Speaker 1: Rehab.
Speaker 2: Joshua runs a small business in Plateau State, Nigeria, selling
Speaker 2: rice and ground maize at the local market. She has
Speaker 2: a great smile, six bright children, a supportive husband, and
Speaker 2: she has lymphatic philariasis. I used to have fever attacks
Speaker 2: and for weeks I could not do anything, not even
Speaker 2: take care of my family. Rahab noticed the symptoms of
Speaker 2: lymphatic philoriasis or l F when she had her fourth child,
Speaker 2: and the progressive swelling of her legs sent her on
Speaker 2: a desperate search for treatment. The journey for relief brought
Speaker 2: none and depleted her family's finances. One man used a
Speaker 2: razor blade. He made cuts in my leg, then used
Speaker 2: the suction device. He told me he had removed something.
Speaker 2: But if he took something out, why was the leg
Speaker 2: getting bigger and bigger. As Perhabs deformity grew, her circle
Speaker 2: of friends shriveled.
Speaker 1: Some.
Speaker 2: One gave me new clothes to pass on to another woman,
Speaker 2: but she refused to collect them because they came through me.
Speaker 2: During that time, I cried a lot. You can't imagine
Speaker 2: how happy I am that my children and grandchildren will
Speaker 2: never have to go through this.
Speaker 1: Wow. Yeah, yes, awful.
Speaker 2: It's unbelievable, and it's still so prevalent.
Speaker 1: It is, and fortunately there are a lot of great
Speaker 1: organizations doing work on this, such as the Carter Center.
Speaker 1: So Rahab's story was featured in a video produced by
Speaker 1: the Carter Center titled Living with Complications from Lymphatic Philriasis,
Speaker 1: and we will post the link to this video as
Speaker 1: well as to the Carter Center's website on all the
Speaker 1: incredible work that they are doing to eliminate or at
Speaker 1: least reduce the burden of lymphatic hilariasis in many countries
Speaker 1: around the world. Yeah, yeah, Hi, I'm Aaron.
Speaker 2: Welsh and I'm Erin Alman Updike.
Speaker 1: And this is this podcast will Kill You, And today.
Speaker 2: We're talking about lymphatic philiasis.
Speaker 1: This has been on our list for a very long time.
Speaker 1: It's kind of amazing that we haven't covered it sooner.
Speaker 1: It's one of the most prevalent and debilitating neglected tropical diseases.
Speaker 1: And I you know, I thought I knew a good
Speaker 1: am out about this disease from like public health classes
Speaker 1: and whatnot, but I was wrong. Same same, yeah, yeah,
Speaker 1: But before we get into all of the things that
Speaker 1: we now know about lymphatic philoriasis.
Speaker 2: Is it quarantiny time?
Speaker 1: It is? What are we drinking this week?
Speaker 2: We're drinking it's a small worm after all.
Speaker 1: Continuing with the worm world puns were our Quarantini titles,
Speaker 1: there's really like, it's a deep well, so it is,
Speaker 1: it's good and what is in It's a small worm
Speaker 1: after all.
Speaker 2: It's a lovely little hard cider bev with you know,
Speaker 2: heart cider and some ginger beer and lemon juice and
Speaker 2: some apple jack in there as well. Yeah, and we'll
Speaker 2: post the full recipe for that quarantini and the non
Speaker 2: alcoholic and equally delicious plusy Burta on our website This
Speaker 2: podcast will Kill You dot com and our social media.
Speaker 1: On our website This Podcast will Kill You dot Com.
Speaker 1: You can find all sorts of things. I have actually
Speaker 1: the website open in front of me.
Speaker 2: I love it when you do.
Speaker 1: If we have got links to bookshop dot org, affiliate account,
Speaker 1: our Goodreads list, merch and we've got some new merch
Speaker 1: coming for you this winter, which is pretty exciting, so
Speaker 1: keep an eye out. We've got links to Patreon. We've
Speaker 1: got a form for your first hand account if you
Speaker 1: want to submit a first hand account. We've got transcripts,
Speaker 1: and we've got the sources to each and every one
Speaker 1: of our episodes, plus some more hidden Easter eggs that
Speaker 1: you might find on the website.
Speaker 2: Ooh, easter eggs, Aaron, Yeah, all right, Well, shall we
Speaker 2: get into the biology of lymphatic philaiasis.
Speaker 1: We shall. We'll take a quick break and then dive in.
Speaker 3: So.
Speaker 2: Lymphatic phileariasis is the disease that is caused by three
Speaker 2: different but closely related nematode worms, specifically a type of
Speaker 2: worms called filarial worms, which are like a whole superfamily
Speaker 2: of these little round worms, small worms that are entirely parasitic.
Speaker 2: So almost all of these filarial worms infect mammals and
Speaker 2: some infect birds or reptiles. Apparently they do not infect
Speaker 2: fish that we know of that we know of, good
Speaker 2: one erin and generally they have a pretty complex life
Speaker 2: cycle with an arthropod intermediate host, so at minimum we're
Speaker 2: talking about a two host life cycle, pretty classic for parasites.
Speaker 2: And the worms that we'll talk about today are all
Speaker 2: in the family Onco Circudae, which we've already talked about
Speaker 2: one other time in our River Blindness episode. Anco circavolvulus.
Speaker 2: But today we're talking about three others. We're talking about
Speaker 2: Wuchereria bancrofty, Brugia or Brugia malai, and Brugia timori.
Speaker 1: Just side note here, we both did a lot of
Speaker 1: digging to try to find the correct pronunciation for these worms.
Speaker 2: Could not come to a solid conclusion.
Speaker 1: There is no consensus. It appears any YouTube video, you're
Speaker 1: bound to find a million different pronunciations. So this is
Speaker 1: what we're going with.
Speaker 2: We tried really hard, we did, but it's these three worms,
Speaker 2: and even more specifically, ninety percent of lymphatic phileariasis infections
Speaker 2: are caused by bancrotan phileiasis, which is caused by Woocheria bancrofty.
Speaker 2: I think that I suspect that most listeners of TPWKY
Speaker 2: are relatively familiar with the life cycle of Arthur bodborne
Speaker 2: parasites by this point. But we'll go over it because
Speaker 2: that's what we do here, and in this case, we'll
Speaker 2: start with the L three larvae. So the third stage
Speaker 2: larvae are what mosquitoes will spit under the skin as
Speaker 2: they bite us in order to infect a human. Is
Speaker 2: spit the technical term for this Yeah, that's the official
Speaker 2: scientific term for a mosquito bite. They will inject from
Speaker 2: their salivary glands the l three larvae during a bite.
Speaker 1: Yeah, that sounds like spit to me, so, yeah, exactly.
Speaker 2: And by the way, you may ask Aaron, what species
Speaker 2: of mosquito are we talking about?
Speaker 1: Is it lats of them?
Speaker 2: It is all all of them almost, it seems.
Speaker 1: That's really amazing.
Speaker 2: Yeah, so this is a parasite or these are parasites
Speaker 2: rather that are found across the globe, especially in the tropics.
Speaker 2: Throughout the tropics, and so in different parts of the world. Unsurprisingly,
Speaker 2: we have different vectors that are predominant in Africa. Across
Speaker 2: most of Africa, the most common vector are anophilies mosquitoes
Speaker 2: of a few different species. In the Americas, it tends
Speaker 2: to be qlex Quinca fasciatis, but eighties mosquitoes and Mansonia
Speaker 2: mosquitoes can also transmit the infection, especially in the Pacific
Speaker 2: in Asia and the Pacific, and these are predominantly Brugia species.
Speaker 2: These are also entire genera of mosquito. It's not just
Speaker 2: like one or two species that we're talking about here.
Speaker 1: Yeah, okay, so tell me what's going on inside of
Speaker 1: these mosquitoes that these parasites are somehow able to do
Speaker 1: everything to all of them.
Speaker 2: Oh, such a good question, Arin, I don't know. So
Speaker 2: these are parasites, and we'll talk about this in how
Speaker 2: they affect humans especially, but they are very well adapted
Speaker 2: to their hosts. They do a lot to modulate our
Speaker 2: immune system in a way that creates tolerance so that
Speaker 2: they can persist for their lifetime. So I imagine, though
Speaker 2: I don't know the details of how they do this
Speaker 2: in all of these various mosquito species as well, it
Speaker 2: is impressive that a single parasite can do so in
Speaker 2: so many different species of mosquito.
Speaker 1: Yeah, I feel like that's sort of the opposite. And
Speaker 1: maybe it's not. Maybe that's just like human bias or
Speaker 1: human infection bias, but that we've seen with a lot
Speaker 1: of vector born diseases where the parasite or pathogen is
Speaker 1: super loyal to their vector species but not necessarily to
Speaker 1: their hope, like they can infect a wide range just
Speaker 1: seems like a gambling like where do you put your
Speaker 1: like which basket do you put your eggs in?
