Speaker 1: Ef Mail, age forty nine, physician, began investigations of tularemia
Speaker 1: in Delta, Utah, July twenty third, nineteen nineteen. His exposure
Speaker 1: differs from the other cases to be reported in that,
Speaker 1: in addition to exposure to laboratory animals, he took blood
Speaker 1: and puss on two occasions from a human case, which
Speaker 1: terminated fatally. On the thirtieth day of his investigation, August
Speaker 1: twenty third, nineteen nineteen, Ef became ill in the late afternoon,
Speaker 1: feeling tired and weak and having a temperature of one
Speaker 1: hundred two point two degrees. His fever continued until the
Speaker 1: twenty fourth day. During the first twelve days of his illness,
Speaker 1: he packed up his laboratory equipment and animals in Utah
Speaker 1: with great difficulty and proceeded with them to Washington, d c. And,
Speaker 1: after his arrival made a futile attempt to continue work.
Speaker 1: The next fourteen days he spent in the hospital, lying
Speaker 1: on the bed, but not confined to the bed. The
Speaker 1: departure of the patient from the hospital on the twenty
Speaker 1: eighth day was attended with some forced exercise, which resulted
Speaker 1: in a secondary rise of temperature which lasted four days
Speaker 1: after which it remained normal. The second month was spent
Speaker 1: in a hotel, lying on the bed most of the time.
Speaker 1: The third month was one of slow convalescence. Throughout the illness,
Speaker 1: there was an absence of localized pain or tenderness, except
Speaker 1: that on the sixteenth day of illness, a sore throat
Speaker 1: developed on the right side. Practically the only complaint was
Speaker 1: that of languor or weakness and a desire to remain
Speaker 1: quiet on the bed.
Speaker 2: Gosh, well, yeah, long, I know, it's such a long
Speaker 2: and then if you kept reading this paper, there were like, oh,
Speaker 2: and then when it recurred or whatever, relapsed or.
Speaker 3: I don't know what what the technical term is for it,
Speaker 3: for tularimia, but yeah. But the thing that I really
Speaker 3: like about this first hand account is that the initials
Speaker 3: e F that stands for Edward Francis as a Francis. Wow.
Speaker 3: Oh poor guy. I know, I know. And it took
Speaker 3: him like a long time, apparently, according to one paper
Speaker 3: I read to realize that this was tularimia, that what
Speaker 3: he was experiencing was tularimia. But then in retrospect, it
Speaker 3: was like, oh, yeah, and then he tested his blood
Speaker 3: and the blood of several other laboratory workers and found
Speaker 3: that indeed it was your toularimia. Oh my gosh. Yeah,
Speaker 3: so that was from a paper that he and a
Speaker 3: colleague wrote in nineteen twenty two. Wow. Yeah, Hi, I'm
Speaker 3: Aaron Welsh and I'm Erin Alman Updyke and this is
Speaker 3: this podcast Will Kill You.
Speaker 1: And today we're talking about tularimia.
Speaker 3: Yeah, this is kind of a classic one, I would say.
Speaker 3: My guess is that a lot of people have never
Speaker 3: heard of it, which is interesting because I knew the
Speaker 3: name tularimia and then I had this vague association with
Speaker 3: rabbits in my head and that was it. But there
Speaker 3: is so much more I know you this.
Speaker 1: And it's such a big name in terms of public
Speaker 1: health because it is, you know, a potential agent of
Speaker 1: bioterrorism and all. So yeah, it's it's very interesting that
Speaker 1: I also knew very little about it, and I think.
Speaker 3: There's probably a lot of people who've never even heard
Speaker 3: of it. Yeah, and by the end of this episode
Speaker 3: you'll be going, how did I not know about them?
Speaker 3: I hope? So that's the goal. Yeah, Okay, but let's
Speaker 3: let's get into the episode, you know, starting with quarantin
Speaker 3: any time, quarantine anytime. What are we drinking this week?
Speaker 1: We're drinking a drople do you We are.
Speaker 3: So named because the infectious dose is like ten to
Speaker 3: fifty individual bacteria. Yeah, ten bacteria. It's what It's scary,
Speaker 3: but the recipe is not. It is a very did
Speaker 3: you like that segue? Yeah? I sure did, A very
Speaker 3: delicious and fairly simple kind of take on a mohito
Speaker 3: with watermelon and of course mint and lime, a little
Speaker 3: bit of simple syrup and some vodka. This time instead
Speaker 3: of rum right, not change it up.
Speaker 1: We'll post the full recipe for that quarantini, as well
Speaker 1: as our non alcoholic plus se Brita on our website,
Speaker 1: This podcast will kill You dot com and our social media.
Speaker 3: I liked that, thanks, And on our website you can
Speaker 3: find all kinds of things, including, but not limited, certainly
Speaker 3: because I don't have the website in front of me,
Speaker 3: to things like our sources for each and every one
Speaker 3: of our episodes, our transcripts, our merch links, links to
Speaker 3: music by Bloodmobile, links to our bookshop, dot org affiliate account,
Speaker 3: our Goodreads list, Patreon, more stuff.
Speaker 1: Check it out, wonderfully, said Erin on that note, shall
Speaker 1: we get start.
Speaker 4: Let's do it right after this break.
Speaker 1: Franciscella tolerensis is a gram negative, facultatively intracellular Coxobacillus bacterium,
Speaker 1: and the causative agent, of course, of tulaimia. It turns
Speaker 1: out that there are four subspecies of Francessella tolerensis subspecies
Speaker 1: Toulrensis subspecies whole Arctica, media asiatica, and Novacida or Novasida.
Speaker 3: That one I saw sometimes put in its own species
Speaker 3: and sometimes a subspecies, and I was like, there's probably
Speaker 3: some drama behind this, but there is some drama.
Speaker 1: And from what I can tell, it was like in
Speaker 1: two thousand and six they made it a subspecies, and
Speaker 1: then twenty ten people were like, no way, it's its
Speaker 1: own species. But then after that they're like, nana, it's
Speaker 1: it's a subspecies. So that's how we'll call it. In
Speaker 1: any case, we're not going to talk about that one
Speaker 1: very much because it's only francis Ella to lorenzis subspecies Tularensis,
Speaker 1: which is endemic to North America that is the most
Speaker 1: virulent and the cause of the most severe disease, and
Speaker 1: Holarctica is found throughout Eurasia. And in North America, and
Speaker 1: is the other major subspecies of franciscella to lorenzis that
Speaker 1: causes disease in humans. So those are the two subspect
Speaker 1: that I'm going to be focused on. They're also sometimes
Speaker 1: called type A and type B in the literature, but realistically,
Speaker 1: I'm just going to be talking about francisselo toulorensis, or
Speaker 1: I might even just say tulaimia for the rest of
Speaker 1: this section.
Speaker 3: Sounds good, great, So, like we said at the.
Speaker 1: Top, erin I kind of knew that this was going
Speaker 1: to be an interesting episode because I at least knew
Speaker 1: that Tularemia was a potential agent of bioterrorism or a
Speaker 1: potential bioweapon. But as I often do with this podcast,
Speaker 1: I really underestimated just how interesting of a bacterium this is.
Speaker 3: We're always underestimating how you would think I'm going by. Now.
Speaker 1: Yeah, well let's get into it, shall we. So, like
Speaker 1: I said off the top, this is a facultatively intracellular bacterium.
Speaker 1: What that means is that it can live both freely
Speaker 1: in the environment as well as live in and replicate
Speaker 1: within other ie hosts cells. And we'll talk a little
Speaker 1: bit more about that what sells it's replicating in in detail,
Speaker 1: But as far as hosts go, this is a bacterium
Speaker 1: that can infect hundreds of animal species, mammals and birds
Speaker 1: and many different species of invertebrates which end up serving
Speaker 1: as arthropod vectors.
Speaker 3: It was giving me Shaga disease vibes in that.
Speaker 1: Regard, Yeah, totally, totally, But even shagas disease, it's mostly
Speaker 1: really just one vector, right, I mean exactly, yeah, multiple species,
Speaker 1: but on one vector.
Speaker 4: Yeah.
Speaker 3: I Meanwhile, to lorensis is just like anytime anywhere, anything,
Speaker 3: you know, let's make it happen.
Speaker 1: So I am going to focus on what the disease
Speaker 1: tulurimia looks like in humans and therefore how the life
Speaker 1: cycle ends up spilling over into human populations, how we
Speaker 1: get infected. But this is by no means primarily a
Speaker 1: disease humans. It's fortunately quite a rare disease of humans
Speaker 1: and primarily a zoonotic disease of many different wildlife species.
Speaker 1: And like we mentioned early on France, Assella is also
Speaker 1: highly infectious. So as I talk about how it gets
Speaker 1: into us and does all of these party tricks, keep
Speaker 1: in mind that as few as ten individual bacteria can
Speaker 1: cause infection in humans.
Speaker 3: Uh, did you just describe causing disease in humans as
Speaker 3: party tricks? Yes? Is that not a party trick for
Speaker 3: a bacteria? I guess technically, Yeah, look what I can do? Yeah,
Speaker 3: look at me, mom. You know.
