Ep 121 Tularemia: Hare today, gone tomorrow

hundred two point two degrees. His fever continued until the twenty fourth day. During the first twelve days of his illness, he packed up his laboratory equipment and animals in Utah with great difficulty and proceeded with them to Washington, d c. And, after his arrival made a futile attempt to continue work. The next fourteen days he spent in the hospital, lying

on the bed, but not confined to the bed. The departure of the patient from the hospital on the twenty eighth day was attended with some forced exercise, which resulted in a secondary rise of temperature which lasted four days after which it remained normal. The second month was spent in a hotel, lying on the bed most of the time.

The third month was one of slow convalescence. Throughout the illness, there was an absence of localized pain or tenderness, except that on the sixteenth day of illness, a sore throat developed on the right side. Practically the only complaint was that of languor or weakness and a desire to remain quiet on the bed.

he was experiencing was tularimia. But then in retrospect, it was like, oh, yeah, and then he tested his blood and the blood of several other laboratory workers and found that indeed it was your toularimia. Oh my gosh. Yeah, so that was from a paper that he and a colleague wrote in nineteen twenty two. Wow. Yeah, Hi, I'm Aaron Welsh and I'm Erin Alman Updyke and this is this podcast Will Kill You.

Holarctica is found throughout Eurasia. And in North America, and is the other major subspecies of franciscella to lorenzis that causes disease in humans. So those are the two subspect that I'm going to be focused on. They're also sometimes called type A and type B in the literature, but realistically, I'm just going to be talking about francisselo toulorensis, or I might even just say tulaimia for the rest of this section.

within other ie hosts cells. And we'll talk a little bit more about that what sells it's replicating in in detail, But as far as hosts go, this is a bacterium that can infect hundreds of animal species, mammals and birds and many different species of invertebrates which end up serving as arthropod vectors.

highly infectious. So as I talk about how it gets into us and does all of these party tricks, keep in mind that as few as ten individual bacteria can cause infection in humans.

conducive to the growth of this bacterium. And keep in mind, like I said, there are several different subspecies that can all persist in the environment and live intracellularly inside of host cells. Because it's a pretty difficult bacterium to grow in the lab in culture, there is some thought that perhaps in the environment it's not just persisting on its own, maybe it's in a host like an amiba or a protozoa.

Who knows it's unclear, but it can infect and be a pathogen of a whole bunch of different animal species. One paper I read said over two fifty other papers said over one hundred and ninety, So like a lot of animals, a lot including mammals and birds and arthropods.

like muskrats and beavers and things. And I had to look up to make sure that all of these things were really rodents. What a diverse group the rodents are, really, truly, Yeah, but in many of these species, this bacterium seems to cause an acute infection and make all of these animals quite sick. So it's perhaps less likely that any of these species that we commonly find Francissella toulrensis in are actually the natural reservoir host in the environment, So we

don't really know. But then how do we actually get exposed? If these are the animals getting infected, we should at least have an answer for how humans get sick, And it turns out that that's more complicated too. Of course, it is like we alluded to already, Francissella toulrensis has been shown to be transmitted not by one or two

or three, but many different arthropod vectors. And by that I mean it can be transmitted by ticks a whole bunch of different species, horse flies or to bannids a bunch of different species, and mosquitoes a whole bunch of different species.

since in Europe we really only see subspecies Holarctica. And North America we see both Holarctica and Toulrensis, as well as a little bit of the other ones that are less important for human infections. But what's really interesting is that when it comes to the life cycle of Francissella

in these arthropods. From one paper that I read, they noted that it has never been demonstrated that this bacterium is found in the salivary glands of any arthropod, and so it's thought that maybe the spread is just mechanical. You have mouth parts becoming infected when a fly or a mosquito bites, but ticks are found infected throughout their life cycle. So if a tick gets infected as a larva, they remain infected as they become a nymph and an adult,

et cetera. And we really have very little data on what is going on in these ticks, which ticks are really the best vectors, and all of that we just simply don't know. Because here's the thing, transmission doesn't stop there.

