, I'll be driving across the country, dropping in on some of the coolest, most fascinating artists working today. We'll go deep into their lives and careers and hear what it was like before the moment that made them. From hitmakers like Miguel...

• 10:13Speaker 05

  That last year, finishing that record was the hardest experience of my life. Regardless of how everyone else buys into this, I believe in this, and I'm gonna push.

• 10:25Speaker 02

  To rising stars like Alex Warren.

• 10:28Speaker 06

  You know, a song is a story and the verse is setting the scene. And for me, at least, it's allowing me to be personal and vulnerable with the audience, whether it's about my wife and I'm being vulnerable about her, or it's about, you know, my parents, I'm being vulnerable to them. And it's almost like a cinematic piece in a way where each song tells that beautiful story.

• 10:46Speaker 02

  It's gonna be one hell of a trip. Experience Before the Moment, a Lincoln original series on the iHeart Radio app, YouTube, or wherever you get your podcasts.

• 11:14Speaker 01

  Histoplasmosis is the name for a disease caused by a fungus called Histoplasma capsulatum.

• 11:22Speaker 04

  Mm-hmm.

• 11:23Speaker 01

  And it turns out that there's actually quite a lot of genetic diversity in this particular fungal species.

• 11:29Speaker 04

  Yeah.

• 11:29Speaker 01

  There's probably, I don't know, they might even be split into multiple species at some point.

• 11:34Speaker 04

  I don't know how fungal species differentiation works.

• 11:37Speaker 01

  Me neither, so I'm not.

• 11:38Speaker 04

  Somebody does.

• 11:39Speaker 01

  I'm not gonna get deep into it today. We're just gonna kind of focus on the Histoplasma capsulatum group, okay?

• 11:47Speaker 04

  Right.

• 11:48Speaker 01

  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 blastomycies.

• 12:02Speaker 01

  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.

• 12:08Speaker 04

  Although, it's a good episode.

• 12:10Speaker 01

  It is a really.

• 12:11Speaker 04

  I remember liking that episode.

• 12:12Speaker 01

  Because there's deep time and dinosaurs and, yeah, it's a really good episode. But unlike blastomycies, the fungus that is the focus of today's episode, Histoplasma, is extremely abundant in the environment, it turns out.

• 12:29Speaker 04

  Extraordinarily so.

• 12:31Speaker 01

  You mentioned, Erin, that classically in the US, we associate histoplasmosis with the Mississippi and Ohio River Valleys. That's like what we learn in med school. And I did look this up this time because... I like 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 cases of histoplasmosis were seen. And so that is

• 13:14Speaker 01

  the kind of association in a lot of people's minds. And it's true that today, the vast majority of cases in the US are centered in these regions. But it is not only these regions where this fungus can be found.

• 13:27Speaker 04

  Nope.

• 13:28Speaker 01

  This fungus exists in the soil as a mold. And it can be found on every continent except Antarctica.

• 13:38Speaker 04

  Yep.

• 13:40Speaker 01

  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.

• 13:53Speaker 04

  Yeah. Oh, I was trying to get deep into like, what, what makes a bird poop different, different amounts of nitrogen and phosphorus? I, I mean, I don't know the answer.

• 14:04Speaker 01

  I love that.

• 14:05Speaker 04

  But I was, there, I, there was a period of time, there was like a few hours where I was like, bird poop composition.

• 14:10Speaker 01

  Composition.

• 14:11Speaker 04

  Yeah.

• 14:12Speaker 01

  Different birds, different, I'm, I'm sure the composition's quite different.

• 14:15Speaker 04

  Right, right. And which one does histoplasma like, you know, I,

• 14:19Speaker 01

  I did find.

• 14:19Speaker 04

  We do know some of that, yeah.

• 14:20Speaker 01

  Exactly. I was gonna say, there are some papers with that. And it, it also seems like bats are a particularly important component of the histoplasmosis cycle.

• 14:28Speaker 04

  Right.

• 14:29Speaker 01

  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 mold to grow, but can actually contain the histoplasma. So they can spread it as they poop around the world.

• 14:44Speaker 04

  Right. Yeah, bats can, although I did also hear, so birds can't be infected, it seems.

• 14:50Speaker 01

  Right. Yeah.

• 14:51Speaker 04

  But their feathers might be able to carry it because they're all poopy.

• 14:54Speaker 01

  Yes, because they're covered in spores.

• 14:56Speaker 04

  Yeah.

• 14:57Speaker 01

  And things. 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, We'll Kill You.

• 15:05Speaker 04

  Okay. Well, we might at some point.

• 15:07Speaker 01

  Maybe, but realistically, we probably wouldn't.

• 15:09Speaker 04

  But it's a pathogen. So what makes it pathogenic?

• 15:12Speaker 01

  Yeah. What makes it pathogenic is that this fungus, like Blastomyces 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.

• 15:28Speaker 04

  Hmm.

• 15:29Speaker 01

  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.

• 16:01Speaker 04

  Okay, so tell me, how does that work? Like, if you are exposed to the mold, can you, will it turn into a yeast? Yeah, tell me about that.

• 16:10Speaker 01

  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, Erin. 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.

• 16:39Speaker 04

  Okay.