Speaker 2: Yeah, and this really is the opposite because especially Wuscheria
Speaker 2: bancrofty is a really human specific disease. It can infect
Speaker 2: other animals, but in general it's not found in other
Speaker 2: animal species, and so it's almost like the opposite where
Speaker 2: this parasite has specialized on its primary host and is
Speaker 2: a generalist when it comes to the vector that transmits it. Question, okay,
Speaker 2: I love that we haven't even started. I'm like, you've
Speaker 2: got a larvae under your skin. Nuts. As far as
Speaker 2: we've gotten this is.
Speaker 1: An important part of the process.
Speaker 2: I love it.
Speaker 1: Do we know whether or not these parasites have detrimental
Speaker 1: effects on their mosquito hosts?
Speaker 2: Such a good question. I don't Okay, I don't know.
Speaker 2: I didn't specific look for that information, so I don't
Speaker 2: know if that information is known. A lot of other
Speaker 2: pathogens we know do have detrimental or at least some
Speaker 2: negative effect on the mosquitoes or arthropods that transmit them.
Speaker 2: I don't know. In the case of the parasites that
Speaker 2: coslymphatic philoriasis, I can tell you that when it comes
Speaker 2: to the development within a mosquito, these worms have to
Speaker 2: molt twice within the mosquito host, and it's a process
Speaker 2: that takes between ten and twelve days or maybe even
Speaker 2: up to two weeks per some papers, before they are
Speaker 2: then able to be transmitted to another host. So there
Speaker 2: is certainly time in there to exert kind of a
Speaker 2: selective pressure on that mosquito, and a mosquito has to
Speaker 2: survive for at least those ten to twelve days in
Speaker 2: order to be able to transmit the infection.
Speaker 1: Okay, yeah, that makes sense.
Speaker 2: Yeah, okay, So back to these L three larvae. They
Speaker 2: developed twice in the mosquito, and now they are spit
Speaker 2: into our skin. These tiny little larvae enter our lymphatics
Speaker 2: and swim their way towards our lymph nodes, and that
Speaker 2: is where they live. They molt into L four larvae
Speaker 2: and then into adults in a process that takes six
Speaker 2: to twelve months long standing infection.
Speaker 1: It's so long.
Speaker 2: Oh just wait, it gets longer. The adult female will
Speaker 2: then mate and then start releasing live young, and these
Speaker 2: young are called microfilaria, and they release them into the lymphatics.
Speaker 2: They can swim out of the lymphatics and into our bloodstream.
Speaker 2: Now erin, you may ask, how many microfilaria are we
Speaker 2: talking about that this adult female worm is releasing.
Speaker 1: That's definitely a question I would ask.
Speaker 2: Well, let me tell you. These adult worms live inside
Speaker 2: of us for up to seven to eight years after
Speaker 2: they become adult worms, and different papers have slightly different estimates,
Speaker 2: like four to six or five to eight. In any case,
Speaker 2: a number of years, and they are releasing ten thousand
Speaker 2: microfilaria wait for it, per day. What that is millions
Speaker 2: upon millions of microflaria over their lifetime.
Speaker 1: That is shocking.
Speaker 2: And then it gets more shocking. The adult worms are
Speaker 2: living inside of our lymphatic system. And we'll talk in
Speaker 2: a lot more detail about our lymphatic system. Don't worry,
Speaker 2: but these microfilaria predominantly travel to our blood vessels, and
Speaker 2: during the daytime preferentially hang out in our larger blood vessels,
Speaker 2: and then at night, when mosquitoes are most active, they
Speaker 2: travel to surface blood vessels so that mosquitoes can more
Speaker 2: efficiently pick them up in their blood meals and then
Speaker 2: go on to transmit them eventually.
Speaker 1: I mean, we've come across parasites that do this, like malaria,
Speaker 1: but it's still every single time is horrifying and fascinating, and.
Speaker 2: It's even more fascinating to me in the context of
Speaker 2: how many different species of mosquito can carry this parasite,
Speaker 2: because we do actually see different circadian cycles in these
Speaker 2: species of filarial worm depending on the part of the
Speaker 2: world that you're looking at and the mosquito species that
Speaker 2: is most commonly transmitting it in that region. So, for example,
Speaker 2: in the Pacific Islands, where they're transmitted by mosquitoes that
Speaker 2: are more diurnal, you see the microfilaria out in the
Speaker 2: surface blood vessels more during the day than at night.
Speaker 2: Like they're just so well adapted. It's incredible.
Speaker 1: That is really interesting, and I wonder how we could
Speaker 1: trace sort of spread or like how quickly that diurnal
Speaker 1: pattern evolves to match the local mosquito host, because like
Speaker 1: what happens if a new mosquito host, you know, comes
Speaker 1: in and is now suddenly the predominant mosquito host and
Speaker 1: can also transmit philariasis and.
Speaker 2: Yeah, yeah, oh, I know. It's it's so much so
Speaker 2: that is the transmission cycle of this parasite, of these parasites.
Speaker 2: So what does this disease, lymphatic philariasis actually look like.
Speaker 2: It turns out that, thankfully, most people who are infected
Speaker 2: are asymptomatic it's about one third of people who are
Speaker 2: infected who end up having clinical disease, actual symptoms of
Speaker 2: this disease. But even when people are asymptomatic, they generally
Speaker 2: still have some degree of damage to the lymphatic system,
Speaker 2: and this damage is progressive. And so the predominant symptom
Speaker 2: of lymphatic philariasis is lymphidema, swelling in a limb or
Speaker 2: in a body part due to disruption of the lymph system.
Speaker 2: And this swelling, this lymphidema lends itself to secondary infections.
Speaker 2: Really really easy to get a secondary infection when you
Speaker 2: have so much stasis of fluid.
Speaker 1: So why does that, like how does that happen? And
Speaker 1: maybe that's maybe my question is just like how does
Speaker 1: the lymph system work? What does it do?
Speaker 2: Let me get into that and then I can talk
Speaker 2: a little bit more about like what those symptoms end
Speaker 2: up looking like. Okay, yeah, So the primary cause of
Speaker 2: disease is the blockage of our lymphatic drink. So we've
Speaker 2: only talked in very brief about our lymph system on
Speaker 2: this podcast, But what our lymphatic system is is a
Speaker 2: system of tubes, vessels, and clusters of nodes.
Speaker 1: Lymph nodes.
Speaker 2: So it's very similar to our blood vessels in that
Speaker 2: what our lymph system is doing is carrying fluid from
Speaker 2: place to place in our body. Our blood vessels are
Speaker 2: carrying blood, and our lymphatic vessels are carrying lymphatic fluid.
Speaker 2: What is lymphatic fluid, it's basically just all the fluid
Speaker 2: in our body that isn't blood. So this means anything
Speaker 2: that either extravasates comes out of our blood vessels and
Speaker 2: into the extracellular space. Any cells that kind of burst
Speaker 2: open and release all of their lovely liquidy juices, that's
Speaker 2: going to become fluid in the extracellular space. So it's
Speaker 2: fluid and large molecules like proteins, et cetera, hanging out
Speaker 2: in all of the space between our cells. This fluid
Speaker 2: eventually is absorbed into the lymphatic system and carried through
Speaker 2: these tubes, through these lymphatic vessels into our lymph nodes.
Speaker 2: It kind of drains into our lymph nodes. Our lymph
Speaker 2: nodes are these areas where a whole horde of our
Speaker 2: immune cells, especially our white blood cells, hangout. Because the
Speaker 2: fluid that's traveling through our lymph it has antigens in it,
Speaker 2: it has pathogens in it, it has just a bunch
Speaker 2: of junk. And so what our lymph nodes are doing
Speaker 2: are essentially cleaning it all up, filtering out all of
Speaker 2: the junk in this fluid, and then eventually running that
Speaker 2: fluid from our lymph nodes through our spleen which is
Speaker 2: like not really a giant lymph node, but kind of
Speaker 2: like a giant lymph node in a way, and then
Speaker 2: sending that fluid eventually back into our vascular system. So
Speaker 2: putting that fluid, once it's all cleaned up, back into
Speaker 2: our blood vessels. Does that make sense what our lymph
Speaker 2: system is and does?
Speaker 1: Yeah, like extra plumbing, non blood plumbing.
Speaker 2: Yeah, extra plumbing. That's a really it's a really good
Speaker 2: way of looking at it. Okay, So then lymphatic philoriasis,
Speaker 2: how do we get here? In lymphatic philriiasis, the adult
Speaker 2: worms are living inside of our lymph system, inside of
Speaker 2: these vessels and near our lymph nodes. And they're not
Speaker 2: just passively hanging out there. They are, like I said,
Speaker 2: making millions, tens of thousands of eggs per day for years.
Speaker 2: The adult worms live in these little nests. They make
Speaker 2: these little nests and because they need to exist in
Speaker 2: a space that is like our lymph node's job is
Speaker 2: to clean out pathogens, right, That's our immune system's literal
Speaker 2: only job is to prevent things like worms from living
Speaker 2: inside of us. So these worms are actively secreting compounds
Speaker 2: to modulate our immune system's response to them existing inside
Speaker 2: of us.
Speaker 1: Like, what better place to do that, It's just hiding
Speaker 1: in plain sight.
