This Podcast Will Kill You - Ep 77 Legionnaires' Disease: A Killer Mist

Episode Date: July 13, 2021

Celebration wasn’t the only thing in the air in Philadelphia in July of 1976. Over the course of several days during the 58th Annual Convention of the American Legion, a killer mist spewed out of the air conditioning units throughout the building and into the sidewalks nearby. The result was a large outbreak of unexplained febrile pneumonia, often fatal, that would acquire the name Legionnaires’ Disease. What was causing this terrifying disease and how could it be stopped? In this episode, we walk through the massive investigation into this outbreak that would lead to the discovery of the causative agent, Legionella pneumophila, and explore the biology of this mysterious pathogen. We wrap up the episode with a look at the current status of Legionnaires’ Disease and a potentially grim forecast for its prevalence as the world slowly gets back to normal. See omnystudio.com/listener for privacy information.

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So in lieu of driving home, she opted to get me a room because I was going to be helping her the following day. Once I opened the hotel door, it was hot and musty, and you could tell no one had entered that room for a while. I turned on the AC and was hit in the face with a musty mist. That smell still lingers with me today. Didn't think anything of it. ate food and went to sleep. Continued with my weekend as scheduled, basically the gym and sleep. That following Monday, I felt out of it. I wasn't sick, just exhausted. I thought it was simply from going to the gym. I didn't have work because it was Memorial Day and wasn't due back to work until Wednesday, but I stayed in bed the whole holiday and the day after. I just remember being at work tired. I thought it was from oversleeping, and the best cure for that was more sleep. As the weekend rolled around, I was back at my friend's house painting, but I noticed I needed a break,

every five to ten minutes or so. I was a bit sore and always out of breath and sweating profusely. Monday rolled around and it had been nine days since I was at the hotel. I went to bed and when I awoke I could no longer walk straight. I was slamming into walls and couldn't see straight. When I awoke it was already midnight. I overslept again but now I lost all motor skills. Couldn't walk at all and my speech was slurring, so Siri didn't recognize my voice. I had to crawl to use the restroom and had a hard time not knocking things over when I did. I awoke in my bed to my mom asking me about the mess in the bathroom. She immediately knew I was sick once she heard me speak. I woke up in the hospital surrounded by nurses and doctors trying to figure out why I couldn't talk or walk and why I had a fever of 106 degrees. It took about four days before they figured out. It was a was legionnaires. I still had a temperature of 103, still couldn't walk, no motor skills at all, and was unable to speak. Hallucinating at this point was the most enjoyable part of the day. I know I had rooms of family and friends, and by the look on their faces, I could tell they were told the

severity of everything, which I didn't even know. I was in the hospital and rehab for about three and a half weeks. I can walk and talk again, and all my motor skills have returned. I'd I'm very forgetful at the minor tasks. I had to relearn what I did for a living and how to drive. I used to love working out, but it's so dangerous now because I can't balance weights like I should and walking hurts after a while. My joints feel like they are on fire most of the day. Steps are my new arch nemesis.

My knees feel like they are about to buckle and crumble whilst walking up or down them. I have dizzy spells, get tired at the drop of a dime, and lose my train of thought halfway through tasks. It has been interesting, and I am glad to know I am not the only one out there dealing with these side effects and that things can get better. Yeah, that sounds very horrible and terrifying. Yeah. So that was from a website called legionella.org, where under a section called share your story.

I didn't realize until kind of reading through some of those firsthand accounts and researching this episode, how long-lasting some of the effects of infection with Legionella can be. Oh, yeah. No, it's like, I think there is a lot more under the surface than, as per usual, than we think there is at the beginning of these episodes. Hi, I'm Aaron Welsh. And I'm Aaron Alman Upday. And this is, this podcast will kill you. And today, of course, we're talking about Legionella, the causative agent of Legionnaire's disease. Yeah, and Pontiac fever.

And Pontiac fever. Other things. It's going to be an interesting, I have lots of biology questions already. Oh, gosh. I knew that was coming, and I, like, hope that I know the answers to them, but you're probably not going to like a lot of them, as usual. You mean like it's, I'm not going to like them because it's, well, we don't quite know. Yep, yeah. Great, great, great, great.

They're not satisfying answers. Dang it. That's okay. Well, we'll get there. But first we do some podcast stuff. We should, yeah, because it's, let me check. Quarantini time? It is quarantini time.

What are we drinking this week? We're drinking losing your cool. Yep. For reasons. I think we all. always say this, but that will become more clear as the episode goes on. Basically, we're talking about air conditioning, we're talking about fevers. You're just going to lose your cool. You're going to lose your cool. And what's in losing your cool, Aaron? It is a, I think it's actually a really

delicious one. So it has normal rum, pineapple rum, lime juice, apricot liqueur, and simple syrup and we will post the full recipe for losing your cool on our website. This Podcast Will Kill You.com as well as on all of our social media channels like Twitter, Facebook, Instagram, and those are the places where you can also find the non-alcoholic placebo recipe. Exactly. Speaking of our website, this podcast will kill you.com, check it out if you haven't already. We have so many things there like merch and a bookshop.org affiliate account. We've got a Goodreads list. We have a Patreon.

We have links to Bloodmobile, our music. We have transcripts for so many of our episodes, soon to be all of them. So definitely check out our website. Yes, check it out. I guess, like, I feel like this was a really fast intro, but I'm like, I don't know what else to do here. I'm excited about this episode, so maybe let's take a quick break and then just get started. Let's do it. Dinner shows up every night, whether you're prepared for it or not.

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now available in Canada too. That's Q-U-I-N-C-E dot com slash this podcast to get free shipping and 365-day returns. Quince.com slash this podcast. So, Legionella is a genus of bacteria that has a whole bunch of species, way more than I realized, I think at least over 50. Yeah. I think that's been a fairly recent development. Yeah.