Speaker 1: So, let's get into this nitty gritty of how this
Speaker 1: bacterium lives its life, how it infects ourselves, and what
Speaker 1: it actually looks like when we get sick to begin
Speaker 1: the life cycle of france Assella to lorensis. It's a
Speaker 1: little bit difficult because we don't fully know ecological niche
Speaker 1: of this bacterium at all. We don't know the major
Speaker 1: natural reservoir hosts or the major environments even that are
Speaker 1: conducive to the growth of this bacterium. And keep in mind,
Speaker 1: like I said, there are several different subspecies that can
Speaker 1: all persist in the environment and live intracellularly inside of
Speaker 1: host cells. Because it's a pretty difficult bacterium to grow
Speaker 1: in the lab in culture, there is some thought that
Speaker 1: perhaps in the environment it's not just persisting on its own,
Speaker 1: maybe it's in a host like an amiba or a protozoa.
Speaker 1: Who knows it's unclear, but it can infect and be
Speaker 1: a pathogen of a whole bunch of different animal species.
Speaker 1: One paper I read said over two fifty other papers
Speaker 1: said over one hundred and ninety, So like a lot
Speaker 1: of animals, a lot including mammals and birds and arthropods.
Speaker 3: Which is amazing. I like just the different Like how
Speaker 3: diverse the animal species are right, That this spacterium can infect.
Speaker 1: All of our different cell types, different immune systems that
Speaker 1: it's having to evade, it's really impressive. Yeah, when it
Speaker 1: comes to spillover from animals into humans, the two biggest
Speaker 1: groups of animals that are commonly found infected and thought
Speaker 1: to be kind of like the culprits of spillovers are lagomorphs,
Speaker 1: so rabbits and hares, and rodents, so things like mice
Speaker 1: and rats, but also prairie dogs, voles, even aquatic rodents
Speaker 1: like muskrats and beavers and things. And I had to
Speaker 1: look up to make sure that all of these things
Speaker 1: were really rodents. What a diverse group the rodents are, really, truly, Yeah,
Speaker 1: but in many of these species, this bacterium seems to
Speaker 1: cause an acute infection and make all of these animals
Speaker 1: quite sick. So it's perhaps less likely that any of
Speaker 1: these species that we commonly find Francissella toulrensis in are
Speaker 1: actually the natural reservoir host in the environment, So we
Speaker 1: don't really know. But then how do we actually get exposed?
Speaker 1: If these are the animals getting infected, we should at
Speaker 1: least have an answer for how humans get sick, And
Speaker 1: it turns out that that's more complicated too. Of course,
Speaker 1: it is like we alluded to already, Francissella toulrensis has
Speaker 1: been shown to be transmitted not by one or two
Speaker 1: or three, but many different arthropod vectors. And by that
Speaker 1: I mean it can be transmitted by ticks a whole
Speaker 1: bunch of different species, horse flies or to bannids a
Speaker 1: bunch of different species, and mosquitoes a whole bunch of
Speaker 1: different species.
Speaker 3: Normally, when we talk about.
Speaker 1: Vector borne diseases on this podcast, I have this whole
Speaker 1: section on the life cycle of the pathogen in the vector. Right,
Speaker 1: we go over, a mosquito sucks up can staminated blood.
Speaker 1: The pathogen travels through the guts, bursts out, goes to
Speaker 1: the salivary glands. The mosquito bites another host and injects
Speaker 1: the pathogen. Blah blah blah. That's how most vector born
Speaker 1: diseases work with whatever species or few species that are
Speaker 1: able to serve as vectors.
Speaker 3: But this is not that are there different vectorial capabilities
Speaker 3: among these different vector species? Like are some mosquitoes better
Speaker 3: than others? I'm sure that there are probably differences between
Speaker 3: the two subspecies of Tularensis of human health importance. Yeah, yeah,
Speaker 3: great question. Who knows.
Speaker 1: So Different geographical regions do have different arthropods that seem
Speaker 1: to serve as the primary vector. For example, in Russia
Speaker 1: and Finland and Sweden it's mostly various species of mosquito.
Speaker 1: Throughout most the rest of Europe it's thought to be
Speaker 1: primarily tabanids, so horseflies and ticks, and in the US
Speaker 1: there are a few species of tick and tabanids that
Speaker 1: seem to be the primary vectors. It's not strictly based
Speaker 1: on just which subspecies of franciscella to Lorenzis we're talking about,
Speaker 1: since in Europe we really only see subspecies Holarctica. And
Speaker 1: North America we see both Holarctica and Toulrensis, as well
Speaker 1: as a little bit of the other ones that are
Speaker 1: less important for human infections. But what's really interesting is
Speaker 1: that when it comes to the life cycle of Francissella
Speaker 1: in these arthropods. From one paper that I read, they
Speaker 1: noted that it has never been demonstrated that this bacterium
Speaker 1: is found in the salivary glands of any arthropod, and
Speaker 1: so it's thought that maybe the spread is just mechanical.
Speaker 1: You have mouth parts becoming infected when a fly or
Speaker 1: a mosquito bites, but ticks are found infected throughout their
Speaker 1: life cycle. So if a tick gets infected as a larva,
Speaker 1: they remain infected as they become a nymph and an adult,
Speaker 1: et cetera. And we really have very little data on
Speaker 1: what is going on in these ticks, which ticks are
Speaker 1: really the best vectors, and all of that we just
Speaker 1: simply don't know. Because here's the thing, transmission doesn't stop there.
Speaker 1: Vector born transmission is one way that people can become infected,
Speaker 1: but human infection with tulurimia is also associated with waterborne
Speaker 1: transmission from contaminated water sources, and perhaps the scariest and
Speaker 1: most severe possible route of transmission is aerosolized bacteria that
Speaker 1: we inhale, and this can come from contaminated soil or grasses,
Speaker 1: or even directly from animal carcasses that were infected it themselves.
Speaker 1: This is the way that makes francissela to lorensis a
Speaker 1: potential bioweapon agent that combined with the very low infectious dose.
Speaker 3: Right, do we know how long francisla to lorensis is?
Speaker 4: Like?
Speaker 3: How durable is it in the environment?
Speaker 1: Excellent question. It's been isolated. I love when you ask
Speaker 1: a question that I actually have the answer.
Speaker 3: For it right away.
Speaker 1: It's like that rarely happens, So love it. It's been
Speaker 1: isolated from water and mud that has been stored like
Speaker 1: in laboratory conditions in a fridge, nice and cold, for
Speaker 1: up to fourteen weeks, so pretty long time.
Speaker 3: Yeah, it's been.
Speaker 1: Isolated from tap water after three months and then in
Speaker 1: like dry straw.
Speaker 3: For six months. My it's a long time.
Speaker 1: It's unclear how long it might persist under real environmental conditions,
Speaker 1: like not ideal conditions, especially in the world health organizations.
Speaker 1: Estimates of what would happen in the case of a
Speaker 1: bioterrorism attack where you're just aerosolizing dried bacteria and spreading it,
Speaker 1: then you'd probably have a lot more like UV decay,
Speaker 1: and things wouldn't probably persist quite as long, is the thought.
Speaker 3: Hmmmm, we don't know really, So that is that is
Speaker 3: definitely an interesting thing in the column of mechanical transmission
Speaker 3: for non tick arthropod vectors.
Speaker 1: Yeah, it's maybe. There's also been suggested that maybe it's
Speaker 1: water that becomes contaminated and that's a reservoir where flies
Speaker 1: and especially mosquitoes during their larval stage could become infected,
Speaker 1: so not necessarily from.
Speaker 3: Biting a host.
Speaker 1: But we really just don't know, and so there's a
Speaker 1: lot of these different theories.
Speaker 3: What route of transmission is the most common or like
Speaker 3: how does that how is that pie sliced? That's such
Speaker 3: a good question.
Speaker 1: I don't really know because surprisingly the epidemiological data that
Speaker 1: I found didn't really break out infections by different type.
Speaker 1: As we'll see, there's different symptoms that you see depending
Speaker 1: on the root of transmission. One paper that I read
Speaker 1: suggested that the form that you see after vectoral transmission,
Speaker 1: or like direct contact with a mucous membrane or like
Speaker 1: a wound, say, which would be a very similar route
Speaker 1: of transmission from like an infected animal through the skin
Speaker 1: through a break in the skin, that that might account
Speaker 1: for up to ninety percent of cases, but I didn't
Speaker 1: see that number reported in very many papers, so.
Speaker 3: I'm not sure. Interesting.
Speaker 1: Yep, Honestly, almost the only way that this is not transmitted,
Speaker 1: and this is a good thing, is directly person to person.
Speaker 1: So human to human transmission is incredibly rare, if not
Speaker 1: entirely non existent, which is very good.
Speaker 3: Yeah.
Speaker 1: Yeah, imagine it would be terrifying, absolutely terrifying. So once
Speaker 1: we are exposed again to even incredibly low bacterial lodes.