• 16:40Speaker 01

  So little bits of these hyphae, 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...

• 17:21Speaker 01

  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.

• 17:49Speaker 04

  That is, oh my gosh.

• 17:52Speaker 01

  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.

• 18:25Speaker 04

  So it's like a virus.

• 18:26Speaker 01

  Inside our body. Yes, it's an intracellular pathogen.

• 18:29Speaker 04

  Okay, I did not know it was an intracellular pathogen. That is, so, okay, so then it, it re, 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?

• 18:46Speaker 01

  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.

• 19:01Speaker 04

  And so it's all macrophages is the intracellular part of it?

• 19:04Speaker 01

  There's other cells too, but macrophages are one of like the main ones.

• 19:09Speaker 04

  Okay.

• 19:09Speaker 01

  Now.

• 19:10Speaker 04

  Yeah.

• 19:11Speaker 01

  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.

• 19:25Speaker 01

  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

• 19:44Speaker 04

  Okay, okay, so you 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 T cells are like, we're shutting this down.

• 20:05Speaker 01

  Absolutely.

• 20:06Speaker 04

  Unless.

• 20:07Speaker 01

  Unless they can't, exactly. So for the vast majority of us, we will have exposure, some kind of immune response, and it's, you know, 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 faceful of these spores.

• 20:51Speaker 01

  They could end up with a symptomatic infection. So let's talk about what that looks like, shall we?

• 20:55Speaker 04

  Yeah.

• 20:57Speaker 01

  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.

• 21:19Speaker 04

  Okay.

• 21:19Speaker 01

  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,

• 21:28Speaker 01

  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.

• 21:40Speaker 04

  Okay.

• 21:41Speaker 01

  Many people might go to the doctor, be treated for bacterial pneumonia.

• 21:49Speaker 01

  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.

• 22:05Speaker 04

  Okay.

• 22:06Speaker 01

  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 breath. 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.

• 22:49Speaker 04

  But.

• 22:49Speaker 01

  That is not the end of the story for some people.

• 22:52Speaker 04

  Okay, real quick, though.

• 22:53Speaker 01

  Yeah, give it to me.

• 22:54Speaker 04

  How long on average does this last if it is a self, self, what do you call it?

• 23:00Speaker 01

  A self-limiting infection?

• 23:01Speaker 04

  Self-limiting infection.

• 23:02Speaker 01

  It's a good question. I don't have like a perfect timeline.

• 23:05Speaker 04

  Okay.

• 23:06Speaker 01

  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.

• 23:25Speaker 04

  And so most of these people are diagnosed based on symptoms and it is, and they're diagnosed as, as having bacterial pneumonia?

• 23:35Speaker 01

  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.

• 23:50Speaker 04

  Right.

• 23:51Speaker 01

  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 histoplasmosis.

• 24:01Speaker 04

  Okay, I have two questions.

• 24:03Speaker 01

  Okay.

• 24:04Speaker 04

  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?

• 24:17Speaker 01

  I don't know. It's a great question.

• 24:19Speaker 04

  Okay.

• 24:19Speaker 01

  I'm nodding because it's such a good question, but I don't have an answer for you.

• 24:23Speaker 04

  Okay.

• 24:23Speaker 01

  Yeah.

• 24:24Speaker 04

  And then the other question is, at what point does, you know, you said these diagnoses are often bacterial. At what point does, does histoplasma become the horse and not the zebra, I guess?

• 24:36Speaker 01

  Yeah.

• 24:37Speaker 04

  Like, at what point do people start to say, this is, it's not resolving with antibiotics? Or like, it's still, yeah?

• 24:43Speaker 01

  That's a really great question, Erin. I don't have any answer for that either. Because it's gonna 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, there's so much that's gonna play into that.

• 25:05Speaker 04

  Do you have risk factors that would suggest this is an opportunistic?

• 25:08Speaker 01

  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 histoplasmosis in 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 gonna think of things that other physicians might not remember as often, or might not be top of mind, when the symptoms are hard to, to kind of pinpoint, so.

• 25:43Speaker 04

  Or if you're not in the geographic region where this is classically a histo, histozone.

• 25:49Speaker 01

  But as we know, as we'll talk about, it happens outside of histozones all the time. So, those are great questions, though. And I, like, how, when does it considered 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?

• 26:12Speaker 04

  Right.

• 26:12Speaker 01

  I mean, if they mounted immune response, then yes, you do consider that, right? Even if you were totally asymptomatic. So, I think a lot of people had been, have been infected, but just really, very few of them end up actually having symptoms.

• 26:26Speaker 04

  And you can become re-exposed and re-infected?

• 26:29Speaker 01

  Absolutely. Yes. Yeah, yeah. And...

• 26:33Speaker 01

  Along those lines, Erin. 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.

• 27:11Speaker 04

  Okay.

• 27:11Speaker 01

  And so it can do this thing that we do with a 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.

• 27:23Speaker 04

  Ah.

• 27:24Speaker 01

  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.

• 27:38Speaker 04

  This is, we've, we've, we've encountered this before because I feel like I made some bad Cask of Amontillado Edgar Allan Poe joke about walling off.

• 27:47Speaker 01

  Probably. That sounds familiar. Yeah. No idea what episode that was. I mean, it could have been blastomycosis.