Speaker 2: Exactly exactly, So it just so happens that these worms
Speaker 2: is secreate all of these compounds that end up favoring
Speaker 2: an anti inflammatory immune response. So what they do is
Speaker 2: suppress the T cells that are pro inflammatory, and they
Speaker 2: upregulate our anti inflammatory response. So this overall suppression of
Speaker 2: inflammation is what allows these worms to persist inside us
Speaker 2: for so long. They create this condition of immunotolerance, and
Speaker 2: that is why that many people with this infection for
Speaker 2: many years might have no clinical signs or symptoms. However,
Speaker 2: that doesn't mean that there's not some degree of inflammation
Speaker 2: happening within these lymphatics because of this infection, because of
Speaker 2: these worms, because they are producing these microfilaria that are
Speaker 2: bursting out of our lymphatics, running rampant and getting into
Speaker 2: our blood vessels. And so what we see is that
Speaker 2: even in people who have subclinical disease, that is, they
Speaker 2: don't have any symptoms of lymphatic philariasis, if you look
Speaker 2: inside of their lymphatics, they do still have some degree
Speaker 2: of inflammation in the lymph system, and over time, eventually
Speaker 2: people are at increased risk for overt disease. So the
Speaker 2: question that you asked is like, what triggers this, right,
Speaker 2: And while we don't fully know as usual, it's thought
Speaker 2: that it's related to the frequency and intensity of our
Speaker 2: eventual immune response to these worms, specifically the response to
Speaker 2: these worms as they die.
Speaker 1: Okay, and these are the adult worms or the microfilaria,
Speaker 1: the adult worms.
Speaker 2: Yeah, as these adult worms die, it causes an increase
Speaker 2: in inflammation. If you think about it, If they're actively
Speaker 2: secreting stuff to reduce inflammation and then they die, now
Speaker 2: they're not secreting those anti inflammatory compounds, right, So now
Speaker 2: you have an increase in inflammation. That increase in inflammation
Speaker 2: causes lymphangitis, which just means like swelling inflammation in your
Speaker 2: lymph system, lymphatinitis, which is inflammation specifically in like the
Speaker 2: lymph nodes themselves, okay, and then that is going to
Speaker 2: cause activation of our immune response. And we've talked a
Speaker 2: lot on this podcast about that like inflammatory cascade, where
Speaker 2: once you have inflammation, you're going to have more swelling.
Speaker 2: You're going to have this positive feedback loop that continues
Speaker 2: to upregulate these inflammatory pathways, which leads to more swelling
Speaker 2: and more swelling and more inflammation and importantly, more pain.
Speaker 2: This is a very painful process, and the frequency and
Speaker 2: severity of these attacks can then lead to chronic changes
Speaker 2: over time. Another factor that's involved in the development of
Speaker 2: this like symptomatic disease is a particular bacterial endosymbiant and
Speaker 2: longtime friend of the pod, h Wilbakia.
Speaker 1: Friend might be a generous term, but yes.
Speaker 2: I know, but I heard you say that on our
Speaker 2: last episode and I loved it so much. It was
Speaker 2: about cook, but I really wanted to say it again
Speaker 2: because I got a kick out of it.
Speaker 1: I love it.
Speaker 2: So These particular little endosymbiotic bacteria live inside of these
Speaker 2: tiny worms, and while the worms themselves are secreting anti
Speaker 2: inflammatory compounds, Walbakia happens to induce our innate immune system
Speaker 2: enormously and stimulate inflammatory pathways. They're like all inflammation.
Speaker 1: And this is again once the adult worm has died,
Speaker 1: or is this while the adult worm is living. These
Speaker 1: wolbachia are secreting these.
Speaker 2: Potentially both, but I think the thought is that a
Speaker 2: lot of it might be on death or like release
Speaker 2: of these wolbachia. So exposure to these likely also plays
Speaker 2: a role in the development of this lymphandritis, this inflammatory
Speaker 2: lymph system, and eventual lymphedema.
Speaker 1: So we talked about this with alco psychiasis. The Wollbacchia
Speaker 1: did the same thing, then, I yeah.
Speaker 2: Right, yeah, yeah, wobochia. Man.
Speaker 1: Yeah.
Speaker 2: Now, the other and possibly most important component of the
Speaker 2: progression of this disease is how open it leaves people
Speaker 2: to secondary infections, both because of the suppressive effec effects
Speaker 2: of this immune modulation, right, suppressing our immune systems so
Speaker 2: that we tolerate these worms makes people more susceptible to
Speaker 2: other pathogens like malaria or tuberculosis, but also because the
Speaker 2: damage that's happening to the lymph system and the eventual
Speaker 2: development of swelling of this lymphidema, this fluid stasis leads
Speaker 2: to secondary bacterial infections, and that process where you have
Speaker 2: fluid stasis, things not draining, and then secondary infections is
Speaker 2: literally how so many infections in our bodies happen, Like
Speaker 2: kidney stones lead to kidney infection, gallstones lead to infection
Speaker 2: of the gallt water milk duct blockage leads to mastitis
Speaker 2: like that is a very common phenomenon, and that is
Speaker 2: what's happening here where you have blockage of your lymph
Speaker 2: system from this inflammation leading to fluid getting backed up
Speaker 2: in a limb, et cetera. And then that's anitis for
Speaker 2: bacterial infection, and that bacterial infection is going to cause
Speaker 2: a lot of inflammation, further damage and exacerbation of all
Speaker 2: the damage that's already been caused. And so secondary infections
Speaker 2: are a huge contributor to the overall disability that we
Speaker 2: see with lymphatic philriosis.
Speaker 1: Question about the swelling and sort of the timeline of symptoms,
Speaker 1: So I know that you said that you can see
Speaker 1: markers of infection even in people who are asymptomatic or
Speaker 1: without these more pronounced severe symptoms. But for those pronounced
Speaker 1: severe symptoms, is that usually like seven to eight years
Speaker 1: after infection, because that's sort of the end of the
Speaker 1: adult worm's life.
Speaker 2: It's a good question. I don't have a number like that, Okay.
Speaker 2: It used to be thought that children didn't get infected
Speaker 2: with lymphatic philriiasis. That is not true. But what we
Speaker 2: know now is that it's this is a chronic disease.
Speaker 2: So even though any individual worm might only be living
Speaker 2: for seven years, only seven is a long time. It's
Speaker 2: the accumulation over time, right, of multiple infections, because generally
Speaker 2: people are not infected with a single or even a
Speaker 2: couple of adult worms, and so it's it's a process
Speaker 2: that takes a long time. But I don't have like
Speaker 2: an exact number on it, but you can think of
Speaker 2: it as very much a chronic disease if it is untreated.
Speaker 1: Okay, So that actually kind of brings up another question
Speaker 1: that I had, which is infectious dose, Like how many
Speaker 1: times do people have to be bitten by an infected
Speaker 1: mosquito or is it just sort of like we don't know.
Speaker 2: Yeah, yeah, great question, we don't Okay. In general, it
Speaker 2: is thought that this is something where people do have
Speaker 2: to be exposed and therefore infected multiple time, because again
Speaker 2: it's not like a single worm is going to cause
Speaker 2: the major symptoms of lymphatic philleriasis. Okay, but yeah, how
Speaker 2: many worms do you have? To have? No idea?
Speaker 1: Okay? Another question? Uh huh?
Speaker 2: What?
Speaker 1: Sorry? I have so many and I've two more written
Speaker 1: down for later too. What is the average worm burden? Oh?
Speaker 2: I have no idea? Okay, okay, Yeah, So that's like
Speaker 2: the pathogenesis, right, that's like what's happening on our lymph system.
Speaker 2: But what does this end up looking like? Like? What
Speaker 2: are people living with? Right, Lymphidema is not a very
Speaker 2: specific thing. So lymphoedema is just the swelling from this
Speaker 2: disruption of the lymphatic drainage. The secondary infections and these
Speaker 2: like inflammatory states drive this process with a very fancy
Speaker 2: term called dermato lymph angioadinitis, and that are these attacks
Speaker 2: of fever, pain, swelling. These are the times at which
Speaker 2: this lymphidema and this lymph system dysfunction is being exacerbated.