Speaker 1: Francissella tularensis exists mostly intracellularly, and it predominantly infects our macrophages,
Speaker 1: which are white blood cells. But it is capable of
Speaker 1: infecting a really wide range of cell types, both in
Speaker 1: animals as well as in humans, which kind of makes
Speaker 1: sense when we think about just how many animals it's
Speaker 1: infecting overall. It's just really versatile.
Speaker 3: Yeah, but like, how like how is it so good
Speaker 3: at doing this when then most other bacteria are not. Yeah,
Speaker 3: great question. Do you want to guess my answer? We
Speaker 3: don't know. We know some things, Okay.
Speaker 1: Part of what they do is they disrupt what's called
Speaker 1: the phagosome. And so this is when something like a macrophage,
Speaker 1: especially in gulfs, a bacterium in order to try and
Speaker 1: you know, our immune response get rid of these bacteria
Speaker 1: or other substances that are potentially pathogenic or just non
Speaker 1: self they form this structure called the phagosome. It's just
Speaker 1: like phase means eat, right. So what franciscella to lorensis
Speaker 1: is able to do is kind of like stabilize this
Speaker 1: phagosome initially prevent it from doing its normal thing of
Speaker 1: killing those bacteria, and then escape and replicate in the cytoplasm.
Speaker 1: While we don't fully understand all the mechanisms by which
Speaker 1: they do this, it's not entirely uncommon compared to other
Speaker 1: intracellular bacteria. A lot of other intracellular bacteria are able
Speaker 1: to do kind of similar things.
Speaker 3: One thing that's.
Speaker 1: Interesting and cool about Francescella to lorensis is that after
Speaker 1: they've you know, burst out of the fagosome replicated a
Speaker 1: whole bunch in the cytoplasm, they then induce apoptosis aka
Speaker 1: cell death in the cells that they've infected, which allows
Speaker 1: for them to be released go throughout the body and
Speaker 1: infect for their cells virus style exactly, and the exact
Speaker 1: mechanism by which they induce this cell death we don't know,
Speaker 1: but it does seem to be unique to francissella to lorensis,
Speaker 1: meaning it's a different method than other intracellular pathogens like Coxiella, legionella, salmonella.
Speaker 3: Et cetera.
Speaker 1: So yeah, we don't fully understand, and that actually continues
Speaker 1: in terms of we don't fully understand our immune response
Speaker 1: to this pathogen either, which then has implications for our
Speaker 1: development of things like vaccines.
Speaker 3: Dark Dawn question. Answer, maybe, if you become infected with
Speaker 3: one of these subspecies, do you then have immunity to
Speaker 3: the second subspecies or to reinfection with the first.
Speaker 1: It's a good question. I don't know the direct answer
Speaker 1: to that. What I can tell you is that the
Speaker 1: initial vaccines that were developed were based on the subspecies Holarctica. Yeah,
Speaker 1: and they provided at least some protection against the Toularensis subspecies,
Speaker 1: which is of course the more virulent subspecies and the
Speaker 1: one that people really wanted to be able to develop
Speaker 1: a vaccine against.
Speaker 3: Yeah.
Speaker 1: So yes, at least some how long does that immunity persist?
Speaker 3: Unclear?
Speaker 1: And that's been one of the big issues is trying
Speaker 1: to develop a vaccine that really does a good job
Speaker 1: of protecting against Tularensis subspecies toulorensis rather than just wlearctica.
Speaker 1: And in the past the vaccines that have been developed
Speaker 1: have been mostly based on Holarctica because it's safer to
Speaker 1: work with, because it's less pathogenic. Right, Okay, gotcha, So yeah,
Speaker 1: that's what it's doing. Let's get to what does this
Speaker 1: illness actually look like? What is tulaimia?
Speaker 3: Right? In general?
Speaker 1: After exposure, the incubation period initially is about three to
Speaker 1: five days. Symptoms often start with a fever, oh and
Speaker 1: then some nonspecific symptoms like chills, malaise, headache. But there
Speaker 1: are multiple different forms of this disease that vary based
Speaker 1: on the root of transmission. So in addition to just
Speaker 1: nonspecific symptoms, let's look at all of the different kind
Speaker 1: of types of tulaimia. The first, and what like I mentioned,
Speaker 1: is in some papers at least reported as the most common,
Speaker 1: like up to ninety percent of cases, is called the
Speaker 1: ulcero glandular form, or less commonly, there can be a
Speaker 1: glandular form without the ulcer at the beginning, What does
Speaker 1: this mean. This happens with vector borne transmission, so from
Speaker 1: a tick or a mosquito or a fly that bit
Speaker 1: you on your skin somewhere, or from direct contact with
Speaker 1: an infected animal with like a break in the skin.
Speaker 1: What you see with this form of tuluremia is at
Speaker 1: the sight of the bite or the infection an ulcer.
Speaker 1: So it usually starts as a papule like a little
Speaker 1: bump that then progresses to a pustule like a blister
Speaker 1: with pus in it that looks inflamed, maybe warm, maybe tender,
Speaker 1: and can often kind of open to form this open ulcer.
Speaker 1: It might just look like a bug bite. It might
Speaker 1: not be that gnarly looking of an ulcer, and it
Speaker 1: usually heals within a week or so. But if it does,
Speaker 1: then what that means is that this infection has spread
Speaker 1: to the lymph nodes nearest the bite, which will then
Speaker 1: start to get enlarged. That's the glandular part of the name.
Speaker 1: These lymph nodes will get swollen and tender, and if
Speaker 1: this infection becomes severe, you can have such severe swelling
Speaker 1: of these lymph nodes that they actually begin to drain
Speaker 1: pus from the lymph nodes to the skin, which is
Speaker 1: very very serious.
Speaker 3: It sounds so painful, I know.
Speaker 1: And on top of that, you're having these systemic symptoms
Speaker 1: right like just fever and chills and feeling very sick.
Speaker 1: In general, that's the ulcero glandular or in rarer cases
Speaker 1: you can have just the lymph nodes without that ulcer
Speaker 1: to begin with. Then there's the respiratory form respiratory meaning
Speaker 1: that most commonly you have inhaled and aerosolized bacteria, which
Speaker 1: is often happening from farming activities where hay or grasses
Speaker 1: or something are mode or dealt with, or from hunting
Speaker 1: activities where you're dealing with carcasses and maybe aerosolizing something
Speaker 1: from a carcass. Now, if you have a respiratory infection
Speaker 1: from Francissela Toulurance's subspecies whole Arctica, usually it's a pretty
Speaker 1: mild flu like nonspecific respiratory illness, but with subspecies tolurensis
Speaker 1: what we see are those fevers, chills, add on a cough,
Speaker 1: very severe chest pain. It can progress then to hemoptosis,
Speaker 1: so that's coughing up of blood. You might also see
Speaker 1: even more systemic symptoms like nausea and vomiting diarrhea. So
Speaker 1: this like GI tract becoming involved commonly. One thing that
Speaker 1: we see is what's called pulse temperature dissociation, which is
Speaker 1: something we talked about way way, way way back.
Speaker 3: I was like, this sounds familiar. What yeah, what episode?
Speaker 3: I can't remember? And I was going to try and
Speaker 3: look through, but it would have taken a long time
Speaker 3: because we covered dengay, legionella, leptosporosis, leshmanisis, typhoid, yellow fever.
Speaker 3: All of those can do this. Maybe it was typhoid
Speaker 3: because that's pretty classic, or maybe dengay. Okay, but what
Speaker 3: does that mean? Yeah, So a typical physiologic response to
Speaker 3: fever when anyone has a fever is that our pulse
Speaker 3: will increase. So as our body temperature increases, our pulse increases.
Speaker 3: That is a typical physiologic response. So what a pulse
Speaker 3: temperature dissociation means is that you see a relative bratacardia,
Speaker 3: meaning your heart rate in comparison to your temperature is low.
Speaker 3: Our pulse does not increase in compared to our temperature.
Speaker 3: So here's slow. It's not that the pulse actually decreases.
Speaker 3: That is fascinating. I want to know so much more
Speaker 3: about this.
Speaker 1: Yeah, I know nothing more unclear what.
Speaker 3: The cause is. Okay, so we don't understand how this works.
Speaker 3: But what are the implications of.
Speaker 1: This, great question. Part of the implication is just that
Speaker 1: it gives clinicians a sign to think there's only a
Speaker 1: few pathogens that tend to cause this, so it can
Speaker 1: help narrow down a diagnosis in terms of what is
Speaker 1: this doing in our bodies. It's kind of a little
Speaker 1: bit unclear, but probably not a good sign because what
Speaker 1: it means is that this infection has significantly altered the
Speaker 1: way that our physiology responds to infection and has disrupted
Speaker 1: that process. So like, what does that mean? It means
Speaker 1: that we're our body is not working the way that it.
Speaker 3: Is supposed to.
Speaker 1: So we can see this in up to forty two
Speaker 1: percent of cases with respiratory tulerremia, and the case fatality
Speaker 1: rate of respiratory tularemia if left untreated, can be upwards
Speaker 1: of thirty percent, and so it kind of tracks that
Speaker 1: this is a sign of a pretty severe infection.