• 27:55Speaker 04

  Yeah.

• 27:56Speaker 01

  Could have been TB.

• 27:57Speaker 04

  Yeah.

• 27:58Speaker 01

  But that was so long ago. I don't know. But these, you can see things like this in tuberculosis, absolutely. And histoplasmosis is easy to conflate with tuberculosis in a lot of cases.

• 28:08Speaker 04

  Mm-hmm.

• 28:09Speaker 01

  Um, 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.

• 28:28Speaker 04

  Decades later.

• 28:29Speaker 01

  It's actually quite a common cause of pulmonary nodules, like asymptomatic pulmonary nodules.

• 28:35Speaker 04

  And so that would just be like a random finding? Or would you be going in for something else?

• 28:40Speaker 01

  No, they're, it's really common that we have just incidental pulmonary nodules.

• 28:45Speaker 04

  They're like, oh.

• 28:46Speaker 01

  Like, didn't know that was there.

• 28:47Speaker 04

  Yeah. Okay.

• 28:49Speaker 01

  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.

• 29:32Speaker 01

  But it's usually only in lungs that already have underlying structural damage.

• 29:36Speaker 04

  Gotcha.

• 29:37Speaker 01

  So that's one way that this disease or that this fungus 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.

• 30:18Speaker 01

  And this disseminated histoplasmosis is what we tend to see in people with immunocompromised, 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.

• 30:49Speaker 04

  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?

• 31:03Speaker 01

  Yes, that's, 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.

• 31:39Speaker 04

  And then what are the symptoms of disseminated disease?

• 31:43Speaker 01

  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.

• 32:27Speaker 01

  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.

• 32:45Speaker 04

  Okay.

• 32:45Speaker 01

  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.

• 33:22Speaker 04

  Yeah, that makes sense.

• 33:23Speaker 01

  Yeah.

• 33:25Speaker 04

  Is there, okay, two, sorry, I feel like I'm like just preempting you.

• 33:30Speaker 01

  I love it. I love it. Keep going.

• 33:33Speaker 04

  What is the breakdown of, let's say, you know, 100 people are, 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?

• 33:52Speaker 01

  Yeah.

• 33:53Speaker 04

  Yeah.

• 33:53Speaker 01

  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 1% of people, so 1%, one out of that 100 would have a symptomatic infection. So we're gonna have to go bigger. We'll go like 1,000.

• 34:09Speaker 04

  Okay.

• 34:11Speaker 01

  And then 60% 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%, I don't know what that breakdown is. How much of that 40% is like a chronic pulmonary histoplasmosis versus a disseminated, someone with immunocompromised having a disseminated infection? I don't have, I don't have a breakdown on that other 40% of the 1%.

• 34:41Speaker 04

  Of the 1%.

• 34:42Speaker 01

  Of the 1%.

• 34:43Speaker 04

  Okay. And treatment.

• 34:47Speaker 01

  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.

• 35:00Speaker 04

  Okay.

• 35:01Speaker 01

  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.

• 35:31Speaker 04

  Right.

• 35:32Speaker 01

  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.

• 35:49Speaker 04

  At which point?

• 35:50Speaker 01

  At which point you needed to do something already, right? 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.

• 36:31Speaker 04

  Yeah.

• 36:32Speaker 01

  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 like 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.

• 37:16Speaker 01

  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 itraconazole, 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.

• 37:46Speaker 04

  Okay.

• 37:47Speaker 01

  Yeah.

• 37:47Speaker 04

  That's, that's a long time to be with those side effects.

• 37:50Speaker 01

  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 five to eight percent. And that's in the US, like that's based on US 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 sub-populations 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 US mortality rate is closer to 10% is what I saw.

• 38:35Speaker 01

  But in some places, like in some areas of Brazil, it's up to 40%.

• 38:40Speaker 04

  Oh my god.

• 38:41Speaker 01

  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.

• 38:53Speaker 04

  Yeah, yeah.

• 38:55Speaker 01

  And that is histoplasmosis, Erin.

• 38:58Speaker 04

  Oh. It's a, I mean fungal infections in general are just harder.

• 39:06Speaker 01

  They're so much harder.

• 39:07Speaker 04

  They, our body doesn't do as well recognizing them often.

• 39:11Speaker 01

  Yeah.

• 39:12Speaker 04

  We have a harder time treating them. And then once they kind of establish a foothold, it seems really difficult to knock them out.

• 39:20Speaker 01

  They're really good at just sort of like resisting our clearance.

• 39:24Speaker 04

  Yeah.

• 39:25Speaker 01

  You know? So.

• 39:26Speaker 04

  Yeah.

• 39:27Speaker 01

  Tell me, Erin. How did we get to here? Where did this fungus among us come from?

• 39:36Speaker 04

  Great, great questions.

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• 42:08Speaker 04

  Our picture of histoplasmosis has taken shape over the past century and change. In fact, 2026 marks 120 years since it was first described.

• 42:19Speaker 01

  Oh, wow.

• 42:20Speaker 04

  Yeah.

• 42:21Speaker 01

  Okay.

• 42:22Speaker 04

  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. 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.

• 42:57Speaker 01

  Okay.