Vector born transmission is one way that people can become infected, but human infection with tulurimia is also associated with waterborne transmission from contaminated water sources, and perhaps the scariest and most severe possible route of transmission is aerosolized bacteria that we inhale, and this can come from contaminated soil or grasses, or even directly from animal carcasses that were infected it themselves.

This is the way that makes francissela to lorensis a potential bioweapon agent that combined with the very low infectious dose.

on the root of transmission. One paper that I read suggested that the form that you see after vectoral transmission, or like direct contact with a mucous membrane or like a wound, say, which would be a very similar route of transmission from like an infected animal through the skin through a break in the skin, that that might account for up to ninety percent of cases, but I didn't see that number reported in very many papers, so.

like phase means eat, right. So what franciscella to lorensis is able to do is kind of like stabilize this phagosome initially prevent it from doing its normal thing of killing those bacteria, and then escape and replicate in the cytoplasm. While we don't fully understand all the mechanisms by which they do this, it's not entirely uncommon compared to other intracellular bacteria. A lot of other intracellular bacteria are able to do kind of similar things.

meaning it's a different method than other intracellular pathogens like Coxiella, legionella, salmonella.

of types of tulaimia. The first, and what like I mentioned, is in some papers at least reported as the most common, like up to ninety percent of cases, is called the ulcero glandular form, or less commonly, there can be a glandular form without the ulcer at the beginning, What does this mean. This happens with vector borne transmission, so from a tick or a mosquito or a fly that bit you on your skin somewhere, or from direct contact with an infected animal with like a break in the skin.

What you see with this form of tuluremia is at the sight of the bite or the infection an ulcer. So it usually starts as a papule like a little bump that then progresses to a pustule like a blister with pus in it that looks inflamed, maybe warm, maybe tender, and can often kind of open to form this open ulcer. It might just look like a bug bite. It might not be that gnarly looking of an ulcer, and it

usually heals within a week or so. But if it does, then what that means is that this infection has spread to the lymph nodes nearest the bite, which will then start to get enlarged. That's the glandular part of the name. These lymph nodes will get swollen and tender, and if this infection becomes severe, you can have such severe swelling of these lymph nodes that they actually begin to drain pus from the lymph nodes to the skin, which is very very serious.

to begin with. Then there's the respiratory form respiratory meaning that most commonly you have inhaled and aerosolized bacteria, which is often happening from farming activities where hay or grasses or something are mode or dealt with, or from hunting activities where you're dealing with carcasses and maybe aerosolizing something

from a carcass. Now, if you have a respiratory infection from Francissela Toulurance's subspecies whole Arctica, usually it's a pretty mild flu like nonspecific respiratory illness, but with subspecies tolurensis what we see are those fevers, chills, add on a cough, very severe chest pain. It can progress then to hemoptosis, so that's coughing up of blood. You might also see even more systemic symptoms like nausea and vomiting diarrhea. So

this like GI tract becoming involved commonly. One thing that we see is what's called pulse temperature dissociation, which is something we talked about way way, way way back.

will increase. So as our body temperature increases, our pulse increases. That is a typical physiologic response. So what a pulse temperature dissociation means is that you see a relative bratacardia, meaning your heart rate in comparison to your temperature is low. Our pulse does not increase in compared to our temperature. So here's slow. It's not that the pulse actually decreases. That is fascinating. I want to know so much more about this.

that process. So like, what does that mean? It means that we're our body is not working the way that it.

When people are infected from contaminated water sources, it can cause like an oropharyngeal infection, so more of like a mouth and throat infection and a GI infection nausea vomiting as the primary symptoms, and it can also cause an oculo glandular infection if the eye is the first root of entry, right, a mucous membrane, which then leads to a conjunct dividis, so infection of the eye and drainage from the eye and then the lymph nodes where your

eye drains. All of these different forms, while they are very different, especially initially, can then lead to a systemic bloodborne infection which can then lead to sepsis and septic shock and death.

than subspecies Holarctica. We don't really know both of them can cause all of these different types of infection, and I don't have enough data to be able to say, like Holarctica is much more likely to cause X than Y, except that overall Holarctica causes much less severe disease right compared to Tolurensis.

wid It's a side note for me here. But I'm sure that there's some very interesting research in terms of the immune response and why this is possible. Right, Is it because it's hang out in our immune cells, it's infecting a lot of our white blood cells. Does it hide in our spleen or our liver?

quote The history of Tullerimia makes fascinating study. It is

in every respect the first American disease. The physicians of this country should be thrilled by the thought that not only was this disease discovered by American investigators, but also because it's specific ideologic agent, the determination of its modes of transmission from animal to animal and from animal to man, the descriptions of its clinical manifestations, and its pathology and bacteriology were made known by American workers and leading all as.