And I believe that at least 30 of these bacterial species can be pathogenic to humans. And in general, these are a much more interesting group of bacteria than I realized. I feel kind of bad because I was just like, oh, they're another gram negative. Like, well, they're much more interesting than that. They are gram negative little rods. And when they're not infecting us humans, they live in freshwater sources, but not just free-floating in water. No, no. I'm so glad you're going to talk about this.

Oh, yeah. It's so cool. So they don't just live free-floating in the environment. They exist as pathogens of amoebe. Uh-huh. And other protozoa. I was, when I was reading that, because I was like reading about the evolutionary history, and I came across that and I was like, this is so well-timed with our Nygleria Fowleri episode.

Exactly. It's wild. And also I was like, oh, this is definitely an errand. Like I'm reading too much about Aaron's biology section. I need to stop. Yeah, it's so fascinating. So I always thought of them as just a waterborne bacteria, which they are. But in water, they can live and persist free floating as well as in biofilms, which is what

makes them very difficult to deal with in pipes or water heaters, air conditioning coolers, etc. But they only multiply inside of another organism like an amoeba or another protozoa. It's really cool. Because that also has implications for like why it infects humans or how it infects humans. That's what I was just going to say. But I'm going to put a pin in that. But keep that in mind because when we talk about the sort of pathophysiology of how it gets us sick, yeah, it makes complete sense. Mm-hmm. Okay.

So we have a lot of different species of Legionella, but the one that's most famous and probably the most common pathogen of humans, at least in the U.S. and throughout Europe, is Legionella pneumophila, which has a whole number of different subgroups and then specific strains within those subgroups. So this is a pretty large overall group of bacteria. And so this is an environmental pathogen. And the way that people get infected with it is through contact, generally aerosol contact with water that is contaminated with Legionella and also amoeba, of course. And Legionella in general grows well at warm temperatures, like 25 to 45 Celsius, just like the amoevas that we talked about in our nigeria phalleri episode.

It's happiest around 35 Celsius, which is like 95 Fahrenheit. It's pretty warm water. Yeah. And what's interesting is that although this is a bacterial species that's found naturally in aquatic environments across the globe, it generally doesn't reach high enough levels to get you sick in those natural environments. So what's the infectious dose then? Erin, I knew you were going to ask that. I have it in bold. We don't know. You have in bold, we don't know. Well, no, I have in bold, what is infectious dose?

because yeah that was my biggest question too because all these papers say you know it's in human altered environments where we're artificially heating water then you have this disproportionate growth of legionella the bacteria in comparison to the amoebae and that's what leads to human infection but there isn't a well-established dose response relationship or even a clear infectious dose or lethal dose. There are some papers that list numbers, but those studies were in guinea pigs, so we really don't know how accurate they are. Well, and it's really interesting, too, because as I'm sure you'll talk about, there's a wide range of, like, host susceptibility where, like, your immune system and your age and your whatever risk factors must change a lot of, like, the infectious

dose for one person might not be the infectious dose for somebody else. Exactly. And we'll talk a little bit more about that when we talk about the symptoms of like the kind of range of symptoms that you see in these disorders because I think that plays a huge part in it. Okay. Yeah. It also makes it difficult in terms of prevention and control to like do environmental monitoring because we don't know what is a safe level versus an unsafe level of legionella in water sources. Yeah.

Yeah. Mm-hmm. Great question, Aaron. But in general, this is not a pathogen that's transmissible. person to person. Astorisk, it has happened maybe a handful of times, at least once that I saw documented, but that's very rare. And in general, outbreaks that happen are from a shared environmental source. What were the circumstances of the person-to-person transmission? It was a mom who was caring for someone who was very severely ill for like over eight hours a day in a very small room

without any ventilation. And so presumably, and she didn't have contact with that same water source that he had had contact with. Okay. Interesting. But that was the one that I saw. Yeah. So. All right.

So let's talk about what happens when these bacteria get inside of our body, because I think it's really fascinating. I might go into more detail than I sometimes do on this, but I think it's going to be fun. Okay? Let's do it. So since these are bacteria, bacteria that generally live inside of amoeba when they're in the environment. It's not surprising that once they get inside our body via inhalation into our respiratory tract, these are also intracellular

bacteria like rickettsia and chlamydia and a lot of other bacteria that live and multiply inside of our cells rather than just in our bodies. So in us, what they do is these bacteria adhere to our cells, I think from what I read, they can infect other cells like our respiratory cells, our epithelial cells, but primarily they infect macrophages. Macrophages are white blood cells that normally serve the function of gobbling up bacteria and then killing them. But Legionella is able to persist inside these macrophages. Here's how they do it. normally when a macrophage gobbles up a bacteria you can imagine them taking their little macrophages kind of almost look like amoeba they have like wiggly arms and they take those

wiggly arms and they wrap it around a bacterium like a giant hug and then they bloop it inside of the macrophage cell but once it gets inside the cell it's wrapped in a little bubble of macrophage cell membrane mm-hmm it's called the phagosome oh yeah yeah yeah you You know this, Erin. And now normally, once that phagosome is inside the macrophage, all of these other mechanisms inside of the macrophage cell would see that bubble and be like, ugh, there's another bacterium, boop, and they'd pop that bubble, release the bacterium, and kill it. But Legionella prevents that bubble from ever popping.

So they persist inside a bubble, inside a macrophage, and they replicate and replicate and replicate. The reason I think this is fascinating is because it's exactly the same thing that they do inside an amoeba because amoebas eat bacteria the same way that our macrophages do. Right. It's also very virus-like behavior. It is. It's very viral. Huh. Yeah. And then inside of us, they do the same thing that they do to amoeba. They kill ourselves, just like they would kill an amoeba. So, That's how we get infected, how we get sick. What does the disease that Legionella Causes actually look like?