• 42:58Speaker 04

  Which oddly enough, started out not as a fungus, but as a protozoan, according to the guy who first observed it.

• 43:05Speaker 01

  Oh, what?

• 43:06Speaker 04

  Yeah, yeah.

• 43:07Speaker 01

  Okay, tell me.

• 43:08Speaker 04

  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.

• 43:52Speaker 04

  A preliminary diagnosis of miliary 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.

• 44:14Speaker 01

  Interesting.

• 44:15Speaker 04

  I don't know. But he, I mean, the way he wrote about that is just sort of like, everyone knows what this

• 44:21Speaker 01

  Everyone knows what this smells like.

• 44:22Speaker 04

  What this smells like, yeah.

• 44:23Speaker 01

  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.

• 44:36Speaker 04

  Totally, totally.

• 44:37Speaker 01

  Yeah, that's so interesting, though. Wow.

• 44:38Speaker 04

  Yeah, I just have never encountered that, like, yeah, I know that, like, C. diff has a particular smell, but like, I didn't, anyway, so. But also, quote, "The lungs-on-section were found studded with pale gray miliary tubercles, tubercles, from 2 to 3 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 lungs was quite red," end quote.

• 45:16Speaker 01

  Interesting.

• 45:17Speaker 04

  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 and alveolar epithelial cells, while others appeared to be free in the plasma of the spleen and rib marrow," end quote.

• 45:40Speaker 01

  I love that description, Erin.

• 45:43Speaker 04

  And to Darling's eye, which admittedly was limited by crude microscope equipment, these round bodies resembled protozoan parasites, like those that cause leishmaniasis.

• 45:55Speaker 01

  Right, yeah.

• 45:56Speaker 04

  And so he concluded that this was a new species of, a pathogenic species of protozoan, distinct enough to warrant a new name, Histoplasma capsulatum.

• 46:05Speaker 01

  Huh, that's how it got its name.

• 46:08Speaker 04

  That's how it got its name.

• 46:09Speaker 01

  How inter- Interesting, Gary.

• 46:11Speaker 04

  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, Henri de Rochelima, published a report where he was like, "Um, 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."

• 46:41Speaker 01

  All right.

• 46:41Speaker 04

  So like, it was corrected pretty shortly after, confirmed a number, you know, years later, but, but like...

• 46:48Speaker 01

  I just love that your description of that made it sound like he was so polite about it.

• 46:53Speaker 04

  I mean, it's like, sure.

• 46:54Speaker 01

  I'm so sorry, dude, but like, I just, I wanted you to know, like...

• 46:57Speaker 04

  I just want to make sure, like, can we just double check this again?

• 47:01Speaker 01

  Really cute.

• 47:03Speaker 04

  That's how I'm imagining.

• 47:06Speaker 04

  Very gentlemanly about the whole thing.

• 47:09Speaker 01

  That's making me cry.

• 47:12Speaker 04

  Wow, your bar for jokes is way too low.

• 47:15Speaker 01

  I don't know what's going on with me.

• 47:21Speaker 04

  This, this correction was ultimately, of course, necessary, like, it was, it had to happen. But it was kind of, 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?

• 47:36Speaker 01

  Okay.

• 47:36Speaker 04

  Histoplasma was not widely known at all, and those who had heard of it, thought it, thought of it as a rare tropical disease, so of, of limited interest, I would say. More of like a medical curiosity than something of like, major, major importance.

• 47:53Speaker 01

  Okay.

• 47:54Speaker 04

  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. Tompkins, 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

• 48:33Speaker 04

  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.

• 48:48Speaker 01

  Huh.

• 48:49Speaker 04

  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.

• 48:59Speaker 01

  Oh, wow.

• 49:01Speaker 04

  Every case prior to this, which was not very many cases, had been diagnosed at autopsy.

• 49:06Speaker 01

  Okay.

• 49:07Speaker 04

  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.

• 49:17Speaker 01

  Wow.

• 49:17Speaker 04

  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 histoplasmosis considered it a rare, almost uniformly fatal disease.

• 49:49Speaker 01

  Huh.

• 49:50Speaker 04

  Very different than the pathogen you described, Erin, where it was, you know, 1% actually is symptomatic.

• 49:57Speaker 01

  1% have symptoms. Yeah.

• 49:58Speaker 04

  Yeah. So what did it take to change that perception? Tuberculosis.

• 50:03Speaker 01

  Everything.

• 50:05Speaker 04

  Everything is tuberculosis.

• 50:08Speaker 01

  [laughing]

• 50:10Speaker 04

  Still happening.

• 50:11Speaker 01

  Yeah, okay.

• 50:12Speaker 04

  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.

• 50:26Speaker 01

  Okay.

• 50:27Speaker 04

  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.

• 50:50Speaker 01

  Oh, my gosh.

• 50:52Speaker 04

  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.

• 50:59Speaker 01

  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.

• 51:08Speaker 04

  Yep, yep. And so a few years after this, so World War II, once, once these, these draft screenings were over, a few years later, by which point a histoplasmosis 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.

• 51:34Speaker 01

  Wow, okay.

• 51:36Speaker 04

  Yeah. A paper from 1962 looked at 81 sanatoriums across the US, Canada, and Cuba, and found that 7.5% of the 45,000 patients screened were positive for histoplasmosis.