Speaker 2: And so each one of these attacks eventually like it
Speaker 2: just causes further damage to the lymph system that over
Speaker 2: time will lead to a finding called elephantiasis, which is
Speaker 2: something a lot of people may have heard of. And
Speaker 2: this is what happens when the lymph system has become
Speaker 2: so damaged that the body part that is being affected
Speaker 2: is significantly enlarged. It's very swollen, and the skin over
Speaker 2: time becomes very thick, very dry, and discolored, so it
Speaker 2: either like darkens or can become kind of like a
Speaker 2: grayish tone. And then you can see these very large
Speaker 2: protuberances on the skin that are caused by dilated loops
Speaker 2: of these lymph vessels, essentially like redundancy trying to be
Speaker 2: able to drain all of this fluid but not being
Speaker 2: able to. And then because there's so much swelling, this
Speaker 2: leads to these redundant skin folds that kind of fold
Speaker 2: over on themselves and create yet another environment that is
Speaker 2: just ripe for secondary skin infections. Right now, the two
Speaker 2: most commonplaces that we see this type of damage, this
Speaker 2: lymphedema is in the legs, the lower limbs, and in
Speaker 2: the testes in people with testes. Hydroceeal, which is fluid
Speaker 2: accumulating in the scrotal sac is actually the most common complication,
Speaker 2: especially in people with testes, and again it leads to
Speaker 2: all of these same issues. It's just this lymph dysfunction
Speaker 2: that ends up accumulating fluid in the scrotum rather than
Speaker 2: a limb, but in addition to leading to eventual elephantiasis
Speaker 2: in the scrotum, this can also lead to other urologic
Speaker 2: complications like infections in the inguinal lymph nodes. It can
Speaker 2: potentially cause issues even leading up towards the bladder. It
Speaker 2: can be pretty severe. And while predominantly this is a
Speaker 2: disease that's affecting the limbs and causing this swelling and
Speaker 2: lymph stasis and disease in the limbs, it's not limited
Speaker 2: to the limbs. Our lymph system is everywhere and it's
Speaker 2: draining all of the fluid in our body, and so
Speaker 2: lymphatic filiasis can also affect the kidneys. Filarial antigens that
Speaker 2: are released and traveling are eventually filtered by the kidneys,
Speaker 2: and these can cause kidney damage. You can also have
Speaker 2: fistullas that form between the lymph system and the kidney,
Speaker 2: which essentially means like the lymph system starts draining directly
Speaker 2: into the drain system of the kidney, which means that
Speaker 2: you lose essential protein and fat because your kidneys aren't
Speaker 2: even filtering that lymph anymore. It's just being drained directly
Speaker 2: into your bladder. Right and if the microfilaria as they're
Speaker 2: traveling through our blood vessels, right, the babies are traveling
Speaker 2: through our blood vessels rather than our lymph system, they
Speaker 2: can get trapped in our lungs and then release antigens
Speaker 2: that can cause inflammation in our lungs and can result
Speaker 2: in a cough and wheezing, especially at night when the
Speaker 2: microfilaria are more active.
Speaker 1: That's horrible. Yeah, it all is. It's all horrible.
Speaker 2: It's all horrible. And so it's maybe unsurprising hearing how
Speaker 2: horrible this disease is and how chronic this infection is
Speaker 2: to know that lymphatic philariasis is, based on many reports,
Speaker 2: the second largest cause of permanent and long term disability
Speaker 2: worldwide because in many cases it can cause the loss
Speaker 2: of function of a limb or both limbs, or just
Speaker 2: these very very enlarged scrotal sacs that are just really
Speaker 2: difficult to be able to live with and kind of
Speaker 2: function with. Yeah, so that's the main biology of lymphatic philleriosis.
Speaker 1: Before we move on to treatment, which I'm assuming is
Speaker 1: the next chapter, I have two questions. The first one
Speaker 1: is can there be coinfection with multiple species of these parasites.
Speaker 2: Yeah, great question. I didn't see anything in the literature
Speaker 2: about it, but they certainly can overlap in distribution, so
Speaker 2: I don't see why not.
Speaker 1: Okay. And then the second question is about differences in
Speaker 1: symptoms among these different parasites species.
Speaker 2: Yeah, it's a good question. I don't have a lot
Speaker 2: of data on that. Because Usheria bancrofty is ninety percent
Speaker 2: of all in infections, all of the literature really tends
Speaker 2: to focus on bencrafty and philariasis or philesis caused by
Speaker 2: Woucheria ban crafty, so I don't really have a lot
Speaker 2: of data on the other species. It's a good question, though. Okay,
Speaker 2: that's it for now. Well, then let's move on to
Speaker 2: the good news. Good ish news is that we do
Speaker 2: have treatment. There are a few different drugs that are
Speaker 2: effective at eliminating this parasite from the body, and so
Speaker 2: the main stay of treatment, and I'll talk in a
Speaker 2: lot more detail in the epidemiology section about this idea,
Speaker 2: but the main stay of treatment across the globe is
Speaker 2: something called mass drug administration, and this means not even
Speaker 2: checking anyone for infection, but giving whole populations anywhere that
Speaker 2: is at risk drugs once or twice a year, depending
Speaker 2: on the drug, to target and kill these parasite And
Speaker 2: what this does is it reduces the density of microfilaria
Speaker 2: in the blood, which then reduces the transmission to mosquitoes,
Speaker 2: which then reduces the spread to the population. The problem
Speaker 2: is that there's a few problems. One is that you
Speaker 2: need really high coverage, like sixty five to eighty percent
Speaker 2: coverage of a population to effectively interrupt transmission. And because
Speaker 2: these aren't necessarily killing the adult worms and these worms
Speaker 2: are living in us for so long, you have to
Speaker 2: then keep this up for five to six years in
Speaker 2: a row at least. Because filarial disease also often co
Speaker 2: occurs with other parasitic diseases, you also have to be
Speaker 2: very cautious about which drugs you use in which regions
Speaker 2: so as not to exacerbate for example, uncosyirchiasis or loiasis,
Speaker 2: which is another worm that infects the eyes.
Speaker 1: Mm hmm.
Speaker 2: But it is possible to do this kind of mass
Speaker 2: drug administration, and that is the mainstay of treatment. However,
Speaker 2: the other big problem, besides how difficult it is logistically,
Speaker 2: is that mass drug administration and really like using the
Speaker 2: drugs that we use for mass drug administration doesn't do
Speaker 2: much at all to treat the people who already have
Speaker 2: clinically overt disease, especially those who have already progressed to
Speaker 2: severe lymphidema or elephantiasis. For those cases, it's all about
Speaker 2: prevention and treatment of secondary bacterial infections, right, so trying
Speaker 2: to prevent as best we can further exacerbation.
Speaker 1: Are there surgeries or anything like that that can help
Speaker 1: with some of that swelling.
Speaker 2: In the case of hydrocyl yes, so in case of
Speaker 2: scrotal infections, surgery can be done to help correct it.
Speaker 2: But I didn't see a lot on if that is
Speaker 2: also true for lymphidema, And in general, lymphidema is really
Speaker 2: difficult to treat, and lymphidema is something that can happen
Speaker 2: from a lot of different causes, it's not just lymphatic phileriasis.
Speaker 2: And it is really difficult because once you have those
Speaker 2: lymph tracts, say going down your leg damaged, there's not
Speaker 2: really a lot of ways to fix that. Whereas with
Speaker 2: a hydro seal, you can kind of close off the
Speaker 2: area that's allowing fluid into the scrotum and then potentially
Speaker 2: drain that scrotum and then prevent further fluid damage because
Speaker 2: it's not like directly the lymphatic system that's draining into
Speaker 2: the scrotum. It's like right, right, But for like the legs,
Speaker 2: which is you know, the most commonplace, it's not not
Speaker 2: really surgically correctable as far as I can tell. Okay,
Speaker 2: So that's lymphatic fileriasis. I mean it's a really awful
Speaker 2: it's really horrible.
Speaker 1: Yeah, it is a really horrible, horrible disease.
Speaker 2: So Aaron, Yes, Aaron, where did this pathogen come from?
Speaker 1: Please?
Speaker 2: How did we get to hear? How?
Speaker 1: Yeah? Well, I've got some answers to some of those
Speaker 1: questions that I'll get to right after this break. Throughout
Speaker 1: its long, long history, lymphatic philariasis has inspired dozens of names,
Speaker 1: caused a whole lot of confusion in the medical field.
Speaker 1: It's been represented in art and myths. It's led to
Speaker 1: tremendous stigma and suffering, and gave rise more or less
Speaker 1: to the field of medical entomology. Yeah, what I know, Okay,
Speaker 1: I'll tell you about it.
Speaker 2: I'll tell you about it please.
Speaker 1: Like so many of the other neglected diseases we've covered,
Speaker 1: on the podcast. The history of lymphatic philariasis is deep
Speaker 1: and rich, and the mystery of its biology was mostly
Speaker 1: completely unraveled long ago. And yet, and yet, and yet,
Speaker 1: this quote unquote old friend of humanity remains today, infecting
Speaker 1: tens of millions of people around the globe, with nearly
Speaker 1: a billion people around the world at risk of infection,
Speaker 1: as well as the tremendous health, economic, and social burden
Speaker 1: that often accompanies these parasites. That's what puts the neglected
Speaker 1: in neglected tropical disease. So what I want to do
Speaker 1: today is to take us through that vast history of
Speaker 1: lymphatic philoriasis up through the period when medicine began to
Speaker 1: figure things out, and then rather than asking why we
Speaker 1: haven't completely eradicated or at least eliminated this disease today,
Speaker 1: because the answer to that is a multifaceted but also
Speaker 1: mostly comes down to there's no profit in curing this
Speaker 1: disease or preventing this disease, which is disappointing and depressing
Speaker 1: and not surprising. But instead of doing that, I want
Speaker 1: to do a mini exploration of a potential target for
Speaker 1: treatment and what exactly is so cool about this target.
Speaker 1: In other words, what the heck is this old friend
Speaker 1: of the pod Wolbachia and why is it so important
Speaker 1: to filarial parasites? And how can we use that to
Speaker 1: our advantage? Yeah, all right, let's get started.