Speaker 3: It is fascinating how differently this infection can manifest based
Speaker 3: on how you get exposed.
Speaker 1: Yeah, and there are a few other forms as well, because,
Speaker 1: like we mentioned, there's a few other possible roots of exposure.
Speaker 1: When people are infected from contaminated water sources, it can
Speaker 1: cause like an oropharyngeal infection, so more of like a
Speaker 1: mouth and throat infection and a GI infection nausea vomiting
Speaker 1: as the primary symptoms, and it can also cause an
Speaker 1: oculo glandular infection if the eye is the first root
Speaker 1: of entry, right, a mucous membrane, which then leads to
Speaker 1: a conjunct dividis, so infection of the eye and drainage
Speaker 1: from the eye and then the lymph nodes where your
Speaker 1: eye drains. All of these different forms, while they are
Speaker 1: very different, especially initially, can then lead to a systemic
Speaker 1: bloodborne infection which can then lead to sepsis and septic
Speaker 1: shock and death.
Speaker 3: So the difference in severity between the two subspecies to
Speaker 3: Lorensis and Holarctica is that due to which type of
Speaker 3: infection they are most likely to cause, or is it
Speaker 3: just like the damage that's done or the likelihood of
Speaker 3: that turning into a blood infection, Like where does that
Speaker 3: difference come into play?
Speaker 1: That is one big question that especially vaccine researchers and
Speaker 1: things are trying to answer. We don't fully know what
Speaker 1: these virulence factors are and what the big determining factors
Speaker 1: are on why subspecies Tolurensis is so much more virulent
Speaker 1: than subspecies Holarctica. We don't really know both of them
Speaker 1: can cause all of these different types of infection, and
Speaker 1: I don't have enough data to be able to say,
Speaker 1: like Holarctica is much more likely to cause X than Y,
Speaker 1: except that overall Holarctica causes much less severe disease right
Speaker 1: compared to Tolurensis.
Speaker 3: So that's a lot.
Speaker 1: When it comes to animals, by the way, because I
Speaker 1: mentioned a lot of the species that we associate with
Speaker 1: Tulerimia actually get quite sick from this pathogen, and in
Speaker 1: a lot of cases, Tulimia has a pretty high mortality
Speaker 1: rate in animals like rabbits and rodents and things.
Speaker 3: But the symptoms of this are.
Speaker 1: Going to vary so much by different animal species that
Speaker 1: I'm not going to go into detail on all of them.
Speaker 1: But in general, it's not super similar to humans in
Speaker 1: that there's a lot of fevers, there's a lot of lethargy.
Speaker 1: It can be kind of a long infection, and again
Speaker 1: there's a potentially pretty high mortality rate.
Speaker 3: What about our domestic animals. We've talked a lot about wildlife,
Speaker 3: but are cats, dogs, horses, cows, gerbils? Obviously gerbils, yes,
Speaker 3: but when would a gerbil encounter a wild animal to
Speaker 3: get to lurimia. I really can't think of any other
Speaker 3: domestic animals tortoises like, I don't.
Speaker 1: I never saw reptiles listed, so I don't know about that.
Speaker 1: Cats and dogs, yes, Cats far more likely to become
Speaker 1: infected and get sick compared to dogs. Dogs get a
Speaker 1: lot less sick from tulurimia. And then among livestock, I
Speaker 1: think it was sheep that tend that tend to get
Speaker 1: the most sick of all of our livestock species.
Speaker 3: Okay, yeah, huh yeah, yeah.
Speaker 1: But all of them potentially can get infected. It's just
Speaker 1: a matter of how they get. The good news is
Speaker 1: that so far at least antibiotics still work.
Speaker 3: That's good. That's good.
Speaker 1: That's good, But it can sometimes take prolonged courses of treatment.
Speaker 1: I didn't get into detail on this, but like was
Speaker 1: kind of mentioned in the first hand account. This is
Speaker 1: something that, even if it's not fatal, can cause a
Speaker 1: very prolonged illness that can also result in relapses where
Speaker 1: people become sick kind of again, like get better and
Speaker 1: then get sick again. I didn't look into detail in this.
Speaker 1: It didn't come up a lot in the papers that
Speaker 1: I read. It mostly was a side note, which is
Speaker 1: wid It's a side note for me here. But I'm
Speaker 1: sure that there's some very interesting research in terms of
Speaker 1: the immune response and why this is possible. Right, Is
Speaker 1: it because it's hang out in our immune cells, it's
Speaker 1: infecting a lot of our white blood cells. Does it
Speaker 1: hide in our spleen or our liver?
Speaker 3: What's going on? I don't know, but it's interesting, it
Speaker 3: is and terrifying. Yeah. I feel like there are so
Speaker 3: many questions I have about like how does it do this? Yeah,
Speaker 3: and I think the intracellular part of it is always
Speaker 3: something that's just like so fascinating.
Speaker 1: Yeah, it's obviously it's a huge part of the story
Speaker 1: of tulaimia, right, especially in that it's doing this living
Speaker 1: inside of cells in so many different species right across
Speaker 1: the entire animal kingdom. It's phenomenal. Yeah, But that is
Speaker 1: the biology of tularemia. So tell me, Aaron, how did
Speaker 1: we get here, Where did it come from?
Speaker 3: What's the deal? Uh? Yeah, let's go through whatever I
Speaker 3: have right after this break. Chances are if you skim
Speaker 3: a scientific article about tularimia or Francessella tolreensis published between say,
Speaker 3: the nineteen thirties and the nineteen seventies or so, you're
Speaker 3: likely to come across some reference to this disease being
Speaker 3: quote unquote an American disease or something to that effect. Ooh.
Speaker 3: From a paper by Walter Simpson published in nineteen twenty eight,
Speaker 3: quote The history of Tullerimia makes fascinating study. It is
Speaker 3: in every respect the first American disease. The physicians of
Speaker 3: this country should be thrilled by the thought that not
Speaker 3: only was this disease discovered by American investigators, but also
Speaker 3: because it's specific ideologic agent, the determination of its modes
Speaker 3: of transmission from animal to animal and from animal to man,
Speaker 3: the descriptions of its clinical manifestations, and its pathology and
Speaker 3: bacteriology were made known by American workers and leading all as.
Speaker 3: The guiding spirit which has made this accomplishment possible is
Speaker 3: Edward Francis of the United States Public Health Service. It's
Speaker 3: a very long quote to kind of kick this off,
Speaker 3: but I feel like whip that kind of sums it up.
Speaker 3: But yeah, this designation of Tulaimia as an American disease,
Speaker 3: first of all, I just find really interesting because I
Speaker 3: don't think that we've come across that before. It's like
Speaker 3: extreme patriotism about a particular disease. Usually it's like more
Speaker 3: like racism about disease or something. Right to like claim it,
Speaker 3: like this one's ours. That's great, right, we stake ourklame. Yeah, yeah, yeah, this,
Speaker 3: but this designation as an American disease would stick with
Speaker 3: Tularimia for a really long time, like long after the bacterium,
Speaker 3: or at least subspecies of this bacterium had been found
Speaker 3: to be globally distributed. But did france Ascella to lorensis
Speaker 3: originate in North America? Hm? Honestly, I have no idea,
Speaker 3: but yeah, we don't fully understand. But yeah, there's like
Speaker 3: quite a bit of really interesting and thorough research on
Speaker 3: the evolutionary relationships among Francissella toulorensis subspecies and with other
Speaker 3: francissella species and like the virulence genes potentially, and when
Speaker 3: it acquired them and when it lost them, and all
Speaker 3: of that cool stuff. But there doesn't seem to be
Speaker 3: a whole lot of consensus on which subspecies came first
Speaker 3: and from where especially, And it's no wonder because the
Speaker 3: ecologies of these bacteria are so different and their distribution
Speaker 3: is so wide ranging. Honestly, it's amazing that anyone has
Speaker 3: been able to make any sense out of it at all.
Speaker 3: So this is what we think we do know about
Speaker 3: the two main subspecies that cause disease in humans. Like
Speaker 3: you said, Aaron Francissella to Lorensis subspecies Tolreensis is the
Speaker 3: big battie, can cause very deadly disease with vast vasus
Speaker 3: vast majority of samples found in North America, with one exception.
Speaker 3: In nineteen ninety eight, a paper reported that two isolates
Speaker 3: of this deadly too Lorensis subspecies were found in Slovakia
Speaker 3: near Broadislava. Huh, isn't that interesting? Yeah? And like, as
Speaker 3: far as I could tell, that's been the only instance
Speaker 3: of this subspecies found outside of North America. And how
Speaker 3: it got there and what it means is still a mystery.