The guiding spirit which has made this accomplishment possible is Edward Francis of the United States Public Health Service. It's a very long quote to kind of kick this off, but I feel like whip that kind of sums it up. But yeah, this designation of Tulaimia as an American disease, first of all, I just find really interesting because I don't think that we've come across that before. It's like extreme patriotism about a particular disease. Usually it's like more

like racism about disease or something. Right to like claim it, like this one's ours. That's great, right, we stake ourklame. Yeah, yeah, yeah, this, but this designation as an American disease would stick with Tularimia for a really long time, like long after the bacterium, or at least subspecies of this bacterium had been found to be globally distributed. But did france Ascella to lorensis originate in North America? Hm? Honestly, I have no idea,

but yeah, we don't fully understand. But yeah, there's like quite a bit of really interesting and thorough research on the evolutionary relationships among Francissella toulorensis subspecies and with other francissella species and like the virulence genes potentially, and when it acquired them and when it lost them, and all

of that cool stuff. But there doesn't seem to be a whole lot of consensus on which subspecies came first and from where especially, And it's no wonder because the ecologies of these bacteria are so different and their distribution is so wide ranging. Honestly, it's amazing that anyone has been able to make any sense out of it at all. So this is what we think we do know about

the two main subspecies that cause disease in humans. Like you said, Aaron Francissella to Lorensis subspecies Tolreensis is the big battie, can cause very deadly disease with vast vasus vast majority of samples found in North America, with one exception. In nineteen ninety eight, a paper reported that two isolates of this deadly too Lorensis subspecies were found in Slovakia near Broadislava. Huh, isn't that interesting? Yeah? And like, as far as I could tell, that's been the only instance

of this subspecies found outside of North America. And how it got there and what it means is still a mystery. Where was it? Like, what kind of sample? That's a good question. I don't remember. Interesting, Yeah, but the paper will be on our website. Okay, so if you want

to check it out. But the other subspecies of human health importance again, like you mentioned aaron subspecies whole Arctica that's been found throughout the northern hemisphere, and so I feel like if you had to guess which came first, you might be more inclined to guess the one that is globally distributed. But in fact, most papers think that the Toularensis subspecies, the one only found in North America asterisk, is actually older and that the whole Arctica species evolved

from it. And researchers think this because of the genetic diversity of the two subspecies. Toulorensis is much more diverse than the whole Arctica they've tested, and in fact, whole Arctica is so unexpectedly not diverse that they think there was some sort of bottleneck event that was just like, okay, everyone is now the same, the same. Yeah, that is interesting.

But the bottom line, and what nearly everyone of these papers ends with, and rightly so, is that there's a whole lot more Francissella to Lorenzis diversity out there, just waiting to be explored, and so this story will probably change, or at least more details will emerge as that research

is done. So we don't know where in the world Francesella Tolrenzis first emerged, nor do we know when in history or prehistory this pathogen, these pathogens first made their appearance, or at least I didn't find it in the papers that I read. But as I was hunting for papers on Google Scholar, I came across at least three papers proposing that Francis sello to lorensis was the causative organism for several different ancient plagues. Each paper went into a

particular plague. All of the papers were by the same individual author, and all were published in the same journal Medical Hypotheses. And these were like wide ranging plagues. Make that point, okay, So that right away kind of stuck out as a little suspicious but interesting enough to look into, and so I started to skim these papers, and the biology proposed in them didn't really make much sense at least as far as what we know about to lorensis. So then I was like, Okay, what's going on with

the strejournal? So I googled. It turns out that it uses quote unquote unconventional peer review, which I looked into it more. It isn't very rigorous, which is intended to be that way because they're publishing the papers that no one else will publish, and it has been known to publish articles denying aids, as well as articles on other