• 51:52Speaker 01

  So like they were in there being treated for tuberculosis, but they actually had histoplasmosis?

• 51:57Speaker 04

  Yeah.

• 51:58Speaker 01

  Fascinating, Erin.

• 51:59Speaker 04

  Yep, yep. At least 1/4 of those had active histoplasmosis.

• 52:05Speaker 01

  Wow.

• 52:06Speaker 04

  And few were also positive for tuberculosis.

• 52:10Speaker 01

  Wow.

• 52:11Speaker 04

  So how many people in sanatoriums actually had histo and not tuberculosis? Or, and then developed TB during their time there?

• 52:18Speaker 01

  Right, of course.

• 52:19Speaker 04

  No, right, no idea. But more- More than zero.

• 52:23Speaker 01

  Interesting, yeah.

• 52:23Speaker 04

  Especially in the areas that we tend to think of as the classic histoplasmosis region.

• 52:29Speaker 01

  Yeah.

• 52:29Speaker 04

  So for instance, it more in on that paper from 1962, the percentage of people who were positive for histoplasmosis in Indiana, Kentucky, and Tennessee respectively was 15%, 14%, and 13%.

• 52:45Speaker 01

  Oh, so like much higher than just the baseline. Oh, wow.

• 52:48Speaker 04

  Much higher than the seven and a half percent.

• 52:49Speaker 01

  Yeah.

• 52:50Speaker 04

  So this definitely pointed towards a tip of the iceberg situation. 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 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 the, as a spreader of histoplasmosis.

• 53:29Speaker 01

  That totally makes sense, yeah.

• 53:30Speaker 04

  Totally makes sense, 100%. And that is tornado zone. Like, it's not quite all of tornado alley, but like there are tornadoes that absolutely happen there, yeah.

• 53:38Speaker 01

  Yeah, yeah.

• 53:39Speaker 04

  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 histogrowth. And birds might be able to carry it in their feathers.

• 54:07Speaker 01

  Right.

• 54:08Speaker 04

  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 and 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.

• 54:39Speaker 01

  They all were trying to clean up for Earth Day, and then they all got histo? It's not funny, but...

• 54:45Speaker 04

  It's not funny, but it is just like, of course.

• 54:48Speaker 01

  Of course. You just try to do something good.

• 54:52Speaker 04

  But yeah, histoplasma capsulatum was later isolated from the soil where they were doing the cleanup.

• 54:59Speaker 01

  That tracks.

• 55:00Speaker 04

  A paper from 2016 by Benedict and Modi examined histoplasmosis 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.

• 55:16Speaker 01

  Yep.

• 55:17Speaker 04

  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.

• 55:38Speaker 01

  What?

• 55:39Speaker 04

  Yeah. Yeah, that's what the estimates are.

• 55:43Speaker 01

  But that's not all symptomatic. That's like how many people total because of, like, based on the symptomatic cases.

• 55:49Speaker 04

  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've 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.

• 56:18Speaker 01

  Histo.

• 56:19Speaker 04

  Yep. And then the 1980s and the AIDS pandemic ushered in the next era of histoplasmosis. Histoplasmosis is a disease that, you mentioned, Erin, 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% 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 to better understand this infection,

• 57:03Speaker 04

  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.

• 57:27Speaker 01

  Yeah.

• 57:28Speaker 04

  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 and 1/2 million years ago, something like that.

• 57:40Speaker 01

  Just a casual 10 million year range estimate?

• 57:43Speaker 04

  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.

• 58:04Speaker 01

  Oh, really, Erin? Warmer and wetter?

• 58:06Speaker 04

  Warmer and wetter. As always, well, wetter in some places, yeah. As always, we can look towards the past to better predict our future.

• 58:14Speaker 01

  Yeah.

• 58:15Speaker 04

  Ongoing, human-induced climate change is altering where this fungus can live and how we interact with it.

• 58:21Speaker 01

  Yeah.

• 58:22Speaker 04

  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.

• 59:03Speaker 01

  Right.

• 59:04Speaker 04

  So what will the impact be? We don't know.

• 59:07Speaker 01

  Time will tell.

• 59:08Speaker 04

  Time will tell. Will increasing construction and land use change affect exposure to this pathogen? Seems pretty likely.

• 59:17Speaker 01

  I'm gonna go yes. That's where my money is.

• 59:20Speaker 04

  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 histo country, the Ohio and Mississippi River Valleys? Why would it have been any different than today? My answer?

• 59:56Speaker 01

  Okay.

• 59:57Speaker 04

  The passenger pigeon.

• 59:59Speaker 01

  Stop it.

• 1:00:00Speaker 04

  Also known as Actopistus migratorius.

• 1:00:03Speaker 01

  Okay.

• 1:00:04Speaker 04

  Erin, do you know about the passenger pigeon?

• 1:00:06Speaker 01

  I mean, I know that they were a thing that people used to send messages and things.

• 1:00:11Speaker 04

  Different, different pigeon.

• 1:00:13Speaker 01

  Oh, that's a different pigeon?

• 1:00:14Speaker 04

  Mm hmm. I think that's the carrier pigeon.