Kind of like in our chickenpox episode, and we already mentioned this at the top, there are two different named diseases that are associated with infection with Legionella bacterium. But as I was reading this, I was like, I find it annoying that we have these two different named diseases because they're not true. truly, really different. They're kind of just a spectrum of symptoms, which all seem possible after a Legionella infection, including asymptomatic infection. There's evidence of people who become infected, zero convert, so they show evidence of infection and immunity, but never have any

symptoms of infection with Legionella. So some places have started just sort of naming this Legionelosis as a spectrum of disease. rather than Legionaire's disease versus Pontiac fever. Right. I mean, and I also think that probably the likelihood of someone being diagnosed with Pontiac fever is much lower than with Legionaire's disease. And like if the exposure is the same, okay, I guess that leads into the question of why are there two diseases, like why are there two named diseases?

I mean, historically it makes sense, but like why did that differentiation persist for so long? Great question. and I knew that you were going to ask this question. It's another place I have it in bold. I don't know. Yeah. So my big question was, is it species specific? Is it different species of legionella that are causing Pontiac fever versus Legionaire's disease?

Maybe, but not really, as far as I can tell from all of my research, because not only do we mostly test for Legionella. pneumophila, zero group one, so like one specific group of legionella pneumophila, that particular bacterial species has been found to cause both legionnaires and Pontiac fever, as well as asymptomatic infections. So it can't be entirely based on sero group, and it can't be entirely based on species of bacteria, because again, there's a lot of different species of legionella. So there's likely a huge amount of host factors that go into it. We know, there are risk factors that make Legionaire's disease a lot more likely, things like if you

smoke or have any kind of chronic lung disease, an older age, especially anyone over age 50, is at higher risk than people younger, and any kind of immunocompromise, especially immunocompromise associated with cancers or being on cancer therapy or steroid treatment. So those things we know make it more likely that someone exposed to Legionella will develop Legionaire's disease. But like you said, Erin, we also just don't know as much about Pontiac fever because it's pretty mild. So Pontiac fever is basically just a mild flu-like illness caused by Legionella. It's fever, body aches, maybe some respiratory symptoms, but it lasts for a few days and then you get better. No pneumonia, no death.

No pneumonia, no death, exactly. Yeah. Legionaire's disease on the other hand is a pneumonia. And we've talked about pneumonia a lot, actually even this season in our coxidioidomycosis episode. That's what kept popping into my head when I was reading about this. Yeah, definitely. So the symptoms of Legionaire's pneumonia generally start anywhere from two to 14 days after infection. So that's the incubation period.

It can be quite long. It starts very often with a fever. and like you heard in the first-hand account, this fever can get quite high. Often you'll have chills, which are associated with such high fevers. A cough. Unlike some of the more, quote, typical pneumonia's, this cough is not often very productive, so you don't have a ton of phlegm that you're bringing up, but you still likely have a cough.

You'll probably have some difficulty breathing and some chest pain because there's intense inflammation happening in the lungs. And if you read the kind of classic descriptions of Legionnaire's disease, it's often described as having GI involvement. So like diarrhea, nausea, vomiting. But in reality, this can happen with other atypical pneumonia as well. Atypical pneumonia just means a pneumonia that doesn't fit the old school, very classic definition of pneumonia that's generally caused by,

streptococcus pneumonia or klebsiella or something like that. So there's a whole group of atypical pneumonia's of which legionnaires disease is one. Right. Yeah, I was, I kept wondering what atypical pneumonia, like what distinguishes atypical pneumonia from typical pneumonia? Yeah, there's, there are things like maybe the x-rays will look a little bit different than pneumonia with strepneumo. but there isn't any one specific x-ray finding that tells you this is legionaire's disease versus something else. So it's kind of, it's a very non-specific way of grouping pneumonia's. So like if somebody came in with symptoms of pneumonia, some kind of pneumonia, like what would

make you go, oh, that's typical pneumonia versus atypical? Would it be like you, you know, screen them for strep or you look at the x-ray? Is it a combination? Like, yeah. It's a really good question. There's not a good answer to that because what we end up doing is just treating for all of it very often. Okay. Yeah. So there are x-ray findings that are maybe more specific for a strep pneumo pneumonia versus more atyyipical pneumonia. Like maybe the x-ray will be a little bit more diffuse and patchy versus like, oh, here's a pneumonia in one lobe of your lung very clear. defined. But that's not specific, right? None of the kind of ways that we use to diagnose like, oh, is your cough productive versus not productive? Are you very, very, very sick versus your X-ray looks terrible, but you don't look that sick? That's something that's usually associated with

an, quote, atypical pneumonia is the X-ray might look really bad, but the person doesn't seem that sick clinically. Gotcha. Also, like I said, GI involvement, right? classically, you would think, well, GI involvement, maybe I'm thinking Legionella is more likely. But that can happen in other pneumonia as well. So there's no like one specific thing that if someone walked in, you would say, oh, well, this is most definitely this one cause, et cetera, et cetera. And that's what makes pneumonia in general difficult because it's often difficult to test for direct causative agents, especially if someone doesn't have a lot of phlegm that they can cough up that you can use as something to culture. Right.

For Legionella, there is another test that you can use on urine. It's a urine antigen test that can test directly for the presence of the bacteria. Which is very cool. It is very cool. And so that is something that you can do to test directly for it. It's, of course, not a perfect test, just like any diagnostic test. but it is effective, so that's pretty awesome. And it's a lot faster than something like culture, which takes many days.

Yeah, so that's kind of what it would look like if somebody was infected. In general, Legionnaires disease, Legionillosis with pneumonia, has about a 5 to 10% fatality rate. That's with treatment. Is that just because of just how fast the bacteria is like already caused damage before it's caught? or is it like the efficacy of treatment isn't as great as for other pneumonia? Like, why is that? So it's actually pretty similar to the fatality rate for pneumonia's in general. Okay.