Speaker 2: Okay.
Speaker 1: All three of the filarial species that infect humans are ancient,
Speaker 1: ancient little worms that likely evolved in Southeast Asia. When
Speaker 1: that happened is, as per usual a slightly trickier question
Speaker 1: to answer. I read one paper that estimated that the
Speaker 1: most recent common ancestor of Ruscheria bancrofty and Brugia malai,
Speaker 1: which are the two species responsible for most lymphatic philoriosis
Speaker 1: and humans, emerged around four to six million years ago,
Speaker 1: which the authors pointed out was around the time that
Speaker 1: the common ancestor of humans and chimpanzees began to diverge.
Speaker 1: But I'm also not sure how well that matches with
Speaker 1: the hypothesized geographic origin of these parasites. But you know,
Speaker 1: it's still question mark here, Okay. But the third, more
Speaker 1: localized species, Brugia timori, is also thought to be ancient
Speaker 1: parasitizing non human primates until humans ventured into their realm,
Speaker 1: and it still parasitizes non human primates. The two genera
Speaker 1: Wucheria and Brugia are thought to have split from each
Speaker 1: other more recently, around six hundred and seventy five thousand
Speaker 1: years ago, but the larger group that includes these filarial
Speaker 1: parasites has ancient roots, probably diversifying around the time that
Speaker 1: mammals did and getting well acquainted with their numerous mosquito vectors.
Speaker 1: I feel like I just used a whole bunch of
Speaker 1: words to say these parasites are old. But you know,
Speaker 1: I like to put a little precision in there, just
Speaker 1: be precise about what we don't know and how much
Speaker 1: we do know about it, which is not very much.
Speaker 2: I love it.
Speaker 1: But even in the earliest medical writings about lymphatic philariasis,
Speaker 1: it seems to be a doomed that the disease was ancient.
Speaker 1: And oh are their writings and stories and alleged sculptures
Speaker 1: and illustrations. Have you ever heard of ski epodes?
Speaker 2: No?
Speaker 4: Okay.
Speaker 1: They are mythical beings dating back at least to ancient
Speaker 1: Greece that are represented as having one big leg which
Speaker 1: they use as shade protection by laying on their backs
Speaker 1: and sticking their legs straight up on a sunny day,
Speaker 1: so like their foot protects them from the shade. They
Speaker 1: were said to be from Ethiopia or India or other
Speaker 1: places as well. The word skiopode comes from the Greek
Speaker 1: for shadowfoot, and some researchers think that the skiopode myth
Speaker 1: has its origins in cases of lymphatic philariasis. Others tend
Speaker 1: to dismiss that idea, and they're like, what evidence do
Speaker 1: you have. There's a lot of different reasons that this
Speaker 1: could have originated, Okay. Another alleged ancient representation of this
Speaker 1: infection is from one of the earliest sculptures, the Queen
Speaker 1: of Punt stella aka like stone slab, which depicts a
Speaker 1: woman ruler visiting Egypt from the land of Punt. This
Speaker 1: stella was found in the funerary temple of the ancient
Speaker 1: Egyptian queen Hatshepsut from around fifteen hundred BCE, and since
Speaker 1: its rediscovery many researchers, particularly in like the mid to
Speaker 1: late twentieth century, they've had many things to say about
Speaker 1: the stella and the queen represented. So the Queen of Punt,
Speaker 1: whose name was Ati, is depicted with a body arms
Speaker 1: legs hips that's larger relative to those of the other
Speaker 1: people on the stella. For decades, researchers decided that she
Speaker 1: must have a physical ailment in order to be portrayed
Speaker 1: in this way, and they would pathologize her appearance to
Speaker 1: a kind of ridiculous extent, like it wasn't conceivable to
Speaker 1: these authors that she just had thick thighs and wide hips.
Speaker 1: She must have had lymphatic p hilariasis, all based on
Speaker 1: one image, no skeletal remains, no writings, just this image.
Speaker 1: And I think it's interesting because I came across the
Speaker 1: Queen of Punt described as like definitely a representation of
Speaker 1: lymphatic hiliasis, and then I found other papers where it
Speaker 1: was like, yeah, this is kind of controversial. And then
Speaker 1: I found another paper that was like, hey, can we
Speaker 1: stop pathologizing women in ancient representations when we have no
Speaker 1: reason to believe that it was representing a disease, Like
Speaker 1: was it part of a medical text or was it
Speaker 1: just a stone slab representing a visit from a queen
Speaker 1: from a different land. But I think that this Queen
Speaker 1: of Punt stella and the discussion around it serves as
Speaker 1: a good reminder to just keep in mind how limited
Speaker 1: we are in making retrospective diagnoses of any kind, and
Speaker 1: to ask whether we're pathologizing something because of our own
Speaker 1: biases or lack of context. Speaking of which, there's also
Speaker 1: the quote unquote curse of Saint Thomas, which was a
Speaker 1: belief held by Christian inhabitants of some regions of India
Speaker 1: that the swollen leg characteristic of lymphatic philariasis happened to
Speaker 1: those who martyred him. But anyway, aside from these more
Speaker 1: questionable ancient references to lymphatic philariasis, we have plenty of
Speaker 1: unquestionable ones. Medical writings from ancient Persia, China, India, Greece
Speaker 1: and elsewhere clearly described the condition, although whether it was
Speaker 1: filarial or non filarial elephantiasis is harder to discern in
Speaker 1: these ancient texts, but in general it was seen as
Speaker 1: a shameful condition, often a punishment, although in at least
Speaker 1: the ancient Indian text The Shrew to Samhita, it was
Speaker 1: observed that high prevalence of the disease happened in areas
Speaker 1: with lots of stagnant water. Kind of interesting observation considering
Speaker 1: what we know about mosquitoes now. So far in the episode,
Speaker 1: we've primarily been using the name lymphatic philariasis, but that's
Speaker 1: far from the only name that has been used historically
Speaker 1: to describe this infection, which, like I found challenging when
Speaker 1: trying to find papers about its history. Oh, I bet,
Speaker 1: because I would just have to search like lymphatic hilariasis
Speaker 1: and then and then like all of the variations that
Speaker 1: it has recalled throughout the decades and centuries. So the
Speaker 1: other common one that you mentioned Aaron is elephantiasis, and
Speaker 1: so we use that now to describe like the particular
Speaker 1: symptom or manifestation, and so historically that was used as
Speaker 1: just sort of a coverall force swollen limbs. And it's
Speaker 1: not entirely clear when and where elephants began to be
Speaker 1: associated with the disease, because that is where it comes from,
Speaker 1: but it may have been in that Indian text I mentioned,
Speaker 1: the Sushruda Samhita from around seventy CE. The author Sushruda
Speaker 1: uses the term slipota slee for elephant and PoTA for
Speaker 1: leg to describe the condition, and about a thousand years later,
Speaker 1: ancient Persian physicians were also using terms like doll, fheel
Speaker 1: or da o phil elephantine disease in reference to lymphatic philiasis.
Speaker 1: As to the why of this, like why elephants, some
Speaker 1: people have suggested it's to describe the changing texture or
Speaker 1: the changing color of skin inaffected areas, or the fact
Speaker 1: that certain limbs would grow to a certain size. And
Speaker 1: I should note that elephantiasis was not used exclusively to
Speaker 1: describe lymphatic philariasis, but also other swelling or thickening of
Speaker 1: the skin caused by other conditions, such as leprosy, which
Speaker 1: was written about in ancient Greece. The first use of
Speaker 1: the word elephantiasis in English was I believe sometime in
Speaker 1: the mid fifteen hundreds, but even into the twentieth century,
Speaker 1: elephantiasis was and still is often used split into filarial
Speaker 1: and non filarial elephantiases. Aside from elephantiasis, there was also
Speaker 1: a whole host of other local names for the condition Barbados,
Speaker 1: leg yamleg, Java, leg, malabar, leg, Saint Thomas leg, Buchnimia tropica,
Speaker 1: sarcoma ucosum, and so on. And listeners of the podcast
Speaker 1: can probably guess what I'm about to say next, which
Speaker 1: is that the wide variety of names for the disease
Speaker 1: I think serves it as an indication of just how
Speaker 1: prevalent and widespread it was in the ancient world, and
Speaker 1: with global travel and trade ramping up in the sixteenth
Speaker 1: century and beyond, these filarial parasites were about to travel
Speaker 1: to strain new worlds, where they would find ample hosts
Speaker 1: and suitable mosquito vectors to continue their life cycle mostly unchecked.