Speaker 3: Where was it? Like, what kind of sample? That's a
Speaker 3: good question. I don't remember. Interesting, Yeah, but the paper
Speaker 3: will be on our website. Okay, so if you want
Speaker 3: to check it out. But the other subspecies of human
Speaker 3: health importance again, like you mentioned aaron subspecies whole Arctica
Speaker 3: that's been found throughout the northern hemisphere, and so I
Speaker 3: feel like if you had to guess which came first,
Speaker 3: you might be more inclined to guess the one that
Speaker 3: is globally distributed. But in fact, most papers think that
Speaker 3: the Toularensis subspecies, the one only found in North America asterisk,
Speaker 3: is actually older and that the whole Arctica species evolved
Speaker 3: from it. And researchers think this because of the genetic
Speaker 3: diversity of the two subspecies. Toulorensis is much more diverse
Speaker 3: than the whole Arctica they've tested, and in fact, whole
Speaker 3: Arctica is so unexpectedly not diverse that they think there
Speaker 3: was some sort of bottleneck event that was just like, okay,
Speaker 3: everyone is now the same, the same. Yeah, that is interesting.
Speaker 3: But the bottom line, and what nearly everyone of these
Speaker 3: papers ends with, and rightly so, is that there's a
Speaker 3: whole lot more Francissella to Lorenzis diversity out there, just
Speaker 3: waiting to be explored, and so this story will probably change,
Speaker 3: or at least more details will emerge as that research
Speaker 3: is done. So we don't know where in the world
Speaker 3: Francesella Tolrenzis first emerged, nor do we know when in
Speaker 3: history or prehistory this pathogen, these pathogens first made their appearance,
Speaker 3: or at least I didn't find it in the papers
Speaker 3: that I read. But as I was hunting for papers
Speaker 3: on Google Scholar, I came across at least three papers
Speaker 3: proposing that Francis sello to lorensis was the causative organism
Speaker 3: for several different ancient plagues. Each paper went into a
Speaker 3: particular plague. All of the papers were by the same
Speaker 3: individual author, and all were published in the same journal
Speaker 3: Medical Hypotheses. And these were like wide ranging plagues. Make
Speaker 3: that point, okay, So that right away kind of stuck
Speaker 3: out as a little suspicious but interesting enough to look into,
Speaker 3: and so I started to skim these papers, and the
Speaker 3: biology proposed in them didn't really make much sense at
Speaker 3: least as far as what we know about to lorensis.
Speaker 3: So then I was like, Okay, what's going on with
Speaker 3: the strejournal? So I googled. It turns out that it
Speaker 3: uses quote unquote unconventional peer review, which I looked into
Speaker 3: it more. It isn't very rigorous, which is intended to
Speaker 3: be that way because they're publishing the papers that no
Speaker 3: one else will publish, and it has been known to
Speaker 3: publish articles denying aids, as well as articles on other
Speaker 3: horribly offensive and completely nonfactual topics. So I dug a
Speaker 3: little bit deeper to see if I could find any
Speaker 3: other mention of tulaimia and the hit type plague, which
Speaker 3: is the subject of one of these papers, and I
Speaker 3: found an amazing book chapter called Beyond the Differential Diagnosis,
Speaker 3: New Approaches to the Bioarchaeology of the Hit Type Plague
Speaker 3: by Smith, Guzman, Rose, and Cufkins. I'll put it on
Speaker 3: our sources on our website, but anyway, I came across
Speaker 3: this chapter because it mentioned that the tulaimia hypothesis had
Speaker 3: been disregarded because of a lack of biological plausibility, and
Speaker 3: then I kept reading because it provided this amazing eleven
Speaker 3: step like step by step discussion of how you could
Speaker 3: incorporate so many different and varied methods to arrive at
Speaker 3: a likely causative agent for ancient epidemics, which often have
Speaker 3: very limited physical evidence. By the way, they concluded that
Speaker 3: malaria was a likely culprit for the hit type plague.
Speaker 3: So this was kind of a long detour with like
Speaker 3: not very much meat to it, but I really wanted
Speaker 3: to include it because I feel like it illustrates how
Speaker 3: hard it can be sometimes to tell whether something is
Speaker 3: a legitimate source or not. Like you can find these
Speaker 3: papers on PubMed and on the National Library of Medicine
Speaker 3: Journal Archive, like it's on Google scholar, right, So just
Speaker 3: because it's on Google scholar, it doesn't mean it's necessarily
Speaker 3: legitimate or you know, just like ah, it just shows
Speaker 3: how crucial it is to keep doing that little bit
Speaker 3: of extra digging to help you decide if something is
Speaker 3: a good source. So keep going down that rabbit hole
Speaker 3: because at the end of it, you'll get better at
Speaker 3: spotting these crappy sources and you get to appreciate the
Speaker 3: good ones and hopefully not get toulurinia but get it home. Sorry.
Speaker 1: Wow, I'm so sorry. I'm so sorry. Moving on, but
Speaker 1: I agree one.
Speaker 3: Yeah, it was kind of like a nice refresher of
Speaker 3: oh yeah, okay, stuff like this is, you know anyway.
Speaker 3: So that's all I've got for tularimia in ancient times,
Speaker 3: which isn't really anything at all, turns out, So instead,
Speaker 3: let's move on to the discovery phase of this disease.
Speaker 3: What the story begins with the night teen six San
Speaker 3: Francisco earthquake, or rather the fallout from it. Not what
Speaker 3: you were expecting, not at all. Yeah, to call this
Speaker 3: earthquake devastating would be an incredible understatement. An estimated eighty
Speaker 3: percent of the city was destroyed and two hundred and
Speaker 3: fifty thousand people were left without a place to live.
Speaker 3: As listeners of this podcast are probably well aware, these
Speaker 3: types of conditions are perfect for diseases to break out
Speaker 3: and just spread like wildfire. Since about nineteen hundred or
Speaker 3: so before the earthquake, San Francisco had been battling bubonic
Speaker 3: plague and things were just starting to seem under control
Speaker 3: when the earthquake struck. Soon after the earthquake, rats swarmed
Speaker 3: the wrecked city, sparking this renewed fear of this deadly disease.
Speaker 3: And there is a lot more to the story of
Speaker 3: rats and bubonic plague and racism and discrimination in San
Speaker 3: Francisco that I'm not going to get into in this episode.
Speaker 3: But one of the things that came out of this
Speaker 3: thread of plague after the earthquake was the push for
Speaker 3: more research on the ecology of this disease of bubonic plague.
Speaker 3: So the director of the US Public Health Service Plague Lab,
Speaker 3: George McCoy, decided to investigate some of the reservoir animals
Speaker 3: for plague in North America, particularly ground squirrels, curious whether
Speaker 3: the plague bacteria they harbored was in any way different
Speaker 3: from those in rats. So to answer this, he went
Speaker 3: out trapping in Tulare County, California. At this point, the
Speaker 3: causative agent of bubonic plague, your sinnea pestis, had already
Speaker 3: been described, but McCoy was having trouble isolating this bacterium
Speaker 3: from some of his ground squirrel samples, even though they
Speaker 3: had symptoms of PLAGUEO like these, soulen lymphnos like lesions
Speaker 3: like yeah and so Eventually, after tinkering with the culture
Speaker 3: media recipe, McCoy and his colleague Charles Chapin were able
Speaker 3: to isolate a new microbe from the squirrels, which they
Speaker 3: named Bacterium to Lorentz after Tulare County. Wow. Eight years later,
Speaker 3: in nineteen nineteen, a researcher at the US Public Health
Speaker 3: Service named Edward Francis was sent out on his first
Speaker 3: field assignment to study an outbreak of something called deerfly
Speaker 3: fever in an area of rural Utah. Frances set to
Speaker 3: examining each person who was sick, taking samples from them,
Speaker 3: trying to grow microbes from the samples to figure out
Speaker 3: what was making them sick. And it didn't take him
Speaker 3: too long to figure out that the likely causative agent
Speaker 3: was Bacterium to lorentz. So he called the disease toulerimia. Wow.
Speaker 3: So forward, Yeah, well, yeah, I mean there also was
Speaker 3: a little bit of this unfortunate situation where Francis got
Speaker 3: to know the bug all too well. Yeah, he picked
Speaker 3: up tulaimia from someone who later died of tularimia, and
Speaker 3: you know the rest from the first hand account. But
Speaker 3: his illness, Francis's illness kicked off what would be an
Speaker 3: unlucky trend among tulerimia researchers, and many of them would
Speaker 3: get sick with the thing that they were studying over
Speaker 3: the next years decades. Really, so I want to read
Speaker 3: you a quote from the same paper describing Francis's illness. Quote.
Speaker 3: All of the men six in number who have been
Speaker 3: intimately connected during the past two years with the laboratory
Speaker 3: investigations of tulerimia which the Public Health Service has been conducting,
Speaker 3: have contracted this disease. Such a record of morbidity among
Speaker 3: investigators of a disease is probably unique in the history
Speaker 3: experimental medicine. Fortunately there were no fatalities end quote. Wow. Yeah.