That's just a bad thing. It's just a bad pneumonia. And I think that historically, Legionnaire's disease was considered a more severe form of pneumonia. And if untreated, the mortality rate can be a lot higher than for other forms of pneumonia. It can be as high as 40 to 80 percent. Whereas for other pneumonia, it might be. less like 30% or so. But as we've gotten better at recognizing legionnaires disease, I think people get diagnosed earlier. And so we've seen that it's not always necessarily the most severe

form of pneumonia. It's just that previously we were only seeing the sickest of sick people, if that makes sense. Yeah, yeah. Yeah. Okay. And the other thing that you would say would make this a more atypical pneumonia, is that if you treat it like we would treat a typical pneumonia with something like a penicillin or cephalosporin, it wouldn't respond because those type of antibiotics that we use for more, quote, typical. And when we say typical and atypical, that doesn't mean common versus uncommon. Atypical pneumonia's are still quite common. It's very confusing. I don't like it at all. But it's, if you read it. If you read it. about pneumonia as they use that terminology all the time. I'm not a fan. But yeah, so it doesn't respond

to those. You have to use different antibiotics, which is why in the U.S. and a lot of other places, if somebody comes in with pneumonia, they'll often get an antibiotic that will cover both the atypicals and the typicals, if that makes sense. Yeah, yeah. Because if we aren't able to test for the exact bacteria that causes it, you just want to cover everything. It makes sense. Yeah. Well, that's the biology, pretty much. Oh, my goodness. That was so fast. It was.

Do you have any more questions? I guess I have more questions about, like, exposure, I think. And so maybe that's for the current status situation. Yeah, we'll probably talk about that a bit. Yeah. Yeah, I think that's, I think I don't have any more for the biology. Even though all my answers were, I don't know. We've hit it through. So, Aaron, do you know more than I do? Like, where did this pathogen come from? And what's up with it?

I will try to answer those right after this break. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands hand cream is such a relief. It's a content. It's a constant. concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented, and absorbs quickly. A little goes a long way. Moisturization that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments.

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I like the story of Legionaire's disease because on the surface, it seems like a fairly straightforward example of a classic outbreak investigation and unraveling the mystery of a new infectious agent, which is basically what I thought it was when I first started researching for this episode. And that investigation, that whole outbreak epidemiology part of it, is super duper interesting. But what I find makes it even more interesting is, of course, the context. Always the context. Why did this outbreak happen when it did?

And what about its circumstances led to the way it played out, both in terms of the epidemiological investigation, as well as how it was portrayed by the media. So let's get into it by going back to 1976 Philadelphia, Pennsylvania, aka the city of brotherly love. This entire year, everyone around the U.S. was celebrating the bicentennial of the country, including more than 4,000 members of the American Legion, which, if you didn't know, because I had to Google it, is an organization of U.S. war veterans. They do a lot of lobbying on behalf of veterans, and they also hold meetings or commemorative events.

And one of these such events took place from July 21st to July 24th at the Bellevue Stratford Hotel in Philadelphia. This was specifically the 58th annual convention of the American Legion Department. Wow. Yeah. Over the course of that convention and in the weeks that followed, 221 people became ill with a mysterious disease and 34 died, which is... a rate of about 15%. Most, but not all of those affected, were members of the American Legion, hence the name Legionnaires disease.

So what went down at this hotel? Yeah. The outbreak was first brought to the attention of the CDC when a local physician at the VA diagnosed several of his patients with pneumonia. But this pneumonia wasn't typical pneumonia. whatever that means. It wasn't, was it? And this one didn't seem to respond well to the normal antibiotics that he generally prescribed.

And alarm bell started going off when four of his pneumonia patients died. Oh, gosh. On the morning of August 2nd, David Fraser, a former EIS officer who worked as an epidemiologist at the CDC, got the call that something was going down in Philadelphia. and he was put in charge of a field team to find out what. Fraser and his team arrived on the scene fairly early on in the epidemic curve, and while they had a lot to go on epidemiologically, that knowledge didn't help them too much in their top priority, like stopping or at the very least slowing the epidemic.

They knew that the linking factor among all of the people getting sick was this convention at the Bellevue-Strafford Hotel, And as it turned out, these first few patients that the doctor at the VA sort of sounded the alarm on, that was just the tip of the iceberg. More and more cases of pneumonia began to appear in doctors' offices around the city and the death toll was mounting. Can you remind me how long after the convention this doctor told the CDC, like what the time frame was? So I think the doctor told the CDC in like the very, like August 1st or like at the very end of July. Okay. And I think the first cases were a few days in the middle of that convention.

Okay. And so which was July 21st to July 24th. And so the CDC got there like the first week of August. Okay. So like pretty soon. And it's like the epidemic curve maybe hadn't quite peaked. It was close to peaking. Yeah.

But, yeah, but more and more cases started to, like, roll in. But it is likely that given the incubation period of two to 14 days, those that were going to get sick had already been exposed. Right. And there may not have been a whole lot more exposures happening. And that that convention was over and they presumably had left the city a lot of people. I think a lot of them were in Pennsylvania at least. Okay. Okay.

So, yeah, so even though probably a lot of the exposures had already happened, the disease was still showing up. And so more and more of these cases of pneumonia began to appear in doctors' offices, the death toll was mounting. And immediately the first thing that they suspected, the CDC suspected, was influenza. But not just any influenza. Swine flu or H1N1. Oh. And so here comes some of the historical context. So earlier that year, there had been some cases of H1N1 swine flu at Fort Dix, New Jersey, which got a lot of public health officials a bit concerned that this could be the start of another influenza pandemic similar to the one that happened in 1918. And these cases of influenza were worrisome for a couple of reasons. One was that although in 1976 people didn't know exactly what strain the 1918 influenza one was, studies had suggested that it was a similar isolate to the H1N1 swine flu that had popped up at Fort Dix. And as we know now, it is like very similar. And another thing that was, you know, concerning was in the timing. So these Fort Dix cases had happened very early in the year, like in January.

which is much earlier than seasonal flu tends to increase in incidents. And that was another characteristic that it shared with the 1918 influenza. Okay. And so even though the 1976 wine flu outbreak at Fort Dix had caused only 13 hospitalizations and one death, these similarities between the 1918 influenza were striking enough to lead to Gerald Ford, who was president at the time, to call for a mass immunization program. Over the next six months, after first appearing at Fort Dix, swine flu had caused no additional cases, no hospitalizations, no deaths,

and its spread seemed unlikely. And so the momentum for its vaccination or control seemed to be slowing somewhat. That is, until these mysterious pneumonia deaths began to happen in Philadelphia. And these deaths led people to urge Congress to pass legislation indemnifying vaccine manufacturers for a swine flu vaccine, which is a decision that Ford later received a lot of criticism for. And in general, this rapid response and some of the subsequent decisions regarding the potential, you know, 1976 swine flu epidemic that never was, they were really controversial. at the time and have in retrospect been called too strong of a response for this outbreak that never was. Sort of like this miscalculation of risk and like being overly cautious.