• 1:00:16Speaker 01

  Okay, so what the heck is the passenger pigeon then?

• 1:00:18Speaker 04

  Okay. Oh, the passenger pigeon. This might be my first tattoo ever.

• 1:00:24Speaker 01

  Okay.

• 1:00:26Speaker 04

  The passenger pigeon was once the most numerous bird in North America.

• 1:00:30Speaker 01

  Okay.

• 1:00:31Speaker 04

  With an estimated population of five to 10 billion, with a B, this before European invasion, three to five billion after, which means that at one point, there were more passenger pigeons than humans on the planet.

• 1:00:44Speaker 01

  Wow.

• 1:00:46Speaker 04

  Wow.

• 1:00:46Speaker 01

  Okay.

• 1:00:47Speaker 04

  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 1, 1914. She was 29 years old.

• 1:01:01Speaker 01

  Oh, wow.

• 1:01:02Speaker 04

  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 passing reference to the passenger pigeon in a textbook called One Health and Mycology, 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, ah, what?

• 1:01:42Speaker 01

  What?

• 1:01:43Speaker 04

  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-

• 1:01:58Speaker 01

  The soil.

• 1:01:59Speaker 04

  -necessary for their growth.

• 1:02:00Speaker 01

  Yeah.

• 1:02:01Speaker 04

  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, like, struck me as horribly sad. 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 mention in that book, I had to pull on that thread. And I was like, okay, where do we go from here? So, just to, just to prepare you, I did not find any conclusive evidence-

• 1:02:34Speaker 01

  Okay.

• 1:02:35Speaker 04

  -linking the passenger pigeon to histoplasmosis, but I did find plenty that is suggestive of a connection. And so if that's all right with you, I thought I'd spend the last bit of time just going through some of these observations and really-

• 1:02:46Speaker 01

  Please.

• 1:02:47Speaker 04

  -just like, this is my time to pay tribute to-

• 1:02:49Speaker 01

  I'm obsessed.

• 1:02:50Speaker 04

  -this amazing species. Yes. Me too. I'm so glad. We'll get tattoos together.

• 1:02:55Speaker 01

  Okay. We've been, I've been trying to get you to do that for a long time.

• 1:02:58Speaker 04

  I know, I know. That first one won't be TPWKY. It'll be the passenger pigeon.

• 1:03:02Speaker 01

  I don't know if mine's gonna be the passenger pigeon, but maybe you're, you're gonna convince me right now.

• 1:03:06Speaker 04

  Your favorite species driven to extinction by humans?

• 1:03:12Speaker 01

  Give it to me, Erin, give it to me.

• 1:03:13Speaker 04

  Yeah, 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 into Canada on the northern side and halfway down Florida.

• 1:03:27Speaker 01

  Okay.

• 1:03:27Speaker 04

  But its breeding range was primarily across the Ohio River Valley and Great Lakes region.

• 1:03:33Speaker 01

  Okay.

• 1:03:33Speaker 04

  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.

• 1:03:45Speaker 01

  Okay, yeah.

• 1:03:46Speaker 04

  Correlation is not causation, and there could be many reasons for that overlap, just like, hey, the, both things like the same environment here.

• 1:03:54Speaker 01

  Right, exactly, other environmental factors that contribute.

• 1:03:57Speaker 04

  And humid, yeah. But it is compelling nonetheless, especially when you consider the poop.

• 1:04:03Speaker 01

  The poop.

• 1:04:04Speaker 04

  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.

• 1:04:29Speaker 01

  Because of how many birds are sitting on there? Oh, my gosh.

• 1:04:33Speaker 04

  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 noonday was obscured as by an eclipse. The dung fell in spots, not unlike 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.

• 1:05:04Speaker 01

  No.

• 1:05:04Speaker 04

  "Which also could have provided excellent substrate for histoplasmosis to grow."

• 1:05:09Speaker 01

  Yeah.

• 1:05:09Speaker 04

  "Histoplasmosis that could have been misdiagnosed as tuberculosis, especially since the diagnostic technology for TB, X-rays and tuberculin skin tests, was only developed in the last years of the bird's existence."

• 1:05:22Speaker 01

  Wow.

• 1:05:23Speaker 04

  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 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.

• 1:05:50Speaker 01

  Right.

• 1:05:51Speaker 04

  So, but I did find, again, going back to just a few compelling statistics. So during World War I, so 1914, 1918, 23% of draftees in Kentucky were rejected due to tuberculosis. And that was compared to the national average of 9%.

• 1:06:09Speaker 01

  Oh, wow.

• 1:06:10Speaker 04

  Which is kind of interesting.

• 1:06:11Speaker 01

  Yeah.

• 1:06:12Speaker 04

  Could be for many different things.

• 1:06:13Speaker 01

  Could be.

• 1:06:14Speaker 04

  Many different things. Could be, you know.

• 1:06:15Speaker 01

  But could be histo.

• 1:06:16Speaker 04

  Could be histo, maybe. Alexander Wilson, the 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 nests, 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

• 1:06:58Speaker 04

  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.

• 1:07:08Speaker 01

  Wow.

• 1:07:09Speaker 04

  Yeah.

• 1:07:10Speaker 01

  I cannot imagine this.