Speaker 3: And then this paper goes on to describe how some
Speaker 3: of these researchers that got to lurehemia had worked with
Speaker 3: deadly pathogens for decades and knew all of the PPE
Speaker 3: tricks and whatever. Some of them worked under rougher conditions
Speaker 3: in terms of like a field lab, and others were
Speaker 3: working in like state of the art labs, and still
Speaker 3: they got sick. Which, yeah, it's just so infectious. Yes,
Speaker 3: you can take as many precautions and still there's like
Speaker 3: such a high risk of getting sick.
Speaker 1: I read it's also especially in laboratory conditions because even
Speaker 1: just opening the culture flask, you're potentially aerosolizing things.
Speaker 3: So yeah, yeah, yeah, yeah, yeah, it's impressive and terrifying. Yeah. So,
Speaker 3: at some point between taking all of these samples and
Speaker 3: recovering from Tulerimia, frances had also carried out extensive testing
Speaker 3: to try to figure out where this bacterium was hiding
Speaker 3: out in nature and how humans got exposed to it, which,
Speaker 3: as we learned, is like a number of ways, so
Speaker 3: not a simple answer. Yeah, Francis isolated the bacterium from
Speaker 3: jack rabbits and ground squirrels, and also showed that deer flies, mouselice,
Speaker 3: and bedbugs could play a role in transmission to humans.
Speaker 3: His extensive and groundbreaking work on the disease would later
Speaker 3: inspire the genus name to be changed to Francis Sella
Speaker 3: Ah love that. Yeah. But the cases of deer fly
Speaker 3: fever that Francis was sent to investigate in nineteen nineteen
Speaker 3: didn't mark the very first outbreak of Tullerimia in humans,
Speaker 3: of course, because, as is so often the case, once
Speaker 3: Francis and his colleagues published their findings, other likely past
Speaker 3: cases or past outbreaks of this disease came to light.
Speaker 3: The oldest of these dates back to eighteen eighteen and
Speaker 3: comes from Japan, a disease named Yato bio hair disease
Speaker 3: that appeared in people who had handled rabbit meat. In
Speaker 3: the eighteen nineties, in Norway, an illness called lemming fever
Speaker 3: was described, And this is maybe a stretch, but there's
Speaker 3: also a description of a tularemia like disease in lemmings
Speaker 3: in Norway from the sixteen hundreds, like sixteen fifty three.
Speaker 3: But even in the US there had been outbreaks or
Speaker 3: at least individual cases of deer fly fever prior to
Speaker 3: Francis's investigations in Ohio, Utah, California, probably other places. This
Speaker 3: was clearly not a disease that was new to humans,
Speaker 3: nor was it limited to North America. After it came
Speaker 3: out that France Sola to Lorenzus can cause disease in humans,
Speaker 3: cases and outbreaks began to be reported all over the globe,
Speaker 3: from Japan, where in nineteen twenty six a widespread disease
Speaker 3: was linked to rabbits and concluded to be caused by
Speaker 3: Francisselo to Lorensis, to Russia, where four outbreaks between nineteen
Speaker 3: twenty six and nineteen twenty nine involving over eleven hundred
Speaker 3: cases were determined to be Tularimia WOW. And in these
Speaker 3: outbreaks in Russia, flooding had driven water rats which I'm
Speaker 3: guessing our European water voles, which are actually voles but
Speaker 3: look like rats anyway, this flooding had driven them out
Speaker 3: of their holes, and the Russian government offered rewards for
Speaker 3: every skin to try to reduce their numbers, which led
Speaker 3: to a lot of exposure by killing all these rats.
Speaker 3: We also see Tulurimia popping up in Turkey, Canada, Austria, Sweden,
Speaker 3: Italy and many other regions, and over time a pattern
Speaker 3: began to emerge and who was most likely to get
Speaker 3: infected basically people handling wildlife, hunters, trappers, cooks, agricultural workers,
Speaker 3: and naturally. War similar to what I mentioned earlier in
Speaker 3: terms of an increased rat population following the nineteen o
Speaker 3: six San Francisco earthquake, War also created tremendous opportunities for
Speaker 3: francis Ela to Lorenzis to thrive, largely through increases in
Speaker 3: rodent populations. For instance, during World War II in the
Speaker 3: Soviet Union, a huge amount of arable land was not
Speaker 3: cultivated harvests were delayed or destroyed, buildings were demolished, and
Speaker 3: poor sanitary conditions all resulted in a ton a ton
Speaker 3: of increased contact between humans and rodents, with an estimated
Speaker 3: sixty seven thousand cases between nineteen forty one and nineteen
Speaker 3: forty two in just one region. What uh huh along
Speaker 3: the Eastern Front there may have been tens of thousands
Speaker 3: of Russian and German soldiers may also have been infected
Speaker 3: during the war, And because this is a pathogen that
Speaker 3: infects wildlife, the increase in human cases and rodent populations
Speaker 3: also meant that Francissela to lorensus subspecies Holarctica, of course
Speaker 3: became more established and disseminated in the environment, causing a
Speaker 3: long term persistence in high case loads. Wow okay. I
Speaker 3: read in a paper that in the nineteen forties there
Speaker 3: were an estimated one hundred thousand cases annually of tulurimia
Speaker 3: in the Soviet Union. Ah yay yayeah. I know, I
Speaker 3: know it was and probably helped along by exposure roots
Speaker 3: like breathing in dust that had been contaminated by dead
Speaker 3: rodents or their poop, or contaminated water supplies like basically
Speaker 3: all the things that you would expect to see increase
Speaker 3: during times of war. Fortunately, sanitary conditions improved in later decades.
Speaker 3: Plus there was that vaccine that was developed and was
Speaker 3: widely administered, like mass vaccination campaigns in the Soviet Union.
Speaker 3: I think sixty million people ended up getting vaccinated between
Speaker 3: nineteen forty six and nineteen sixty Wow. Yeah. And by
Speaker 3: the nineteen nineties, annual cases there had decreased to one
Speaker 3: hundred to four hundred Wow. Yeah, yeah, But I'm getting
Speaker 3: ahead of myself there. The incredible increase in both the
Speaker 3: number of cases and the distribution of this pathogen prompted
Speaker 3: more research into Francisolo to lorensis throughout the nineteen thirties
Speaker 3: and nineteen forties. It's ecology, it's clinical picture, exposure roots,
Speaker 3: the role of arthropod vectors like tics, other animals that
Speaker 3: could infect, and so much more. And we are know
Speaker 3: from Francis's research in nineteen nineteen that this pathogen could
Speaker 3: be a dangerous one to work with. And so what
Speaker 3: do you think happened? Once more and more bacteriologists turned
Speaker 3: their attention to it. Oh yeah, more and more cases
Speaker 3: among these researchers frances Solo tou Lorenzis had earned a
Speaker 3: reputation as a deadly microbe that was disturbingly difficult to
Speaker 3: avoid in lab settings, so much so that in some
Speaker 3: countries researchers just flat out refused to work with it.
Speaker 3: Other countries, however, saw a silver lining. Oh dear, The
Speaker 3: potential of Francislo to Lorenzis as a biological weapon working
Speaker 3: in its favor are the following. There are seven, so
Speaker 3: buckle up. Number one it's highly infectious, like you said,
Speaker 3: as few as ten to one hundred bacteria and needed
Speaker 3: to cause disease. Number two it's easy to find in
Speaker 3: nature because of its wine distribution. Number three it's easy
Speaker 3: to make a lot of Number four it can be
Speaker 3: aerosolized very easily, as lawnmower associated outbreaks have shown. There
Speaker 3: were like started out on Martha's vineyard. There's been some
Speaker 3: in Colorado, Like yeah, it's really horrible. Fine. Yeah. Number
Speaker 3: five it can spill back from humans into the environment
Speaker 3: and stay there for a long time, continuing to pop up.
Speaker 3: Number six. Only a few antibiotics work on it, and
Speaker 3: resistant strains could you know in theory be easily engineered.
Speaker 3: And number seven, no vaccine is currently available. As early
Speaker 3: as World War Two, countries such as Japan, the US,
Speaker 3: the USSR, and probably many others devoted a lot of
Speaker 3: time and effort into determining whether or not Francissela to
Speaker 3: lorensis could be developed into a suitable biological weapon. And
Speaker 3: this wasn't the only pathogen considered, of course, but it
Speaker 3: was given really high priority for those reasons I mentioned.
Speaker 3: And some of this quote unquote research involved just straight
Speaker 3: up torture, right injecting people with tulaimia. One of the
Speaker 3: most publicized was the horrific torture carried out by the
Speaker 3: Japanese Research Unit seven thirty one operating in Manchuria, and
Speaker 3: the US used human quote unquote volunteers in the nineteen
Speaker 3: fifties who were infected with Francissela tou loreensis using different
Speaker 3: exposure roots, especially aerosol, in different levels of bacteria. And
Speaker 3: so this is how we know that the infectious dose
Speaker 3: is ten to fifty.
Speaker 1: I read that in several papers, and it's disturbing how
Speaker 1: all of the papers that I read literally just say
Speaker 1: human volunteers, that's what they say.