And I mean, I think it just serves as an example of like it's really hard to know what the right move is. But I bring it up because it's really important in understanding, at least in part, why there was such media frenzy around this mysterious illness in Philadelphia. You know, you have newspaper headlines calling it like the, you know, Philly Killer or Killer Fever, you know, ill in Philly. And actually, I think I made that last one up. Everyone was just sort of primed to be paying attention to something like this.

Yes, exactly. Okay. That makes sense. I mean, it's sort of like I was thinking about it in the context of today and COVID and how, like, if there was a convention, let's say like this summer and next summer and it was like, oh, these cases of atypical pneumonia and fever, people would be very concerned for a good reason. Uh-huh. Yeah.

Remember that for later. Yeah. Oh, great. Okay. Oh, yeah. And the other thing is that swine flu, this H1N1, this wasn't the only potentially deadly epidemic disease that was featuring in headlines during the 1970s. Ebola, Lassa fever, Marburg virus,

Campleobacter enteritis, and gastritis, Lyme disease. These were all making themselves known and scaring the world along the way throughout the 1970s. And there's a quote that's often used to characterize the attitude of Western medicine in the middle of the 20th century regarding infectious disease.

Quote, it's time to close the books on infectious diseases, declare the war against pestilence, one and shift national resources to such chronic problems as cancer and heart disease. So it turns out, and I found this out while trying to find this exact quote, that this is an urban legend. I knew it. I feel like I remember looking up that quote, like when we first started this podcast and being

like, it's not real. It's not real. Yeah. No. Like this no one, like this quote was never said. It's just, yeah, no one can find the origin. I know, I know. And so, yes, it may be a misquote.

And while the war on infectious disease was never declared over, it is true that advancements in antibiotics and vaccines may have made many clinicians a bit, say, overconfident maybe, regarding their ability to handle, like, whatever came their way. Totally. And even if we lacked the tools to take care of. a pathogen, the number of newly diagnosed human pathogens, especially those that could cause epidemics, was kind of slowing to a near crawl, like since the heyday of, you know, early germ theory and et cetera. If the first half of the 20th century was basically like stick some sputum

onto a slide, pop that slide under the scope, and then describe a global pathogen that had been infecting humans for millennia, then the second half of the 20th century felt to like many people that there's like nothing new under the sun. We've got it all. Or just like a few things. Like it's it's more of an anomaly to find a new pathogen than it is to just see your typicals. Right. Then just your typical pneumonia. Right. And obviously that's not a lot. our feeling now, right? Like, not in the age of COVID-19, of Zika, of bird flu, of synombris virus. Like, we are keenly aware, the globe right now is keenly aware that emerging infectious

diseases are very much a part of life. But this was not necessarily the case in 1976. Legionaire's disease would really become one of the first, or at the very least, like, part of the first cohort of emerging infectious diseases, which was this like concept, new concept at that time that would eventually force humans to evaluate the ways that they interact with their environment that may increase the risk of a spillover event or at the very least alter the ecology of the pathogen that could lead to an increase in human disease. And this trend of emerging infectious disease isn't solely one due to environmental disturbance, of course. It's also due to the constant development of technology and the growth of our own

knowledge base that allows us to see more detail where previously it was all sort of a blur. Like we're going to describe new species because we described one genus in the first place or a new genus, right? So it just kind of like it builds and builds and builds. But let's head back to the hotel. Let's check it on what's going on there. Yeah. The CDC had shown up in full force and were quickly at work, surveying those with the mysterious pneumonia, as well as other attendees of the convention that hadn't gotten sick. These surveys revealed that older age and smoking were pretty big risk factors and that men were three times as likely to get the disease as women.

They checked hospital logs to determine whether it was just the Legionnaires or if other hotel guests or if anyone local had gotten sick to. And they certainly had. There were several cases of what was referred to as Broad Street Nomania, which is the street where the hotel was on that had popped up. Basically, these were people who weren't legionnaires or had not even necessarily gone into the hotel. Some had just been on the sidewalk next to the hotel. So what the heck was causing this disease and even more pressing? How was it transmitted? And it would take some time for the second question to be answered, and I'll get to it. But what all of

this shoe leather epidemiology did was help with the second question, at least in the form of ruling out. So food board transmission was ruled out. Arthropod vector-borne transmission was ruled out. Person-to-person transmission was ruled out, which also kicked influenza to the curb at the same time. And it seemed most likely to Fraser and the others on this field team who were investigating the outbreak that either airborne or water contamination might be the culprit. Oh. But extensive sampling of the sources of water and all of the air ducts in the hotel, it turned up nothing.

Like they were baffled. Not long after the CDC had arrived on the scene, cases began to decline. And eventually there was nothing left to do, but go back to Atlanta and begin preparing the reports, which they did on August 20th. It was really just like two and a half weeks of like hardcore investigation, like so many people on the ground. Right.

And even though the field workers had covered and tremendous amount of ground in their investigation of the outbreak, the fact that they had come back without a causative agent and that they seemed no closer to being able to prevent a subsequent outbreak of whatever this was, it made the CDC a big target in the media reporting at the time, which was already super critical of their handling of this whole swine flu situation. Right. And also, like, this was in the headlines for ages. It became, like, part of popular culture almost. Right.

Like, Bob Dylan wrote a song called Legionaire's Disease. I, okay, I know who Bob Dylan is, so that's like almost a first for the two of us. Good first step. Mm-hmm. But I feel like even today, most people will have heard of Legionnaires disease. Like, it's a thing. People have heard of it. It's a headline, et cetera.