• 1:07:15Speaker 04

  I know. Doesn't it seem like fantastical?

• 1:07:18Speaker 01

  Yes.

• 1:07:19Speaker 04

  But it was real.

• 1:07:21Speaker 01

  It was real.

• 1:07:22Speaker 04

  I mean, like, some of this was exaggerated, no doubt, but like, you can't, not all of it.

• 1:07:27Speaker 01

  No.

• 1:07:28Speaker 04

  Because this is also many, many, many, many, many different accounts.

• 1:07:29Speaker 01

  Right.

• 1:07:30Speaker 04

  Of how many birds there were.

• 1:07:31Speaker 01

  How many birds there were.

• 1:07:32Speaker 04

  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 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.

• 1:08:05Speaker 01

  Hmm.

• 1:08:06Speaker 04

  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.

• 1:08:13Speaker 01

  Oh, wow.

• 1:08:14Speaker 04

  Yeah. Can you imagine traveling through a passenger pigeon roosting site tens of miles long?

• 1:08:21Speaker 01

  No.

• 1:08:22Speaker 04

  Or even just standing beneath a flock as it passed overhead?

• 1:08:26Speaker 01

  Right.

• 1:08:27Speaker 04

  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 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."

• 1:09:04Speaker 01

  15 minutes of so many birds that they blocked out the sun. And you thought it was a tornado?

• 1:09:12Speaker 04

  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

• 1:09:55Speaker 04

  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. Like, they just would...

• 1:10:11Speaker 01

  For sport?

• 1:10:12Speaker 04

  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. Just complete waste. Yeah. And it's possible that also, as they declined and their strength and 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

• 1:10:57Speaker 04

  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, this technology is proprietary, so good luck." Yeah.

• 1:11:12Speaker 01

  No. Jeff Goldblum said it best.

• 1:11:16Speaker 04

  It's like, yeah, that's a whole... That's a soapbox that I should probably just not...

• 1:11:25Speaker 01

  I know, exactly.

• 1:11:26Speaker 04

  At this point.

• 1:11:27Speaker 01

  That's exactly how I feel.

• 1:11:28Speaker 04

  But when passenger pigeons were made extinct, North America lost a major ecosystem engineer. These birds preferentially fell en masse 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, 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 forests of eastern North America shifted from white oak to red oak, which is just kind of an interesting

• 1:12:04Speaker 01

  Gosh, Erin.

• 1:12:05Speaker 04

  Component of this.

• 1:12:06Speaker 01

  I love, this makes me just love ecology so much.

• 1:12:09Speaker 04

  Me too.

• 1:12:10Speaker 01

  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, ugh, keystone species.

• 1:12:19Speaker 04

  Keystone species, everything is connected.

• 1:12:21Speaker 01

  Everything is connected.

• 1:12:23Speaker 04

  It is, it is just amazing also how little people have heard, like, it's also amazing.

• 1:12:32Speaker 01

  I hadn't heard of this at all.

• 1:12:32Speaker 04

  Yeah, and it was just over 100 years ago.

• 1:12:36Speaker 01

  Yeah.

• 1:12:36Speaker 04

  That Martha died. But also of interest, forests lost a major seed distributor and tree mast consumer as well, so like acorns, like all of the stuff, the seeds and stuff that trees, that these trees produced, and that opened up a niche for competitors like deer and rodents.

• 1:12:56Speaker 01

  Oh, like Lyme disease?

• 1:12:58Speaker 04

  Leading to an explosion in their populations, which may have contributed to the rise of Lyme disease. Passenger pigeon extinction, man.

• 1:13:04Speaker 01

  It's all connected.

• 1:13:06Speaker 04

  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.

• 1:13:49Speaker 04

  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, Erin, 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?

• 1:14:10Speaker 01

  I can.

• 1:14:12Speaker 04

  My little guy.

• 1:14:12Speaker 01

  So cute.

• 1:14:13Speaker 04

  Yeah, in honor of the passenger pigeon.

• 1:14:16Speaker 01

  Oh, Erin, I don't even want to say anything, I just want to end it there. But I will.

• 1:14:28Speaker 01

  Only because I already wrote it down. So listen.

• 1:14:31Speaker 04

  Don't let good work go to waste.

• 1:14:32Speaker 01

  Right. We'll wrap this up real quick here.

• 1:15:01Speaker 01

  Oh gosh, that was so much. I'm like still reeling.

• 1:15:06Speaker 01

  So histoplasmosis has been described as the most common endemic mycosis in the Americas.

• 1:15:16Speaker 01

  And the fungus itself has been reported, like you mentioned, Erin, 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 US, which is where we have probably the most data on like incidence and prevalence,

• 1:16:01Speaker 01

  the estimated incidence overall is between one to two cases per 100,000 people.

• 1:16:08Speaker 04

  Okay.

• 1:16:08Speaker 01

  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.

• 1:16:34Speaker 04

  Yeah.

• 1:16:34Speaker 01

  And in the US, 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.

• 1:16:46Speaker 04

  Right.

• 1:16:47Speaker 01

  And that one to two cases per 100,000 is averaged across the whole country. So it is higher incidence in places like Kentucky, Ohio, et cetera, where this is more common. Right?