Speaker 3: Yeah, so I don't know the circumstances of what that
Speaker 3: volunteering look like. Were they given a consent form, were
Speaker 3: they given right, you know, full disclosure about the risks
Speaker 3: associated with this.
Speaker 1: I mean nineteen fifties almost certainly not, No, I know,
Speaker 1: definitely not.
Speaker 3: Yeah. I think it just sort of the fact that
Speaker 3: it's just like and they were volunteers.
Speaker 1: Right, it's just like brushed under. It's like, oh, we
Speaker 1: learned this from human volunteers. Like what right, sorry, back
Speaker 1: it up more detail please.
Speaker 3: Yeah, yeah, yeah. But interest in this pathogen as a
Speaker 3: potential biological weapon continued to rise, and of course with
Speaker 3: it was increasing concern about its actual use. And so
Speaker 3: this actually led the WHO to develop this model that
Speaker 3: you talked about earlier, Aaron, to estimate just how bad
Speaker 3: an attack using the pathogen could be, and they incorporated
Speaker 3: things actually like meteor aloge conditions, decay rate of the
Speaker 3: bacteria in the air, antibiotic sensitivity or resistance, infectious dose,
Speaker 3: case fatality rate, et cetera. And they estimated that if
Speaker 3: fifty kilograms of an antibiotic resistant strain of francissela to
Speaker 3: lorensis was released in a metropolitan area with a population
Speaker 3: of five million people, two hundred and fifty thousand individuals
Speaker 3: would become incapacitated and nineteen thousand would die. Yeah, and
Speaker 3: I say incapacitated just because, like you said earlier, Aarin,
Speaker 3: there's this really long period of recovery with relapses in
Speaker 3: later months. And the CDC also performed its own cost estimate.
Speaker 3: I love that it's always cost always, which is, you know,
Speaker 3: equate human lives to monetary value. I mean, is that
Speaker 3: not America? Yeah, And in nineteen ninety seven dollars, they
Speaker 3: estimate that it would cost five point four billion dollars
Speaker 3: for every one hundred thousand people exposed in an aerosol attack.
Speaker 3: Ooh yeah, every Oh wow. I mean now that we
Speaker 3: are equating human lives with money, that's really expensive. Yeah,
Speaker 3: really expensive.
Speaker 4: Yeah.
Speaker 3: Only smallpox and anthrax were estimated to be more expensive. Actually. Wow.
Speaker 3: And although the US officially ended its bioweapon development program
Speaker 3: in the early nineteen seventies, research on antibiotic and vaccine
Speaker 3: resistant Francislo to lorensis as a bioweapon allegedly continued in
Speaker 3: the Soviet Union until the early nineteen nineties, although this
Speaker 3: has not been confirmed, but to this day, Francisla to
Speaker 3: Lorensis is on the very short list of Category A
Speaker 3: Select Agents by the CDC, which are organisms that quote
Speaker 3: pose a risked national security because they can be easily
Speaker 3: disseminated or transmitted from person to person, result in high
Speaker 3: mortality rates, and have the potential for major public health impact,
Speaker 3: might cause public panic and social disruption, and require special
Speaker 3: action for public health preparedness. And it really is a
Speaker 3: very short list. Anthrax, bachelism, plague, smallpox, some viral hemorrhagic fevers, Ebola, Marburg, Lasa, machupo,
Speaker 3: and tularimia. That's it. That's it.
Speaker 1: I did want to point out one thing about that list.
Speaker 3: We have covered.
Speaker 1: Almost every single thing on that list.
Speaker 3: I know, we're still missing Lasa and Melissa, and that's it.
Speaker 4: I know.
Speaker 3: So wow wow, I know, and Marburg very recently, Yeah, exactly,
Speaker 3: just a couple episodes ago, actually, But yeah, I think
Speaker 3: that just underlines how seriously people take this bacterium, and
Speaker 3: for very good reason, and because of this, and because
Speaker 3: of all the other really fascinating aspects of the biology
Speaker 3: of tularimia that you explored, aarin research on this pathogen
Speaker 3: is still an incredibly active field. Yeah, And we're learning
Speaker 3: so much more about this deadly microbe every year. So Aerin,
Speaker 3: what can you tell me about Tulerymia today? Oh?
Speaker 1: I can't wait to get into it right after a
Speaker 1: short break. So, like you mentioned, aarin tuler Amia Francescla
Speaker 1: toulorensis and all of its subspecies has really only been
Speaker 1: found in the northern hemisphere. But in the northern hemisphere
Speaker 1: it's reported very widely throughout North America, Europe, Russia, into Japan, China,
Speaker 1: throughout a lot of Asia. Not really reported in the
Speaker 1: southern hemisphere, although at least one subspecies has been found
Speaker 1: in Australia at least one time, I don't know. But
Speaker 1: throughout its range, tula Amia is generally considered an emerging
Speaker 1: or re emerging disease. That is that over the last
Speaker 1: twenty years, it's being found in expanded geographic ranges, popping
Speaker 1: up in places that we didn't know that it was,
Speaker 1: either because it wasn't there before or because we just
Speaker 1: hadn't found it there before. Hard to say which. It's
Speaker 1: being found in new hosts species same qualifiers. Was it
Speaker 1: just not there or had we.
Speaker 3: Not found it?
Speaker 1: And it's popping back up in locations that it hadn't
Speaker 1: been seen for quite some time. And this is true
Speaker 1: really throughout its range and throughout all of the Northern Hemisphere.
Speaker 1: It's not an even distribution across various countries or territories
Speaker 1: or regions. This tends to be an infection that's more
Speaker 1: common in rural areas of various countries. But it's not
Speaker 1: entirely clear what all of the different determining factors are
Speaker 1: that go into when you're going to have, say an
Speaker 1: epizootic outbreak in animals, or an epidemic in humans, or
Speaker 1: even sporadic cases. And part of that comes back to
Speaker 1: that we don't really know what the environmental reservoirs are,
Speaker 1: We don't really know what the conditions are that facilitate
Speaker 1: this spread per se.
Speaker 3: Yeah, it's so weirdly patchy, Yes, very patchy, and like
Speaker 3: I can only imagine how many variables would go into
Speaker 3: a model that would begin to try to estimate where
Speaker 3: and when and how, And yeah.
Speaker 1: I love thinking about it though, because it would be
Speaker 1: such a complicated model. The other thing, too, is that
Speaker 1: it's very patchy in terms of identification and reporting. Right
Speaker 1: every different country or even different regions of different countries
Speaker 1: might have different things that they're doing to both actively
Speaker 1: surveil or passively surveil for this disease in animals and
Speaker 1: in humans, and maybe are reporting it differently on a
Speaker 1: country by country level.
Speaker 3: Right.
Speaker 1: One quote from a paper that I really liked that
Speaker 1: kind of sums up why it is so difficult to
Speaker 1: really understand what the kind of global prevalence and incidents
Speaker 1: of this disease is. Sums up like this, end I quote. Thus,
Speaker 1: a correct assessment requires extensive trapping of the primary mammalian
Speaker 1: reservoirs of f to lourensis, such as rodents and lagomorphs,
Speaker 1: and of vectors, ticks, flies, and mosquitoes. In most countries,
Speaker 1: such epidemiological investigations are not made currently since they are
Speaker 1: very time consuming and expensive.
Speaker 3: End quote. Well, there you have it.
Speaker 1: There, you have it, right, we don't know we're not
Speaker 1: doing it. We need a one health approach, and we
Speaker 1: mostly don't have one. Yeah, but we do have some things.
Speaker 1: So let's go over some of the numbers that we
Speaker 1: do have, shall we. In the US, the most recent
Speaker 1: official like Morbidity Immortality Weekly report on this which sums
Speaker 1: up data from two thousand and one to twenty ten
Speaker 1: reported one thousand, two hundred and eight cases in the
Speaker 1: US in that time, so that's an average a median
Speaker 1: of about one hundred and twenty six cases per year.
Speaker 1: Now on the CDC website you can also find much
Speaker 1: more up to date data from every year since then.
Speaker 1: So from twenty ten to twenty twenty, the numbers seem
Speaker 1: to have gone up again. I can't tell you if
Speaker 1: this is statistically significant because the reports are not out,
Speaker 1: but just the raw numbers that exist tell us that
Speaker 1: over the most recent ten years, the median number of
Speaker 1: cases is two hundred and fourteen compared to one twenty
Speaker 1: six the year before, and the range also is on
Speaker 1: the higher end, between one hundred and forty nine and
Speaker 1: three hundred and fourteen cases, so overall, greater numbers every year.
Speaker 3: Interesting.
Speaker 1: It is interesting in that timeframe the year with the
Speaker 1: greatest number of cases in the US was twenty five fifteen,
Speaker 1: where there were three hundred and fourteen cases reported. Over
Speaker 1: one hundred of these were in Colorado, Nebraska, South Dakota,
Speaker 1: and Wyoming. These are states that many years do see
Speaker 1: some numbers of tularemia, but this was a huge increase
Speaker 1: in those states. Compared to like the prior ten years combined.
Speaker 1: So this is part of what I mean when I
Speaker 1: say that this is an emerging and re emerging disease.