Yeah. Yeah. Yeah. Do you want to hear the Bob Dylan, like a couple lines? I would love to. Okay. Okay. Some say it was radiation.

Some say there was acid on the microphone. Some say a combination that turned their hearts to stone. but whatever it was it drove them to their knees oh legionaire's disease i love it yeah and it goes on there's more um i i haven't listened to the actual song so i don't know how the melody goes but it exists but anyway i think that the song i think that the you know the little lyrics that i shared really speaks to the fact that no one knew what was going on. And that was part of the reason that it was like so persistent in, you know, headlines and, like, the news stories at the time.

Right. People love a mystery. Exactly. And all that the CDC and the affiliated institutions could do, all they could say was what Legionnaires disease was not. And this was such an enormous investigation, even in just this short time period. Like, for instance, the Franklin Institute looked into the air conditioning system. The Academy of Natural Sciences examined the water supply.

Drexel University used mass spectrometry to look at whether there was anything in the water. Harvard and MIT were involved in testing hair of survivors to look for an environmental toxin. University of Connecticut examined nickel poisoning, which was actually a pretty popular hypothesis for a minute, until it was revealed that autopsy knives, which were nickel-coded, was leading to the, like, inflated appearance of contamination. Yeah. Huh. Like, but this was a huge undertaking.

Yeah. And nobody, even when they tested, like, the air conditioning and things, they didn't, they couldn't find it. They couldn't find it. They have a suspicion why, but. Yeah. There was, at the end of this, like, after some of reports had been produced, committees of infectious disease specialists and committees of pathologists came to one conclusion

regarding the Legionnaire's disease outbreak. Whatever had caused it, it definitely wasn't a bacterium. Yeah. Oh, gosh. Yeah. I love it when those kind of conclusions happen. I know. I know. I mean, it's so easy in retrospect to be like, well, come on, but it is like, yeah. So like, why were they so sure? Well, I mean, it wasn't showing up on any of their routine or even in their non-routine screens. Yeah. Microbiologists had swabbed and smeared and cultured and stained every sample they could think of on all different types of culture media, but to no avail. Like, nothing was there. Antigen tests revealed nothing.

The pneumonia itself more closely resembled that of a viral pneumonia than a bacterial pneumonia. And so they were like, well, it must be either some sort of virus or some strange environmental contaminant. And I should note that there were some groups that did believe it was some sort of like undescribed bacterium. But like by and large, there were committees that were like, no, this is not bacterial. And now that the outbreak appeared to be over, the window of opportunity for uncovering what caused it seemed to be narrowing.

of course the failure to identify the causative agent led to constant criticism of CDC researchers assigned to the task and there were still so many people assigned to the task one of them was dr. Joseph McDade who was a microbiologist at the CDC and he had started working there in 1975 I think just like eight months or so before this 1976 Philadelphia outbreak. And he worked in the department for rickettsial diseases. Oh. He had spent the previous decades studying various rickettsiae, both in the lab and in the field, including outbreaks of typhus in Egypt and Ethiopia.

And if you think back to our Rocky Mountain Spotted Fever episode, which is a rickettsial disease, you may remember that rickettsiae are notoriously difficult to cultivate, to culture, since there are these intracellular pathogens. Right. And so McDade's background working on Rickettsier would prove to be key in finding the missing piece of the puzzle of Legionnaire's disease. And that's just fortuitous.

Like, just lucky that McDade was there. Or was it? Because there were so many people working on so many different angles of this. Like, was it fortuitous? Was it serendipitous or was it inevitable? Yeah, yeah. So like I mentioned, all kinds of these different hypotheses were being put forth to explain the outbreak all at the same time.

So you had a million different moving parts all looking at this angle and that angle and this virus and that virus and this fungus and that fungus, whatever. And one of these hypotheses was Q fever, which is a mild infection caused by Coxiella Burnettii, which is a rickettsia-like pathogen, so it's really small and intracellular, that can cause atypical pneumonia in people. It doesn't generally do that, but it can. And McDade didn't really think that this deadly outbreak, like I said, 15% mortality rate, was cue fever, especially since people get cue fever through exposure to contaminated animals

and, like, inhaling dust from them. But he was like, well, no, no, of course. I'm going to, you know, rule it out. And so he's set to work. And so like other rickettsial pathogens, coxiella burnettii is a bit tricky to culture and isolate. So first you need to take the blood or tissue sample, grind it up and then put it in solution and then inject that into guinea pigs. And then you call the guinea pigs and take tissue from them to put in embryonated eggs.

And when McDay did this with lung tissue from people who had died, night of Legionnaires disease, the guinea pigs became febrile, like, right away, like with a severe fever. Okay. Nothing grew in the eggs when he tried to do that part of it. But when he looked at smears of guinea pig spleen that had been stained by a technique common for, like, staining rickettsial species, he saw rod-shaped bacteria. And he showed other researchers who kind of.

shrugged it off, saying it was a contaminant and not in high enough numbers to be the causative agent. Oh, my gracious. Well, and around the same time, the nickel hypothesis had gathered steam because it was kind of being consistently found in all of the people who had died from Legionnaire's disease, which makes sense because it was on the autopsy knives. Anyway. And so, but so he didn't pursue this like rod-shaped bacterium too much. Oh, my gosh.