horribly offensive and completely nonfactual topics. So I dug a little bit deeper to see if I could find any other mention of tulaimia and the hit type plague, which is the subject of one of these papers, and I found an amazing book chapter called Beyond the Differential Diagnosis, New Approaches to the Bioarchaeology of the Hit Type Plague

by Smith, Guzman, Rose, and Cufkins. I'll put it on our sources on our website, but anyway, I came across this chapter because it mentioned that the tulaimia hypothesis had been disregarded because of a lack of biological plausibility, and then I kept reading because it provided this amazing eleven step like step by step discussion of how you could incorporate so many different and varied methods to arrive at a likely causative agent for ancient epidemics, which often have

very limited physical evidence. By the way, they concluded that malaria was a likely culprit for the hit type plague. So this was kind of a long detour with like not very much meat to it, but I really wanted to include it because I feel like it illustrates how hard it can be sometimes to tell whether something is

a legitimate source or not. Like you can find these papers on PubMed and on the National Library of Medicine Journal Archive, like it's on Google scholar, right, So just because it's on Google scholar, it doesn't mean it's necessarily legitimate or you know, just like ah, it just shows how crucial it is to keep doing that little bit of extra digging to help you decide if something is

a good source. So keep going down that rabbit hole because at the end of it, you'll get better at spotting these crappy sources and you get to appreciate the good ones and hopefully not get toulurinia but get it home. Sorry.

earthquake devastating would be an incredible understatement. An estimated eighty percent of the city was destroyed and two hundred and fifty thousand people were left without a place to live. As listeners of this podcast are probably well aware, these types of conditions are perfect for diseases to break out and just spread like wildfire. Since about nineteen hundred or so before the earthquake, San Francisco had been battling bubonic plague and things were just starting to seem under control

when the earthquake struck. Soon after the earthquake, rats swarmed the wrecked city, sparking this renewed fear of this deadly disease. And there is a lot more to the story of rats and bubonic plague and racism and discrimination in San Francisco that I'm not going to get into in this episode. But one of the things that came out of this thread of plague after the earthquake was the push for more research on the ecology of this disease of bubonic plague.

So the director of the US Public Health Service Plague Lab, George McCoy, decided to investigate some of the reservoir animals for plague in North America, particularly ground squirrels, curious whether the plague bacteria they harbored was in any way different from those in rats. So to answer this, he went

out trapping in Tulare County, California. At this point, the causative agent of bubonic plague, your sinnea pestis, had already been described, but McCoy was having trouble isolating this bacterium from some of his ground squirrel samples, even though they had symptoms of PLAGUEO like these, soulen lymphnos like lesions like yeah and so Eventually, after tinkering with the culture media recipe, McCoy and his colleague Charles Chapin were able

to isolate a new microbe from the squirrels, which they named Bacterium to Lorentz after Tulare County. Wow. Eight years later, in nineteen nineteen, a researcher at the US Public Health Service named Edward Francis was sent out on his first field assignment to study an outbreak of something called deerfly fever in an area of rural Utah. Frances set to examining each person who was sick, taking samples from them, trying to grow microbes from the samples to figure out

what was making them sick. And it didn't take him too long to figure out that the likely causative agent was Bacterium to lorentz. So he called the disease toulerimia. Wow. So forward, Yeah, well, yeah, I mean there also was a little bit of this unfortunate situation where Francis got to know the bug all too well. Yeah, he picked up tulaimia from someone who later died of tularimia, and

you know the rest from the first hand account. But his illness, Francis's illness kicked off what would be an unlucky trend among tulerimia researchers, and many of them would get sick with the thing that they were studying over the next years decades. Really, so I want to read you a quote from the same paper describing Francis's illness. Quote.

All of the men six in number who have been intimately connected during the past two years with the laboratory investigations of tulerimia which the Public Health Service has been conducting, have contracted this disease. Such a record of morbidity among investigators of a disease is probably unique in the history experimental medicine. Fortunately there were no fatalities end quote. Wow. Yeah.