Speaker 1: We're seeing sporadic cases here and there in places where
Speaker 1: maybe it existed, but not necessarily to the extent that
Speaker 1: we see today or in some years.
Speaker 3: I'm curious about those strong year to year fluctuations because
Speaker 3: it makes me think about, like, okay, our rodent populations
Speaker 3: going up, and was it a really strong, you know,
Speaker 3: rainy year the year before where there's a lot of whatever,
Speaker 3: you know, more nuts of a certain kind.
Speaker 1: Oh, Aaron Brian Allen would be so pro out of
Speaker 1: u U disease ecolleges U. But yes, that is one
Speaker 1: of the possible thoughts on an explanation. Is it there
Speaker 1: may have been increased rainfall which promotes vegetation growth and
Speaker 1: potentially pathogen survival in the environment and then leads to
Speaker 1: increased rodent and rabbit populations. Again very allah lime disease.
Speaker 3: Yeah, where you have these very complex cycles that really
Speaker 3: require a very integrated approach to be able to understand.
Speaker 3: But even more complicated because it's not just one or
Speaker 3: two or a few species that we have to look
Speaker 3: at right, right, a vector and reservoir and et cetera.
Speaker 3: So that's the US.
Speaker 1: In Europe, the European Centers for Disease Control and Prevention
Speaker 1: also collects data on tulurimia. It's a notifiable disease, but
Speaker 1: each country, each member state of the EU has different
Speaker 1: surveillance systems and different degrees of public awareness. But let's
Speaker 1: go over some numbers, shall we. Between nineteen ninety two
Speaker 1: and twenty twelve, over eighteen thousand cases were reported to
Speaker 1: either the World Health Organization or the ECDC. The majority
Speaker 1: of these were in Finland, Sweden, and Turkey, like the
Speaker 1: highest numbers overall. And then there's a more recent paper
Speaker 1: from twenty twenty one that reported that in that year,
Speaker 1: just over eight hundred cases of tularemia in humans were
Speaker 1: reported across twenty six member countries. That was an increase
Speaker 1: over twenty twenty and an increase over the average of
Speaker 1: twenty seventeen to twenty nineteen, though in twenty nineteen there
Speaker 1: was a large outbreak in Sweden, so the total number
Speaker 1: that year was over twelve hundred. And then Aaron, just
Speaker 1: because you mentioned Russia so much, and those numbers back
Speaker 1: in the Soviet in the former Soviet Union, I did
Speaker 1: find one paper that reported in twenty nineteen only forty
Speaker 1: two cases reported in Russia.
Speaker 3: Wow, right, way better, way better those there some much
Speaker 3: much better numbers. Yeah. Yeah.
Speaker 1: But in addition to this geographic variation, the other thing
Speaker 1: that we see with tularemia is seasonal variation, which isn't
Speaker 1: surprising since we do have a lot of arthropod born
Speaker 1: infection and environmental transmission. Really, so it's northern hemisphere summer
Speaker 1: months that tends to have the highest number of cases.
Speaker 1: But this of course varies right across all of Europe
Speaker 1: and between Europe and North America. Different states in the
Speaker 1: US report cases year round. Oh, there's not so much,
Speaker 1: et cetera, et cetera. But that's at least what we
Speaker 1: know of the epidemiology of tularemia across its distribution. I
Speaker 1: do think that one of the things that's most interesting
Speaker 1: scary about it is that we do seem to be
Speaker 1: seeing these increases, right, and how much of that is
Speaker 1: just better surveillance versus true increases.
Speaker 3: We don't know. We really don't know, right, And it
Speaker 3: seems like there's still so much that we don't know
Speaker 3: about the ecology that getting an answer to that is
Speaker 3: not going to be possible without more research exactly.
Speaker 1: Speaking of more research, in addition, I think to this
Speaker 1: one health approach and a better understanding of not just
Speaker 1: the incidents and prevalence in humans but in animals and
Speaker 1: the ecology of this infection and all of that, I
Speaker 1: think that that's a really important part of the future
Speaker 1: research that is being done, that needs to be done.
Speaker 1: But the other part of this, of course is the vaccines,
Speaker 1: of which we don't half one currently, not one that's licensed.
Speaker 1: There was a vaccine, it was a live vaccine, It
Speaker 1: was effective, It was based on the whole Arctica subspecies,
Speaker 1: but had at least some efficacy against the more virulent
Speaker 1: Toulurancis subspecies. But part of the reason that it was
Speaker 1: never fully licensed in the US, at least by the FDA,
Speaker 1: is in part because we did not and still don't
Speaker 1: understand the mechanisms by which this vaccine derived strain was
Speaker 1: attenuated was made to be even less virulent. Ah, And
Speaker 1: because we didn't understand that, and we still don't really
Speaker 1: understand the virulence of this pathogen, how does it make
Speaker 1: us so sick. Why does this one make us so
Speaker 1: much sicker than the other. There's a lot of concern
Speaker 1: that this could easily revert to a more pathogenic strain.
Speaker 1: So for longtime listeners, you might remember from our vaccines
Speaker 1: episode that there's a lot of different types of vaccines
Speaker 1: that exist, and there's pros and cons to all of these.
Speaker 1: With live vaccines, which are a live virus, these are
Speaker 1: a strain of virus that gives us a very robust
Speaker 1: immune response, really good usually long lasting immunity, but without
Speaker 1: any illness, without a real infection per se. But with
Speaker 1: live vaccines, there's the possibility that these vaccine derived, attenuated,
Speaker 1: less virulent strains can gain some of those vrulance factors
Speaker 1: back and then actually cause disease. And we see this
Speaker 1: on occasion with things like the live polio vaccine, for example,
Speaker 1: and that's why across the globe, we really don't use
Speaker 1: that vaccine in most of the world. Because polio is
Speaker 1: no longer in most of the world, the risk benefit
Speaker 1: analysis has changed, so we now use an inactivated, injected
Speaker 1: vaccine for most people that are getting vaccinated with polio.
Speaker 1: When it comes to tularemia, the risk benefit analysis is
Speaker 1: already going to be very different because this is a
Speaker 1: rare disease, right, so the risk of using a live
Speaker 1: virus that has the potential to revert to something more
Speaker 1: virulent is already like that calculus is already different than
Speaker 1: something that's very prevalent. Does that make sense, Yes, yeah,
Speaker 1: no it does. So there's a lot of research being
Speaker 1: done and in the US, especially since two thousand and one,
Speaker 1: when the anthrax letters came and were a thing and
Speaker 1: the fear of a bio weapon attack kind of increased again,
Speaker 1: there has been a ton of research on alternative vaccines,
Speaker 1: alternative live vaccines, killed vaccines, component vaccines, and all the
Speaker 1: different types of vaccines. For tulerimia, we still don't have one.
Speaker 1: All of the other vaccine types so far just haven't
Speaker 1: come to fruition in a way that has led to
Speaker 1: a vaccine coming to market, essentially. But I do have
Speaker 1: a great paper. It's a little old now, it's from
Speaker 1: twenty fifteen, but it kind of goes over what we
Speaker 1: had so far and where we may go from here.
Speaker 1: But that's tulaimia.
Speaker 3: So much more to it than I thought. I know,
Speaker 3: I say that a lot, but.
Speaker 1: Yeah, it's I underestimated. It won't do that again.
Speaker 3: Yeah, certainly not. I want to keep an eye on
Speaker 3: Colorado numbers in the next few years, see if these
Speaker 3: this rainy spring will have any impact down the line. Oh,
Speaker 3: I'm so here. We'll have to do an update episode
Speaker 3: Erin source sources, I have so many because I think
Speaker 3: I just like pulled snippets from a thousand papers. I'm
Speaker 3: going to shout out three right now, but there are
Speaker 3: so many more out there. For the history, I really
Speaker 3: liked a paper by Suistat from two thousand and seven
Speaker 3: called Tulaimia History, Epidemiology, pathogen Physiology and Clinical Manifestations. And
Speaker 3: for the bioweapon aspects of Tulerimia, there's a great paper
Speaker 3: by oystin at All from two thousand and four called
Speaker 3: Tularemia Bioterrorism Defense Renews Interest In Francisselo to Lorenzis, I
Speaker 3: read that paper too. I liked it a lot. Yeah.
Speaker 1: I had for the biology a couple of other also
Speaker 1: older papers, but they were really nice. One from Jamma
Speaker 1: in two thousand and one that was called tula Reimia
Speaker 1: as a Biological Weapon, Medical and Public Health Management. That
Speaker 1: was a fun one, uh, huh. I wrote that one,
Speaker 1: and then I had a whole bunch of papers updating
Speaker 1: the epidemiology in the US and in Europe and across
Speaker 1: its range. We'll post the sources from this episode every
Speaker 1: one of our episodes on our website This podcast will
Speaker 1: Kill You dot Com under the episodes tab.
Speaker 3: Thank you to Bloodmobile for providing the music for this
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Speaker 3: I hope you liked this episode. Yeah, hope you learned
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