But a few months later, the nickel theory had been debunked, and McDade found himself, like, wondering about it, just kind of like, why, he was like, why can't I drop this idea about this rod-shaped bacterium? He was like, why is it there? Why was Nick culture in the eggs? Blah, blah, blah. And so he went in over, like, the Christmas break and was like, there's no one here. So I'm going to have the lab all to myself and I'm going to be able to do this work without

being disturbed. Oh my gosh. And so he went back and he like started to look at all of the slides again that he had prepared. And on one of them, he saw not just a single, you know, rod-shaped bacterium, but a cluster of bacteria, which made him realize that this probably wasn't just a random contaminant, but likely the culprit. And additional testing revealed that he was right. More than 90% of the Philadelphia patients had antibodies to this bacterium, and they were also able to isolate it from additional autopsy specimens. Oh. But they still didn't know exactly what it was. Like, was it a rickettsia? No. It certainly didn't look like or behave like a rickettsial species. So maybe it was something else. Eventually, through

lots of trial and error, researchers were able to put together a recipe for a culture medium that met the very specific needs of this super fastidious new bacterium. It's very picky. Yeah, I love the word fastidious for bacteria. It's a good one. It's a good one. And through this, they were also able to solve the mystery of its outbreak, because it turned out that this bacterium loves warm water, and the warm weather in July proved a perfect time for this bacterium to be misted out by the air conditioning system into the lobby of the hotel and into the sidewalk next to it. Just this, like, killer mist. By the time that the CDC had examined the AC system, it had been cleaned, so no traces of the bacterium had been found. Huh. Yeah. Interesting. And this new

bacterium was given the name Legionella pneumophila as a nod to this outbreak who was affected by it and then the tendency of it to cause disease in the lungs so like lung loving and this turned out to be like a whole new genus of bacteria but new doesn't necessarily mean new to humans it may just mean newly described so had the world seen Legionella pneumophila before absolutely Always. All you needed to do, it seemed, was just to look. Once Legionella and Numa Phila was pinpointed as the causative agent, researchers immediately began combing through past unsolved outbreaks that resembled the one in 1976 to see if it had emerged before. And it absolutely had. In 1968, for example, when 95 out of 100 people who worked in a health department in Pontiac, Michigan became ill with a mild illness, no deaths. And at that time, there had been extensive

epidemiological investigation into the outbreak and the air conditioning units had been suspected, but it again didn't yield like any solid answers. And so it was kind of just like, it's a mystery. But then once Legionella and Numophila had been described, people who had Pontiac fever, like were in that outbreak, were tested for antibodies, and it was shown that they were one and the same. Interesting, because of just the sort of epidemiological similarities, even though the disease itself wasn't nearly as severe. Fascinating. Yeah. And even at the Bellevue Stratford Hotel, so the same place where like this 1976 Legionaire's disease outbreak, first outbreak, two years before during a meeting of the Odd Fellows Society, yeah, several people had become

ill with atypical pneumonia. So it was again shown that the same bacterium had been hiding out there. And then another outbreak of unexplained pneumonia in St. Elizabeth's Hospital in Washington, D.C., in August of 1965, that was also linked to the bacterium. And there was a specimen from 1943 that revealed a strain of Legionella McDadyi. And then another sample, 1947 turned up Legionella. And so, like, it had definitely been around. I didn't really find anything on, like, the evolutionary origins of it. But it was clear that, like, outbreaks or cases of the disease weren't just a thing of the

past and also not just something that happened in the U.S. after the bacterium was discovered and described in December, January of 1976, 1977, additional outbreaks occurred in Vermont in 1977, in England in 1985, in the Netherlands in 1999, a big outbreak in Spain in 2001 involving like 700 people, 2005 in Canada, and Portugal in 2014, the Bronx in 2014. I mean, happening all over the world. And those are just the outbreaks. Like this disease also happens very sporadically, just like individual cases. Yeah, I feel like that's important to say because I think people think of it as just this outbreak

pathogen, but really it can cause pneumonia in anyone anywhere, even just one case. Yeah, absolutely. And so I am almost ready to turn it over to you, Aaron. But first, I want to talk about the timing. of all of this? Why did this disease seem to emerge in the mid-20th century? Because, you know, I didn't say anything about ancient Rome or Hippocrates or the Ebers papyrus. So was it truly new to at least the 20th century?

No, not at all. I mean, like you said, this is an environmental bacterium. Like it doesn't need humans to infect in order to live out its life. So it's possible that it caused cases here and there before the 20th century, but there were two important developments or trends, I guess, that happened to lead to its emergence then. The first is simply advancements in microbiological technology and epidemiological techniques that allowed us to isolate and describe this pathogen. The second is air conditioning and water cooling towers.

like outbreaks with this bacterium are often linked to the HVAC systems in various buildings, especially hospitals and prisons, as the source of exposure, which historically, obviously, you know, wouldn't have been an issue. Like there were passive air conditioning systems, but they weren't the things that we have today. The things that we have today, those sort of developed for more widespread commercial and at-home use around the middle of the 20th century. And so that's right when these like outbreaks of Legionella first started to happen. Right.

And so it all comes back to timing and context yet again. Why did it happen when it happened? Why was it discovered then and not earlier? Why was there so much media attention? How did the demographics of the victims affect the attention it got? I didn't go into it here, but there has been a lot of discussion about that and like the fact that these were members of the American Legion who were largely impacted and comparing and contrasting that to the early days of the AIDS crisis and how little attention that got in comparison. All of these things play a huge role in how epidemics or outbreaks, including this one, play out. So, Erin, as I sit here, sweating because my own air conditioning unit is broken in my apartment,

and it's summer in Chicago. So it's kind of funny to just read constantly about air conditioning. I'm like, okay, yeah. You're like dripping, dripping, like, at least I'm not breathing in Legionella. Will you get me up to speed on where we stand with Legionella today? I would love to right after this break for a cold glass of water. Since the theme of this episode is, we don't really know, we'll continue that here in the epidemiology portion, Erin. We know some things.

It seems as though worldwide and in the U.S. specifically, the overall risk for Legionella infections seems to be increasing. Or at least the overall case numbers are certainly increasing, even though we have better guidelines in terms of cleaning of air conditioning systems, et cetera, on how to try to prevent legionella contamination. So in the U.S., from the year 2000 to around 2014, the U.S., which reports case numbers a little bit differently than the rest of the world, of course, the U.S. case numbers increased from about less than one per 100,000 people to one and a half cases per 100,000 people per year. This brings to mind that paper from Nygleria Fowleri where it was like, is this an emerging parasite?