And then this paper goes on to describe how some of these researchers that got to lurehemia had worked with deadly pathogens for decades and knew all of the PPE tricks and whatever. Some of them worked under rougher conditions in terms of like a field lab, and others were working in like state of the art labs, and still they got sick. Which, yeah, it's just so infectious. Yes, you can take as many precautions and still there's like such a high risk of getting sick.

not a simple answer. Yeah, Francis isolated the bacterium from jack rabbits and ground squirrels, and also showed that deer flies, mouselice, and bedbugs could play a role in transmission to humans. His extensive and groundbreaking work on the disease would later inspire the genus name to be changed to Francis Sella

Ah love that. Yeah. But the cases of deer fly fever that Francis was sent to investigate in nineteen nineteen didn't mark the very first outbreak of Tullerimia in humans, of course, because, as is so often the case, once Francis and his colleagues published their findings, other likely past cases or past outbreaks of this disease came to light. The oldest of these dates back to eighteen eighteen and comes from Japan, a disease named Yato bio hair disease

that appeared in people who had handled rabbit meat. In the eighteen nineties, in Norway, an illness called lemming fever was described, And this is maybe a stretch, but there's also a description of a tularemia like disease in lemmings in Norway from the sixteen hundreds, like sixteen fifty three. But even in the US there had been outbreaks or at least individual cases of deer fly fever prior to

Francis's investigations in Ohio, Utah, California, probably other places. This was clearly not a disease that was new to humans,

nor was it limited to North America. After it came out that France Sola to Lorenzus can cause disease in humans, cases and outbreaks began to be reported all over the globe, from Japan, where in nineteen twenty six a widespread disease was linked to rabbits and concluded to be caused by Francisselo to Lorensis, to Russia, where four outbreaks between nineteen twenty six and nineteen twenty nine involving over eleven hundred

cases were determined to be Tularimia WOW. And in these outbreaks in Russia, flooding had driven water rats which I'm guessing our European water voles, which are actually voles but look like rats anyway, this flooding had driven them out of their holes, and the Russian government offered rewards for every skin to try to reduce their numbers, which led to a lot of exposure by killing all these rats.

We also see Tulurimia popping up in Turkey, Canada, Austria, Sweden, Italy and many other regions, and over time a pattern began to emerge and who was most likely to get infected basically people handling wildlife, hunters, trappers, cooks, agricultural workers,

and naturally. War similar to what I mentioned earlier in terms of an increased rat population following the nineteen o six San Francisco earthquake, War also created tremendous opportunities for francis Ela to Lorenzis to thrive, largely through increases in

rodent populations. For instance, during World War II in the Soviet Union, a huge amount of arable land was not cultivated harvests were delayed or destroyed, buildings were demolished, and poor sanitary conditions all resulted in a ton a ton of increased contact between humans and rodents, with an estimated sixty seven thousand cases between nineteen forty one and nineteen

forty two in just one region. What uh huh along the Eastern Front there may have been tens of thousands of Russian and German soldiers may also have been infected during the war, And because this is a pathogen that infects wildlife, the increase in human cases and rodent populations also meant that Francissela to lorensus subspecies Holarctica, of course became more established and disseminated in the environment, causing a

long term persistence in high case loads. Wow okay. I read in a paper that in the nineteen forties there were an estimated one hundred thousand cases annually of tulurimia in the Soviet Union. Ah yay yayeah. I know, I know it was and probably helped along by exposure roots like breathing in dust that had been contaminated by dead rodents or their poop, or contaminated water supplies like basically all the things that you would expect to see increase

during times of war. Fortunately, sanitary conditions improved in later decades. Plus there was that vaccine that was developed and was widely administered, like mass vaccination campaigns in the Soviet Union. I think sixty million people ended up getting vaccinated between nineteen forty six and nineteen sixty Wow. Yeah. And by the nineteen nineties, annual cases there had decreased to one hundred to four hundred Wow. Yeah, yeah, But I'm getting

ahead of myself there. The incredible increase in both the number of cases and the distribution of this pathogen prompted more research into Francisolo to lorensis throughout the nineteen thirties and nineteen forties. It's ecology, it's clinical picture, exposure roots, the role of arthropod vectors like tics, other animals that could infect, and so much more. And we are know from Francis's research in nineteen nineteen that this pathogen could be a dangerous one to work with. And so what

