Ep 77 Legionnaires' Disease: A Killer Mist

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 one hundred and six degrees. It took about four days before they figured out it was Legionnaire's I still had a temperature of one hundred and three, 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 drop things a lot, and 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. Wow. Yeah, that sounds very horrible and terrifying. Yeah, so that was from a website called legionella dot org, where under a section called share your Story.

so it's 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 amiba of course, and Legionella in general grows well at warm temperatures like twenty five to forty five celsius, just like the amibas that we talked about in our Nigeria palrite episode. It's happiest around thirty five celsius, which is

like ninety five 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.

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.

Legionella in water sources. Yeah, yeah, great question, Eric, But in general, this is not a pathogen that's transmissible person to person asterisk. 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.

their little macrophages kind of almost look like amiba. 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 macrofage cell. But once it gets inside the cell, it's wrapped in a little bubble of macriphage cell membrane. M hm. It's

called the phagosome. Yeah, yeah, you know this erin And now normally, once that fhagosome is inside the macrophage, all of these other mechanisms inside of the macrofage cell would see that bubble and be like, ugh, there's another bacterium. Boop, and they'd pop that bubble, release the bacterium.

Legionella bacteria. But I as I was reading this, I was like, I find it annoying that we have these two different named diseases because they're not 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 legionellosis as a spectrum of disease rather than legionnaire's disease versus pontiac fever.

of Legionella that are causing pontiac fever versus legionnaire'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 pneumophilla zero group one, and so like one specific group of Legionella numophila, 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 zero 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 Legionnaire'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 fifty is at higher risk than people younger, and any kind of immunal compromise, especially immuno compromise 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 Legionnaire's disease. But like you said, Erin, we also just don't know as much about pony because.

which are osociated with such high fevers, a cough. Unlike some of the more quote typical pneumonias, 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 pneumonias 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

clebcila or something like that. So there's a whole group of atypical pneumonias of which Legionnaire's disease is.

is your cough productive versus not productive? Are you very very very sick versus your X ray looks terrible, but you.

most severe form of pneumonia. It's just that previously we were only seen the sickest of sick people. If that makes such 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 a 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 pneumonias are still quite common.

of course, the context always the context. Why did this outbreak happen when it did, and what about it? Stances 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 nineteen seventy six Philadelphia, Pennsylvania aka the

City of Brotherly Love. This entire year, everyone around the US was celebrating the bi centennial of the country, including more than four thousand members of the American Legion, which, if you didn't know because I had to google it, is an organization of US 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 twenty first to July twenty

fourth at the Bellevue Stratford Hotel in Philadelphia. This was specifically the fifty eighth annual convention of the American Legion Department wow YE. Over the course of that convention and in the weeks that followed, two hundred and twenty one people became ill with a mysterious disease and thirty four died, which is a rate of about fifteen percent. Most, but not all, of those affected were members of the American Legion, hence the name Legionnaire's 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 VIA diagnosed several of his patients with pneumonia. But this pneumonia wasn't typical pneumonia whatever it what means 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 two, 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

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 Stratford 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 doctor's offices around the city, and the death toll was mounting.

roll in. But it is likely that given the incubation period of two to fourteen 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.

the historical context. So earlier that year, there had been some cases of H one N one 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 nineteen eighteen. And these cases of influenza were

worrisome for a couple of reals. One was that although in nineteen seventy six people didn't know exactly what strain the nineteen eighteen influenza one was, studies had suggested that it was a similar isolate to the H one N one 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 nineteen eighteen influenza. Okay, and so even though the nineteen seventy six swine flu outbreak at Fort Dix had caused only

thirteen hospitalizations and one death. These similarities between the nineteen eighteen 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 like rapid response and some of the subsequent decisions regarding the potential you know, nineteen seventy six 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 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.

medicine in the middle of the twentieth century regarding infectious disease. Quote, it's time to close the books on infectious diseases, declare the war against pestilence I and shift national resoarch 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.

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 twentieth 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 and half of the twentieth century felt to like many people, that there's like nothing

new under the sun. We've gone 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 pneumonias, right and obviously that's not our feeling now right like not in the age of COVID nineteen of Zeka of bird flow of sin nombree virus, like we are keenly away 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 nineteen seventy six, Legionnaire'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 concept, a 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 they determine whether it was just the legionnaires or if other hotel guests or if anyone local had gotten sick too, and they certainly had. There were several cases of what was referred to as Broad Street pneumonia, 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 born and transmission was ruled out,

Arthur pod 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 ducks 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 twentieth, usually 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 a 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 the whole swine flu situation. Right and also like this was in the headlines for ages, it became like part of popular culture. Almost like Bob Dylan wrote a song called Legionnaire's Disease.