Speaker 1: The Transatlantic slave trade beginning in the sixteenth century led
Speaker 1: to Wischeraia bancrofty becoming endemic in some Caribbean islands as
Speaker 1: well as on the North and South American mainland. Lymphatic
Speaker 1: philariasis was actually endemic in Charleston, South Carolina, until the
Speaker 1: early twentieth century. As its distribution grew, so did the
Speaker 1: medical community's interest in this infection. Over the preceding centuries,
Speaker 1: medical writers had, of course paid lots of attention to
Speaker 1: lymphatic philariasis, but they were mostly at a loss to
Speaker 1: do anything more than just describe it and try out
Speaker 1: some mostly unsuccessful treatments. For real medical progress on understanding
Speaker 1: what exactly was going on with this disease under the surface,
Speaker 1: A key piece of technology had to be invented and refined,
Speaker 1: the microscope. A microscope. This tool is what French physician
Speaker 1: Jean Nicolaus de Marque would use in eighteen sixty three
Speaker 1: to inspect the milky fluid that he extracted from the
Speaker 1: swollen scrotle sac of an eighteen year old with elephantiasis
Speaker 1: I know awful. In the first major breakthrough on the
Speaker 1: infection in centuries. De Marque reported, quote attention was drawn
Speaker 1: above all to a little elongated and cylindrical creature that
Speaker 1: had extremely rapid movements of coiling and uncoiling end quote.
Speaker 1: He wasn't sure what exactly he was looking at besides worms,
Speaker 1: nor could he explain why they were absent once the
Speaker 1: scrotal fluid had cooled down. The answers to those questions
Speaker 1: would have to wait for other physicians. Four years after
Speaker 1: Marque's report, Otto Edward Heinrich Wucherer Woockerer was in Brazil
Speaker 1: inspecting a urinary blood clot from someone experiencing bloody urine
Speaker 1: and found similar worms. Woucherier was curious whether these worms
Speaker 1: were the same as those that Theodore Bill Hars had
Speaker 1: found fifteen years earlier to be the cause of Hematuria
Speaker 1: the aka the causative agent of schistasiasis BLARSA. One look
Speaker 1: under the microscope told him that he had some very
Speaker 1: different worms on his hands, but he wasn't sure exactly
Speaker 1: what they were. He published his finding quote as an
Speaker 1: incentive for some of my colleagues, better qualified and more
Speaker 1: fortunate than I, to attempt to shed light on a disease,
Speaker 1: the ideology of which is still enigmatic today. End quote.
Speaker 2: I love that's a really cute quote.
Speaker 1: Somehow it is. It's also sort of like, I don't know,
Speaker 1: but someone else can do that.
Speaker 2: Yeah, Hey, here, you guys, go someone figure it out.
Speaker 1: Someone more intelligent and gifted than I. Yeah. The next
Speaker 1: step in understanding lymphatic philariasis was taken by a physician
Speaker 1: named Timothy Richards Lewis, who found worms which he called filaria,
Speaker 1: in the blood and milky urine of a couple of
Speaker 1: his patients. Also noting that the filaria were not present
Speaker 1: in the blood at all times. He named the parasite
Speaker 1: Filaria hominous sanguiness, which I found interesting. I know that
Speaker 1: names change, they don't stick around, but like, literally none
Speaker 1: of those names remained for very long to describe that parasite.
Speaker 1: At this point in the eighteen seventies, what we've got
Speaker 1: are some enticing pieces of information about a parasitic worm
Speaker 1: and the infection that it causes, but no comprehensive picture
Speaker 1: of how this parasite caused disease and how it was spread.
Speaker 1: Enter Patrick Manson. I feel like I must have mentioned
Speaker 1: Patrick Manson. I'm sure that I have, and at least
Speaker 1: a couple of other episodes on parasitesianmiasis, yeah, dracunculiasis more.
Speaker 1: I don't know, but he's a pretty famous dude in
Speaker 1: the history of parasitology and medical entomology especially, and he
Speaker 1: owes a big part of that fame to lymphatic hlariasis.
Speaker 1: In the late eighteen sixties and into the eighteen seventies,
Speaker 1: Manson worked as a medical officer in the Chinese Imperial
Speaker 1: Maritime Custom Service, and as a result, he treated many
Speaker 1: people with the infection. Seeing the full range of manifestations
Speaker 1: from what he called quote unquote scrotal tumor to classic
Speaker 1: elephantiasis and tropical chyleria like lymph in your urine, he
Speaker 1: realized that these conditions, which had been treated as distinct
Speaker 1: diseases for the most part, were actually all caused by
Speaker 1: the filaria worm that had been described by Lewis. Manson
Speaker 1: then went even further, suggesting that mosquitoes played a necessary
Speaker 1: role in the transmission of these filaria. His first hypothesis
Speaker 1: was wrong, though, which is that humans got infected when
Speaker 1: they drank water contaminated by the filaria which had escaped
Speaker 1: from their dead mosquito hosts. He later revised this with
Speaker 1: some colleagues and got it right. He also suggested that
Speaker 1: the diurnal activity of the worms in the bloodstream was
Speaker 1: directly tied to the periods when mosquitoes were most active.
Speaker 2: That's incredible. This was in what years did.
Speaker 1: You say, eighteen seventies?
Speaker 2: Wow, that is really fascinating.
Speaker 1: It's and this was the first time that an infection
Speaker 1: of humans was directly linked to mosquitoes, like shown to
Speaker 1: be linked to mosquitoes, that mosquitoes played a necessary role
Speaker 1: in the development and transmission of this parasite.
Speaker 4: Ah.
Speaker 1: So this was the birth of medical entomology as a field.
Speaker 1: Essentially what yeah. Manson's final major contribution to lymphatic philariasis
Speaker 1: was finding out exactly where those filaria go. When they
Speaker 1: disappear from the peripheral blood, the microflaria turns out its
Speaker 1: larger blood vessels like of the lungs and other places. Really,
Speaker 1: the only thing that he didn't do when it came
Speaker 1: to understanding the life cycle of lymphatic philariasis was demonstrate
Speaker 1: the presence of adult worms in patients with the infection.
Speaker 1: That honor would go to Joseph Bancroft, earning him the
Speaker 1: Bancrofty in Wucheria Bancrofty. Side note, Woucheria wasn't originally the
Speaker 1: genus name, but Ucheria's colleague wrote in after the name
Speaker 1: was announced, saying, my friend also deserves credit for discovering
Speaker 1: this parasite.
Speaker 2: My friend, I love that.
Speaker 1: Yeah, I mean, I don't know if it was my
Speaker 1: friend or it was like my colleague will not stop
Speaker 1: talking about this and complaining in the break room, and
Speaker 1: I really need you to make this change so that
Speaker 1: we can move on with our lives.
Speaker 2: I don't know. Could have been that too, either one.
Speaker 2: Either one.
Speaker 1: It works. The twentieth century saw more advances in lymphatic
Speaker 1: philariasis research, treatment, and control, including the discovery of additional
Speaker 1: species of filarial parasites, as well as patterns and disease
Speaker 1: manifestations associated with different species. Effective anti parasitic treatments were
Speaker 1: only developed really in the nineteen seventies, and they leave
Speaker 1: something to be desired considering the sometimes serious side effects
Speaker 1: associated with their use, as well as the fact that
Speaker 1: while many of them are great at killing the tiny
Speaker 1: larval worms of Microfilaria, they aren't super effective for the
Speaker 1: adult parasites. This is what you mentioned, Aaron, So treatment
Speaker 1: has to continue for many years, like you said, five
Speaker 1: to six before there's a chance of stopping the transmission cycle.
Speaker 1: And there is some suggestion that resistance to these drugs
Speaker 1: might be on the rise, which is terrible, terrifying. Given
Speaker 1: all of this, we better start looking for alternatives, right right.
Speaker 1: That's where Wolbachia comes in. What the heck is wolbacchia.
Speaker 1: It may sound familiar to you listeners out there because
Speaker 1: we've mentioned it here and there on the podcast before.
Speaker 1: A quick search of our transcripts shows that we've mentioned
Speaker 1: Wolbachia in our Dengae, chicken gunya, Rocky Mountain spotted fever,
Speaker 1: and of course our uncle ssarchiasis episodes. Walbacchia is a
Speaker 1: genus of intracellular bacteria, so they have to live inside
Speaker 1: cells that infects arthropods like mosquitoes and filarial nematode parasites
Speaker 1: like Wicheraia bancrafty and Brugia malai. I feel like I
Speaker 1: haven't said those species names the same way twice throughout
Speaker 1: this entire episode so far. Anyway, Waalbacchia are extremely widespread,
Speaker 1: with an estimated sixty five percent of all insect species
Speaker 1: infected with Wolbacchia pipientis, and nearly half of filarial species
Speaker 1: in Oncocircudae are infected, including nearly all of those that
Speaker 1: infect humans and those that cause heartworm in dogs and cats,
Speaker 1: which we should do an episode on.
Speaker 2: Ooh, it's on our list, it is.
Speaker 1: Yeah, you're right. How do these Wolbacchia get into their
Speaker 1: arthropod and filarial hosts in the first place?
Speaker 2: Well, I don't know.
Speaker 1: Yeah. For arthropods, it's a combination of vertical transmission to
Speaker 1: like female to offspring, along with horizontal transmission, which is
Speaker 1: unusual considering that these are intracellular bacteria like they have
Speaker 1: to live within a cell, but it seems that at
Speaker 1: least some research suggests that they can live outside of
Speaker 1: host cells for brief periods of time and go across
Speaker 1: cell membranes.
Speaker 2: So what are like mosquitoes pooping them out and infecting
Speaker 2: other mosquitoes? Like, how does that work?
Speaker 1: I don't know?