do you think happened? Once more and more bacteriologists turned their attention to it. Oh yeah, more and more cases among these researchers frances Solo tou Lorenzis had earned a reputation as a deadly microbe that was disturbingly difficult to avoid in lab settings, so much so that in some countries researchers just flat out refused to work with it. Other countries, however, saw a silver lining. Oh dear, The potential of Francislo to Lorenzis as a biological weapon working

in its favor are the following. There are seven, so buckle up. Number one it's highly infectious, like you said, as few as ten to one hundred bacteria and needed to cause disease. Number two it's easy to find in nature because of its wine distribution. Number three it's easy to make a lot of Number four it can be aerosolized very easily, as lawnmower associated outbreaks have shown. There were like started out on Martha's vineyard. There's been some

in Colorado, Like yeah, it's really horrible. Fine. Yeah. Number five it can spill back from humans into the environment and stay there for a long time, continuing to pop up. Number six. Only a few antibiotics work on it, and resistant strains could you know in theory be easily engineered.

And number seven, no vaccine is currently available. As early as World War Two, countries such as Japan, the US, the USSR, and probably many others devoted a lot of time and effort into determining whether or not Francissela to lorensis could be developed into a suitable biological weapon. And this wasn't the only pathogen considered, of course, but it was given really high priority for those reasons I mentioned. And some of this quote unquote research involved just straight

up torture, right injecting people with tulaimia. One of the most publicized was the horrific torture carried out by the Japanese Research Unit seven thirty one operating in Manchuria, and the US used human quote unquote volunteers in the nineteen fifties who were infected with Francissela tou loreensis using different exposure roots, especially aerosol, in different levels of bacteria. And so this is how we know that the infectious dose is ten to fifty.

case fatality rate, et cetera. And they estimated that if fifty kilograms of an antibiotic resistant strain of francissela to lorensis was released in a metropolitan area with a population of five million people, two hundred and fifty thousand individuals would become incapacitated and nineteen thousand would die. Yeah, and I say incapacitated just because, like you said earlier, Aarin, there's this really long period of recovery with relapses in

later months. And the CDC also performed its own cost estimate. I love that it's always cost always, which is, you know, equate human lives to monetary value. I mean, is that not America? Yeah, And in nineteen ninety seven dollars, they estimate that it would cost five point four billion dollars for every one hundred thousand people exposed in an aerosol attack. Ooh yeah, every Oh wow. I mean now that we are equating human lives with money, that's really expensive. Yeah, really expensive.

And although the US officially ended its bioweapon development program in the early nineteen seventies, research on antibiotic and vaccine resistant Francislo to lorensis as a bioweapon allegedly continued in the Soviet Union until the early nineteen nineties, although this has not been confirmed, but to this day, Francisla to Lorensis is on the very short list of Category A Select Agents by the CDC, which are organisms that quote pose a risked national security because they can be easily

disseminated or transmitted from person to person, result in high mortality rates, and have the potential for major public health impact, might cause public panic and social disruption, and require special action for public health preparedness. And it really is a very short list. Anthrax, bachelism, plague, smallpox, some viral hemorrhagic fevers, Ebola, Marburg, Lasa, machupo, and tularimia. That's it. That's it.

what can you tell me about Tulerymia today? Oh?

in Australia at least one time, I don't know. But throughout its range, tula Amia is generally considered an emerging or re emerging disease. That is that over the last twenty years, it's being found in expanded geographic ranges, popping up in places that we didn't know that it was, either because it wasn't there before or because we just hadn't found it there before. Hard to say which. It's being found in new hosts species same qualifiers. Was it just not there or had we.

common in rural areas of various countries. But it's not entirely clear what all of the different determining factors are that go into when you're going to have, say an epizootic outbreak in animals, or an epidemic in humans, or even sporadic cases. And part of that comes back to that we don't really know what the environmental reservoirs are, We don't really know what the conditions are that facilitate this spread per se.

and of vectors, ticks, flies, and mosquitoes. In most countries, such epidemiological investigations are not made currently since they are very time consuming and expensive.

do have, shall we. In the US, the most recent official like Morbidity Immortality Weekly report on this which sums up data from two thousand and one to twenty ten reported one thousand, two hundred and eight cases in the US in that time, so that's an average a median of about one hundred and twenty six cases per year. Now on the CDC website you can also find much more up to date data from every year since then. So from twenty ten to twenty twenty, the numbers seem

to have gone up again. I can't tell you if this is statistically significant because the reports are not out, but just the raw numbers that exist tell us that over the most recent ten years, the median number of cases is two hundred and fourteen compared to one twenty six the year before, and the range also is on the higher end, between one hundred and forty nine and three hundred and fourteen cases, so overall, greater numbers every year.