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.

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 not which were nickel coated was leading to the like inflated appearance of contamination. Yeah, huh, like, but this was a huge undertaking.

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. Right. 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 doctor Joseph McDade, who was a microbiologist at the CDC, and he had started working there in nineteen seventy five, I think, just like eight months or so before this nineteen seventy six Philadelphia outbreak, and he worked in the department for Rickettsial Diseases.

ricketzial disease. You may remember that ricketsie are notoriously difficult to cultivate to culture since they're these intracellular pathogens, right, And so mcdaide's background working on Rickettsia would prove to be key in finding the missing piece of the puzzle of Legionnaire's disease.

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 Ricketzia

like pathogen. So it's really small and intracellular that can cause a typical pneumonia in people and it doesn't generally do that, but it and mcday didn't really think that this deadly outbreak, like I said, fifteen percent mortality rate was q fever, especially since people get Q fever through exposure to contaminated animals and like inhaling dust from them. But he was like, well, no, no, of course I'm gonna, you know, rule it out. And so he set to work.

And so, like other ricketzial 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 like 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 of Legionnaire's 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 pigs spleen that had been stained by a technique common for like staining raquetzial 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 shape bacterium? He was like, why is it there? Why 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 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 shape 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 ninety percent 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 Ricketsia. No, it certainly didn't look like or behave like a Ricketzio 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 festidious new bacterium. It's very picky. I yeah, I love the word festidious 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 missed. Oh, 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 numophila as a nod to this outbreak who was affected by it, and then the tendency of it to cause disease in the lungs 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 numophilla before, absolutely always aways. All you needed to do, it seemed, was just to look.

Once Legionella numophila was pinpointed as the causative agent, researchers immediately began combing through past unsolved outbreaks that resembled the one in nineteen seventy six to see if it had

emerged before. And it apps lutely had in nineteen sixty eight, for example, when ninety five out of one hundred 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 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.

And then another outbreak of unexplained pneumonia in Saint Elizabeth's Hospital in Washington, d C. In August of nineteen sixty five that was also linked to the bacterium, And there was a specimen from nineteen forty three that revealed a strain of Legionella macdadi, and then another sample in nineteen forty seven 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 US. After the bacterium was discovered and described in December January of nineteen seventy six nineteen seventy seven, additional outbreaks occurred in Vermont in nineteen seventy seven, in England in nineteen eighty five, the Netherlands and nineteen ninety nine, a big outbreak in Spain in two thousand and one involving like seven hundred people, two thousand and five in Canada and Portugal, and twenty fourteen the bronx in twenty fourteen,

I mean happening all over the world, and those are just the outbreaks. Like this disease also happens very sporadically, just like individual cases.

live out its life. So it's possible that it caused cases here and there before the twentieth 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 twentieth century. And so that's right when these 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 the fact that these were members of the American legion who are 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, Aaron, 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.

the Epidemiology portional, Aaron, we know some things. It seems as though worldwide and in the US 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 system, et cetera on how to try to prevent

Legionella contamination. So in the US from the year two thousand to around twenty fourteen, the US, which reports case numbers a little bit differently than the.

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.

pathogen that's causing that pneumonia. So we not only don't have a good handle on the number of true legionnaire's cases every year, we also don't have great stats on the overall mortality rates every year because.

percent of all pneumonias might be associated with legionella. Other papers that looked more globally suggested even up to fifteen percent of pneumonias that required hospitalization were associated with legionella. So if we go back in the coxsidioido my kosis episode, I did a bunch of like air in math right where we tried to calculate, like how many cases might

there be. So there are in the US at least between twenty three and twenty seven cases per ten thousand adults of community acquired pneumonia that results in hospitalization every year. So if we think that maybe on the high end, ten percent of those might be caused by legionella, that would be two and a half cases per ten thousand adults every year, which is of course a lot more than are reported, And that would be about fifty two thousand cases per year in the US.

to specific environmental sources. So yeah, that's Legionnaire's. 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 our cells,

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.