There's a very similar paper for Legionella. Yeah. And so these numbers include both outbreaks and those single sporadic cases. like we talked about, which do happen. And it also importantly includes both Legionaire's disease and Pontiac fever. But the biggest problem is that in all the surveillance systems in the U.S., in Europe, over like 99% of cases that are reported are Legionnaire's disease. Why? Because that's the severe disease. So those are the people who are going to the doctor, going to the hospital, getting really sick, and then that disease is then reported. question.

Uh-huh. Has the frequency of outbreaks or the intensity or the size of outbreaks increased or is it the number of sporadic cases that have increased or have they increased in parallel? Good question. It seems like both have increased. Okay. Interesting. In Europe, the European surveillance system in 2011 reported a prevalence of 9.7 per 1 million people. so it's a different scale. But, and here's the biggest problem,

we talked about this as well with our coxidioidomycosis episode. Even when you have a surveillance system in place, when we're dealing with a pneumonia, it's not super common that we're able to actually test for or identify a specific pathogen that's causing that pneumonia. So we not only don't have a gumon, good handle on the number of true legionnaires cases every year. We also don't have great stats on the overall mortality rates every year because we just don't know. In the U.S., in one paper from

CDC, they suggested that the overall burden in terms of, like, if you look at all pneumonia, about 2 to 9% of total community-acquired pneumonia. And again, that doesn't include hospital-acquired pneumonia. And like you mentioned, Aaron, the HVAC systems and hospitals are a big place where contamination is possible, and therefore this could be a hospital-acquired infection. But if we just look at community infection, 2 to 9% of all pneumonia's might be associated with Legionella. other papers that looked more globally suggested even up to 15% of pneumonia's that required hospitalization were associated with Legionella.

So if we go back in the coxidioidomycosis episode, I did a bunch of like Aaron math, right, where we tried to calculate like how many cases might there be. So there are in the U.S. at least, between 23 and 27 cases, per 10,000 adults of community-acquired pneumonia that results in hospitalization every year. So if we think that maybe on the high end, 10% of those might be caused by Legionella, that would be two and a half cases per 10,000 adults every year, which is, of course, a lot more than are reported. Right. And that would be about 52,000 cases per year in the U.S.

So a substantial number. It's a substantial number, yeah. So for sure, globally, tens of thousands of people are becoming infected, potentially even hundreds of thousands, but we don't exactly know how many. The good news, though, is that unlike with coxidioidomycosis, in many countries and in many parts of the world, the sort of standard treatment for community-acquired pneumonia does include antibiotics that treat against legionnaires. Right. So that's at least a small silver lining. And have there been any seroprevalence studies that just like look at it out of the blue? Good question.

I didn't find many. Okay. Yeah. And overwhelmingly, that's one of the biggest areas that we still need to do research on, is just getting a handle on the true, like, epidemiological risk. Mm-hmm. Yeah. So a question about that.

Like, what is it about certain air conditioning systems? How are they cleaned? how does it get there in the first place? And like how do you protect yourself or know whether you're inhaling, you know, this killer mist? Yeah, killer mist. Yeah, it's a good question, Aaron. And not to freak you out. Excellent.

Yeah, but the biggest thing I've seen recently is a lot of news articles talking about the risk of legionnaires increasing as the pandemic. of COVID-19 begins to wane because, so you asked, like, what are the, like, what kind of conditions lead to this growth, right? Unused air conditioning units that have a little bit of water in them, those kind of stagnant water in pipes, that is beautiful biofilm territory. Oh, no, all of these office buildings. Exactly. All the office buildings, all the hotels, all of these things that were closed or vacant.

during the pandemic, all of these months of these systems not being used, there's a huge potential, again, not to freak people out, but for legionnaires to increase. Wow. But the good news is that people have been thinking about this. I read one article. It was just from like a news source, but it was about someone whose entire job during the pandemic was running the water in hotel like bathrooms. and flushing all the toilets and running water through the pipes every week so that this hotel maintains good quality of water.

How many of these cases are linked to, or is it really known whether it's like these industrial HVAC systems or like personal at home HVAC systems? It's a good question. I don't think that we have a good handle on it, especially because we really just don't know how many cases there are per year. And I would guess, especially if you're talking about a personal age fact system that, you know, maybe only one person ever gets exposed to it and gets infected, those cases are going to be even harder to pick up and to link to something specific. Okay. Right.

It's the larger outbreaks that you can then trace back to specific environmental sources. Mm-hmm. So, yeah. that's legionnaires. There's some other pretty cool research being done. There's a lot of cool research being done, especially on the kind of detailed molecular biology. I'll link to a couple of papers on that to try and understand how Legionella is able on a molecular level to survive and persist in ourselves, as well as on vaccine development. So we're nowhere near having a vaccine, but there are people who are working on mouse models to try and develop a vaccine because it's

at least theoretically possible based on how much of an immune response humans mount to it. Okay. So, well, sources. Man, this was like short and sweet episode. Not that sweet, I guess, but short and moderately horrific. Yeah, absolutely. Yeah, I have a bunch, but I want to shout out a few that I found super helpful. One by Weiss from 1992.

called A Plague in Philadelphia, another by McDade himself from 2002. Legionaire's disease 25 years later, lessons learned. And by Wynn from 1988, Legionnaire's disease, a historical perspective. Wow. I love that there was a historical perspective like 12 years later. Yeah, I know, right? I had a number of different papers. There's a really great comprehensive one from the Lancet, 2016, just called Learrow.

Legionnaires disease, another from 1993 in clinical infectious diseases called Legionnaires Disease. We'll post the links to all of our sources on our website, this podcast will kill you.com where you can find every single source that we use for this episode and all of our episodes. Thank you to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to the exactly right network of whom we're very proud to be a part. And thank you to you, listeners. we hope you enjoyed this one.

Actually, we just got an email like the other day being like, can you do one on Legionnaires disease? Yeah. I was like, come in your way. You ask, we answer. And a big special thank you also to all of our patrons. You are amazing. We love you.

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