• 1:16:58Speaker 04

  Right. Yeah, yeah.

• 1:17:00Speaker 01

  And so then how do we, like, how many cases are there in the US 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.

• 1:17:27Speaker 04

  Wow, because it's not, it's not reportable.

• 1:17:29Speaker 01

  Only in 14 states.

• 1:17:30Speaker 04

  Only in 14 states across, so.

• 1:17:32Speaker 01

  So this was looking at like Medicare data, like hospital data and things like that. So where there was like a histoplasmosis, you know, case documented.

• 1:17:40Speaker 04

  Yeah.

• 1:17:40Speaker 01

  But another paper suggested that there could be upwards of 500,000 new infections each year in the US.

• 1:17:47Speaker 04

  I saw that because, I mean, and that makes sense if you think about.

• 1:17:50Speaker 01

  If you think about the asymptomatic infections.

• 1:17:52Speaker 04

  Or the people who recover, even though they're in there diagnosed with bacterial pneumonia.

• 1:17:56Speaker 01

  Exactly, exactly. 100%. So that's, 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 US at least have been infected. And that's probably an underestimate.

• 1:18:12Speaker 04

  That is.

• 1:18:15Speaker 01

  It's like so common. So, so, so common.

• 1:18:18Speaker 04

  Oh, my gosh.

• 1:18:19Speaker 01

  And like I said, the more places that we look for it, the more places that we find it.

• 1:18:24Speaker 04

  Yeah.

• 1:18:24Speaker 01

  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 Yangtze River Valley in China.

• 1:18:35Speaker 04

  River valleys, man.

• 1:18:36Speaker 01

  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.

• 1:18:48Speaker 01

  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

• 1:19:33Speaker 01

  HIV with histoplasmosis are equivalent to, if not exceeding, the mortality due to tuberculosis.

• 1:19:41Speaker 04

  That's, oh my god.

• 1:19:43Speaker 01

  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.

• 1:19:52Speaker 04

  Totally.

• 1:19:54Speaker 01

  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 immunocompromised 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.

• 1:20:26Speaker 04

  Not great, yeah.

• 1:20:28Speaker 01

  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.

• 1:20:57Speaker 04

  Absolutely.

• 1:20:59Speaker 01

  So, that's what I got.

• 1:21:02Speaker 04

  We should be talking more about it.

• 1:21:03Speaker 01

  We should be talking more about it. We should be talking more about it.

• 1:21:07Speaker 04

  And about the passenger pigeon, but that's my personal, my, my, my personal, like,

• 1:21:13Speaker 01

  I love it. Now, I need to look up, like, images of the passenger pigeon.

• 1:21:16Speaker 04

  They're, they're really. I mean, it's certainly pigeon-like, but it's, it's, I think it's quite beautiful. And there was a strong amount of sexual dimorphism, which not all pigeons have, anyway, so.

• 1:21:26Speaker 01

  Oh, cute. I, I love, that's my favorite thing I've learned.

• 1:21:32Speaker 04

  I'm glad.

• 1:21:32Speaker 01

  If you want to learn more, we'll tell you.

• 1:21:34Speaker 04

  We have, I have, like I said, I really, because of the, the rabbit hole, pigeon hole.

• 1:21:41Speaker 04

  Again, you're showing how low your bar for jokes is, Erin.

• 1:21:46Speaker 01

  So I'm in a good mood, I guess.

• 1:21:48Speaker 04

  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 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 et al., "Considerations About the Geographic Distribution of Histoplasma Species."

• 1:22:14Speaker 01

  Yep, saw that one.

• 1:22:16Speaker 04

  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 few, there's like a number of passenger pigeon books out there. And I have a couple of papers about the genome. Anyway, it's, um, it's, it's, and did I find one about its diet? I did find one about its diet, yeah. Anyway. Go ahead, Erin.

• 1:22:39Speaker 01

  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 et al. that was called "Histoplasmosis: Around the World, A Global Perspective on the Presentation, Variance Factors, and Treatment of Histoplasmosis." There's too many, and they're all just like really long titles. There's a whole bunch there, okay? 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, thispodcastwillkillyou.com, right under the Episodes tab.

• 1:23:23Speaker 01

  You can find the list of sources from this and every single one of our many episodes.

• 1:23:28Speaker 04

  Many episodes, yeah. Thank you again so much, Macy, for sharing your story with us. We really appreciate it.

• 1:23:34Speaker 01

  We do. Thank you, thank you.

• 1:23:36Speaker 04

  Thank you also to Blood Mobile for providing the music for this episode and all of our episodes.

• 1:23:41Speaker 01

  Thank you to Leanna and Tom and Pete and Mark and everyone at Exactly Right for everything that you do.

• 1:23:47Speaker 04

  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.

• 1:24:01Speaker 01

  If you already have a tattoo of a passenger pigeon, can you send it so that Erin can get some inspo?

• 1:24:05Speaker 04

  Please, please. It's gonna be that and the Tasmanian tiger.

• 1:24:09Speaker 01

  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.

• 1:24:20Speaker 04

  It, it, it really does. It means so much to us. Thank you. Until next time, wash your hands.

• 1:24:26Speaker 01

  You filthy animals.

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• 1:25:26Speaker 06

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