So this is part of what I mean when I say that this is an emerging and re emerging disease. We're seeing sporadic cases here and there in places where maybe it existed, but not necessarily to the extent that we see today or in some years.

either the World Health Organization or the ECDC. The majority of these were in Finland, Sweden, and Turkey, like the highest numbers overall. And then there's a more recent paper from twenty twenty one that reported that in that year, just over eight hundred cases of tularemia in humans were

reported across twenty six member countries. That was an increase over twenty twenty and an increase over the average of twenty seventeen to twenty nineteen, though in twenty nineteen there was a large outbreak in Sweden, so the total number that year was over twelve hundred. And then Aaron, just because you mentioned Russia so much, and those numbers back in the Soviet in the former Soviet Union, I did find one paper that reported in twenty nineteen only forty two cases reported in Russia.

et cetera, et cetera. But that's at least what we know of the epidemiology of tularemia across its distribution. I do think that one of the things that's most interesting scary about it is that we do seem to be seeing these increases, right, and how much of that is just better surveillance versus true increases.

There was a vaccine, it was a live vaccine, It was effective, It was based on the whole Arctica subspecies, but had at least some efficacy against the more virulent Toulurancis subspecies. But part of the reason that it was never fully licensed in the US, at least by the FDA, is in part because we did not and still don't understand the mechanisms by which this vaccine derived strain was

attenuated was made to be even less virulent. Ah, And because we didn't understand that, and we still don't really understand the virulence of this pathogen, how does it make us so sick. Why does this one make us so much sicker than the other. There's a lot of concern that this could easily revert to a more pathogenic strain.

So for longtime listeners, you might remember from our vaccines episode that there's a lot of different types of vaccines that exist, and there's pros and cons to all of these. With live vaccines, which are a live virus, these are a strain of virus that gives us a very robust immune response, really good usually long lasting immunity, but without

any illness, without a real infection per se. But with live vaccines, there's the possibility that these vaccine derived, attenuated, less virulent strains can gain some of those vrulance factors back and then actually cause disease. And we see this on occasion with things like the live polio vaccine, for example, and that's why across the globe, we really don't use

that vaccine in most of the world. Because polio is no longer in most of the world, the risk benefit analysis has changed, so we now use an inactivated, injected vaccine for most people that are getting vaccinated with polio.

When it comes to tularemia, the risk benefit analysis is already going to be very different because this is a rare disease, right, so the risk of using a live virus that has the potential to revert to something more virulent is already like that calculus is already different than something that's very prevalent. Does that make sense, Yes, yeah,

no it does. So there's a lot of research being done and in the US, especially since two thousand and one, when the anthrax letters came and were a thing and the fear of a bio weapon attack kind of increased again, there has been a ton of research on alternative vaccines, alternative live vaccines, killed vaccines, component vaccines, and all the different types of vaccines. For tulerimia, we still don't have one.

All of the other vaccine types so far just haven't come to fruition in a way that has led to a vaccine coming to market, essentially. But I do have a great paper. It's a little old now, it's from twenty fifteen, but it kind of goes over what we had so far and where we may go from here. But that's tulaimia.

called Tulaimia History, Epidemiology, pathogen Physiology and Clinical Manifestations. And for the bioweapon aspects of Tulerimia, there's a great paper by oystin at All from two thousand and four called Tularemia Bioterrorism Defense Renews Interest In Francisselo to Lorenzis, I read that paper too. I liked it a lot. Yeah.

its range. We'll post the sources from this episode every one of our episodes on our website This podcast will Kill You dot Com under the episodes tab.