Speaker 2: Or is it like in arthropods that like consume other arthropods,
Speaker 2: so like that like food born?
Speaker 1: Yeah? Actually, I mean I I feel like it could
Speaker 1: be that for sure.
Speaker 3: Interesting and I think that it's and it's so fascinating
Speaker 3: because these patterns of transmission help to explain the genetic
Speaker 3: relationships among Wolbachia and their insect hosts.
Speaker 1: Whire's not necessarily a super close match.
Speaker 2: Interesting.
Speaker 1: Yeah. On the other hand, the bond between Wolbachia and
Speaker 1: filarial hosts is extremely tight. You can trace the evolutionary
Speaker 1: relationships among different species of filarial parasites by looking at
Speaker 1: the Wolbachia they harbor, because there doesn't seem to be
Speaker 1: exchange or much exchange of different Wolbachia strains among the parasites.
Speaker 1: Interesting In these species, Waalbaccia is transmitted exclusively vertically from
Speaker 1: female to offspring. What does Walbacchia do inside their arthropod
Speaker 1: and filarial hosts. I feel like we've talked about this
Speaker 1: a little bit a little bit, and I'm just going
Speaker 1: to talk about it, probably repeat a little bit again,
Speaker 1: no great detail. In arthropods, they often act as reproductive parasites,
Speaker 1: affecting things like sex determination, sexual differentiation, sperm egg incompatibility,
Speaker 1: and even the cell cycle, while in filarial parasites, Waalbaccia
Speaker 1: are more in a teammate mutualistic role necessary for reproduction,
Speaker 1: and that's generally how I found they're talked about. So
Speaker 1: for arthropod hosts, it's like Walbaccia can be detrimental to
Speaker 1: or at least like change things in a ways that's
Speaker 1: not necessarily beneficial to the arthropod host, whereas in filarial
Speaker 1: parasites they're necessary and it's like a mutualistic relationship. How weird,
Speaker 1: isn't that bizarre? Yeah? Yeah. Without Wolbacchia, many species of
Speaker 1: filarial parasites can't reproduce, and without their filarial hosts, those
Speaker 1: Wolbacchia also can't replicate. And it's this key feature of
Speaker 1: the filarial infecting wolbacchia. That has gotten researchers so excited
Speaker 1: over the past couple of decades because if there was
Speaker 1: some way to kill the Wolbachia inside the adult parasites,
Speaker 1: say through the use of antibiotics, it may not kill
Speaker 1: the parasites themselves, but it will prevent them from reproducing.
Speaker 2: Huh.
Speaker 1: And an antibiotic in combination with these existing antifilarial drugs
Speaker 1: could be the ultimate solution. So you're getting rid of
Speaker 1: the microfilaria throughout the bloodstream while also preventing the production
Speaker 1: of more microfilaria.
Speaker 2: Huh.
Speaker 1: Yeah. And Aaron, you talked about this treatment strategy in
Speaker 1: our Uncle Archias's episode, and you also mentioned I totally
Speaker 1: forgot to have your face.
Speaker 2: Is crazing, no memory of that whatsoever.
Speaker 1: So I didn't either because I looked up while back
Speaker 1: You're being like, okay, when do we talk about this,
Speaker 1: and you you went through this whole thing. It was great, Listen,
Speaker 1: we cover a lot of stuff.
Speaker 2: We do. I almost forgot that we had covered that
Speaker 2: until I was researching this and I was like, oh,
Speaker 2: we did, we did that already, we did that.
Speaker 1: Yeah, yeahsh I know.
Speaker 2: Yay.
Speaker 1: Yea.
Speaker 2: Anyway, but that's awesome.
Speaker 1: Yeah, yeah, And you also so in your wonderful explanation
Speaker 1: of how this could work, it really, it really was great.
Speaker 1: You also mentioned a couple of drawbacks, one of which
Speaker 1: is that while most anti filarial drugs can be a
Speaker 1: ministered once or twice a year, which is great in
Speaker 1: terms of like logistics, the recommended course for antibiotics primarily doxycycling,
Speaker 1: which is what would be used to treat the wallbacchia.
Speaker 1: That course is four to six weeks long, which, as
Speaker 1: you can imagine, is super logistically difficult, and taking doxy
Speaker 1: for that long is not recommended for children under the
Speaker 1: age of nine and people who are pregnant or breastfeeding.
Speaker 1: Those are some pretty major hurdles. Fortunately, there has been
Speaker 1: some promising research done on alternative antibiotics that have shorter
Speaker 1: treatment regimens or more specifically, target wallbacchia and leave the
Speaker 1: other parts of the human microbiome alone, right, Like, you
Speaker 1: don't want to just continually wipe out your gut microbiome
Speaker 1: for four to six weeks. Yeah, and then there's phase therapy,
Speaker 1: so possibly using bacteria phases, so viruses that infect bacteria
Speaker 1: to kill the Wolbacchia, and anyone who's interested in learning
Speaker 1: more about phage therapy should listen to our Antibiotics Part
Speaker 1: two episode for more of that story. In general. Yeah,
Speaker 1: but to me, the moral of the Wolbachia and lymphatic
Speaker 1: filariasis story is not a very surprising one at all.
Speaker 1: It's just that the more that we invest in learning
Speaker 1: about Wolbachia, in identifying species differences among these filarial parasites,
Speaker 1: in disentangling the relationship between the mosquito vectors and these parasites,
Speaker 1: in developing treatment programs that take into consideration logistical ease
Speaker 1: and long term efficacy, and in understanding the tremendous social
Speaker 1: and economic impacts resulting from infection. The more we do
Speaker 1: all of these things, the more we can reduce the
Speaker 1: burden that these ancient parasites continue to have on the
Speaker 1: tens of millions of people around the globe living with
Speaker 1: this infection. So, Aarin, tell me, where are we with
Speaker 1: lymphatic philiasis today?
Speaker 4: You have any good news for me? I have news, okay,
Speaker 4: I guess we'll settle for that. We'll get to it
Speaker 4: right after this break. So our numbers are unsurprisingly imperfect,
Speaker 4: but we have more than I feel like we've had lately,
Speaker 4: so let's get into it. So, first of all, an
Speaker 4: important piece of context when it comes to lymphatic philriasis
Speaker 4: is that in nineteen ninety seven, the World Health Organization
Speaker 4: classified this disease as erradicable or potentially irradicable, which I
Speaker 4: think we've talked in previous episodes about like what makes
Speaker 4: a disease a good candidate or a good target for eradication,
Speaker 4: But it's a lot to do with how it's transmitted,
Speaker 4: whether it can infect non human animals, et cetera. So
Speaker 4: in any case, the World Health Organization said, yeah, this
Speaker 4: is one we could do this, and in two thousand
Speaker 4: they created the Global Program to Eliminate Lymphatic Fileriasis and
Speaker 4: they pass a resolution with a goal to eliminate the
Speaker 4: parasitic infection of lymphatic philriosis by the year twenty twenty.
Speaker 4: This isn't that story, it's not eliminated spoilers, But let's
Speaker 4: talk about where we were and where we are. So
Speaker 4: where did things stand in the year two thousand and
Speaker 4: where do things stand now in the year twenty twenty three,
Speaker 4: three years after this elimination target. In two thousand. Before
Speaker 4: this program, it was estimated, depending on which paper you read,
Speaker 4: that's somewhere between one hundred and twenty five to two
Speaker 4: hundred million people were living with lymphatic philariasis. Most papers
Speaker 4: were around the one hundred and twenty million people estimate,
Speaker 4: but at least one was two hundred thousand.
Speaker 1: That's just it's so many people. It's so many people.
Speaker 2: It's so many people. And within that that's an estimated
Speaker 2: forty to forty five million of whom had actual clinical
Speaker 2: overt symptomatic disease mm hmm. And in addition, between one
Speaker 2: point one and one point two billion people, that's eighteen
Speaker 2: percent of the global population was living in an area
Speaker 2: at risk.
Speaker 1: Oh my gosh, mm hmm.
Speaker 2: At this time in the year two thousand. It was
Speaker 2: also estimated that lymphatic filariasis caused almost five million billion
Speaker 2: disability adjusted life years annually, which is the highest of
Speaker 2: any tropical disease after malaria. It cost over a billion
Speaker 2: dollars just in lost productivity every year, and the total
Speaker 2: cost of the burden of lymphatic filariasis was estimated at
Speaker 2: five and a quarter billion dollars every year.
Speaker 1: And again is still to this day a leading.
Speaker 2: Cause of disfigurement, which leads to so much stigmatization and ostracization,
Speaker 2: and the second leading cause of permanent disability worldwide. So
Speaker 2: that's two thousand. Then there's this initiative mass drug administration
Speaker 2: all over the place. Let's eliminate it. By twenty eighteen,
Speaker 2: it was estimated that the number of people living with
Speaker 2: lymphatic philariasis had dropped to just over fifty million people.
Speaker 1: That's amazing progress.
Speaker 2: It's amazing progres It is nowhere near eliminated, No, but
Speaker 2: it is incredible progress. And this is where I really
Speaker 2: want to get into some public health information because what
Speaker 2: I think is really interesting to look at in these
Speaker 2: numbers is to try and understand not just how have
Speaker 2: we decreased the global burden of disease, but how much
Speaker 2: disease have we potentially prevented? Yeah, because when you think
Speaker 2: about it, especially in the case of lymphatic philoriasis, the
Speaker 2: mainstay of these programs was and remains mass drug administration
Speaker 2: of these anti parasitic drugs that sure can prevent the
Speaker 2: progression of disease, but primarily are designed to interrupt transmission.
Speaker 2: And what interrupting transmission does is prevent people from getting
Speaker 2: infected or from getting more infected than they already are.
Speaker 2: These campaigns were not and are not curing disease for
Speaker 2: those who already have damage done. It's not fixing the
Speaker 2: damage causing lymphianema, causing eventual elephantiasis, right, And so in
Speaker 2: public health, one of the things that can be really
Speaker 2: difficult is quantifying that impact. Because if you're doing a
Speaker 2: good job in public health, and we've talked about this before,
Speaker 2: you're preventing things from happening. And if you're doing that,
Speaker 2: you're not like making money, which is what agencies care about.
Speaker 2: You're saving money and saving lives and preventing disability. But
Speaker 2: it's really difficult to measure that because you're measuring things
Speaker 2: that don't happen rather than things that do happen.
Speaker 1: Right.
Speaker 2: So to try and quantify this, I found a really
Speaker 2: great paper from twenty twenty two that I really enjoyed
Speaker 2: that used modeling math modeling to try and estimate based
Speaker 2: on how many treatments have been provided, based on places
Speaker 2: where risk still exists, and what the numbers were like
Speaker 2: in terms of infections prior to the start of these
Speaker 2: campaigns compared to what they are now to try and
Speaker 2: mathematically estimate how much of an impact these mass drug
Speaker 2: administration programs have had on the global burden of lymphatic philoriasis,
Speaker 2: specifically at three different cohorts of people. First is people
Speaker 2: who are protected from ever getting infected in the first place.
Speaker 2: Secondly is the cohort of people who had disease but
Speaker 2: are being protected from progression to symptomatic disease, which is
Speaker 2: like secondary prevention. And then thirdly is that those you
Speaker 2: are preventing from having even worse morbidity from this disease. So,
Speaker 2: based on this paper, the estimates are that between twenty
Speaker 2: and twenty twenty, this program has benefited a total of
Speaker 2: fifty eight and a half million individuals, six million of
Speaker 2: whom that's forty four percent are primary prevention. That's twenty
Speaker 2: six million people who never got infected as a result
Speaker 2: of this program.
Speaker 1: That's amazing.
Speaker 2: Fourteen point eight million people were in that second cohort
Speaker 2: that is people who had the disease but are prevented
Speaker 2: from symptomatic disease by administration of these drugs at large,
Speaker 2: and seventeen point seven million in that third cohort. People
Speaker 2: who already have clinical disease, but at least are prevented
Speaker 2: from getting worse and worse and worse. So what that
Speaker 2: overall looks like is the prevention of an estimated forty
Speaker 2: four million cases of symptomatic lymphatic phileiasis, symptomatic hydroceal or lymphidema.
Speaker 2: And if you project that over the lifetime, it's estimated
Speaker 2: that these programs have averted two hundred and forty four
Speaker 2: million dollar disability adjusted life years. So like, you're not
Speaker 2: seeing that progression of disease. Does that make sense? Yeah?
Speaker 1: And it's it's incredible and I feel like it's a
Speaker 1: really important thing that you can you know, we look
Speaker 1: at oh, the elimination goal was twenty twenty and there
Speaker 1: were still fifty million cases, But like, okay, what aren't
Speaker 1: we seeing, right, Like what what else has been done?
Speaker 1: And it's a long process, but it is I think
Speaker 1: it's really I like hearing about these things that are
Speaker 1: more difficult to measure, but that are estimated secondary impacts
Speaker 1: of this program, of this initiative.
Speaker 2: Right because it's also again a chronic disease that people
Speaker 2: who at the start of this program, who already had
Speaker 2: clinical and symptomatic disease. These mass drug administration programs are
Speaker 2: not treating them. They are, as we see in this
Speaker 2: math model, potentially preventing further morbidity. But the point of
Speaker 2: these mass drug administration campaigns is really in the prevention
Speaker 2: of disease, primary and secondary prevention, which is really incredible. Now,
Speaker 2: what's important is that these are models, and like all models,
Speaker 2: they're only as good as the data that is input
Speaker 2: into them, and inevitably the data that existed prior to
Speaker 2: the start of these campaigns was limited in terms of
Speaker 2: what the true prevalence was prior to any of these
Speaker 2: controls and the baseline disease burden. And of course we
Speaker 2: are still talking about tens of millions of people who
Speaker 2: already have clinical disease, and these campaigns are not ever
Speaker 2: going to be enough to treat their conditions. So there
Speaker 2: is a huge need for accessible and adequate treatment and
Speaker 2: management even after the interruption of transmission for this chronic disease.
Speaker 2: Because despite how much progress we've made, there are also still,
Speaker 2: like you mentioned, Aaron, nearly a billion people who live
Speaker 2: in areas that are still at risk. So where do
Speaker 2: we go from here? Yeah, like you mentioned, aaron. In
Speaker 2: addition to the mass drug administration campaigns, there is a
Speaker 2: promise of potentially targeting this bacterial and asimbiant Wolbachia. And
Speaker 2: I find it hilarious that I talked so much about
Speaker 2: this in the onco psarchiasis episode, because I don't remember that,
Speaker 2: and because nothing that I saw talked specifically about using
Speaker 2: antibiotics per se to target it. But there have been
Speaker 2: an effort to produce vaccines that specifically target Wolbakia rather
Speaker 2: than vaccines that target the filarial worm itself. However, there's
Speaker 2: also a theoretical promise for the development of vaccines to
Speaker 2: target Worschharia bancrofty specifically, although most of the vaccines under
Speaker 2: development use Brugia as their model because it's easier to
Speaker 2: grow in other animal species, so it's easier to use
Speaker 2: in the lab.
Speaker 1: Like one great thing about w. Scheria bancrofty. The only
Speaker 1: great thing is that it is potentially irradicable because it
Speaker 1: only infects humans. But that does make it harder to
Speaker 1: study in lab settings.
Speaker 2: Right, So we have this other species that we use
Speaker 2: primarily to like grow and do these vaccine studies and
Speaker 2: things like that, but not it's imperfect. Yeah, but there's
Speaker 2: a theoretical promise based on like this possibility that you
Speaker 2: can in fact develop immunity against these parasites. But it's
Speaker 2: really tricky because mostly our immune system develops this tolerance,
Speaker 2: which isn't necessarily going to be enough to have a
Speaker 2: vaccine that actually prevents infection. So far, the studies that
Speaker 2: have been done have at least suggested that any vaccine
Speaker 2: that is developed would have to be a multi antigen
Speaker 2: vaccine because anything that they've tried so far that targets
Speaker 2: just a single parasitic antigen definitely hasn't worked, which makes
Speaker 2: sense when you think about how complex and interrelated the
Speaker 2: relationship between this pherasite and our immune system is at baseline.
Speaker 2: So all that is to say that there is a
Speaker 2: lot of work being done to try and develop novel
Speaker 2: therapies and novel vaccines to try and reduce the burden
Speaker 2: further of this disease, but it remains the second leading
Speaker 2: cause of disability worldwide, and a huge cause of stigmatization
Speaker 2: and ostracization in so many parts of the world, predominantly
Speaker 2: in parts of the world that are incredibly impoverished and
Speaker 2: have limited access to healthcare already. So that's lymphatic philriosis sources. Sources.
Speaker 2: People can read so much more.
Speaker 1: There is so much more out there. I have a
Speaker 1: bunch of sources, but I want to shout out in
Speaker 1: particular the Cambridge World History of Human Disease, which had
Speaker 1: some great info on the history of lymphatic philriide. And
Speaker 1: then there's a great paper on Wolbachia by Baucherie at
Speaker 1: All from twenty thirteen called the Symbiotic Role of Wolbachia
Speaker 1: and Ancosirchia day and its Impact on Philariasis.
Speaker 2: I had a few papers for this. One of my
Speaker 2: favorites for just like general biology, was a twenty ten
Speaker 2: paper in the Lancet titled Lymphatic Philriasis and Oncopsychiasis, and
Speaker 2: another one titled Emphatic Philariasis that was in the Journal
Speaker 2: Nursing Clinics from twenty nineteen. And if you want to
Speaker 2: know more about that math modeling study which was an
Speaker 2: excellent read, that is from Parasites and Vectors twenty twenty
Speaker 2: two and it was titled a Refined and Updated Health
Speaker 2: Impact Assessment of the Global Program to Eliminate Lymphatic Philariasis.
Speaker 2: But we will post all of our sources from this
Speaker 2: episode and every one of our one hundred something or
Speaker 2: other episodes on our website, This podcast will Kill You
Speaker 2: dot com under the episode's tab.
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Speaker 1: learned something new.
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Speaker 1: You are amazing. Well, until next time, wash your hands
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