It just went completely white. This is how fishermen A Coo yo Osumaka describes going blind in twenty eleven in the remote village of Babagulu in the Democratic Republic of Congo. It was a slow creeping blindness that began a year earlier. It robbed him of his livelihood and threw his family life into disarray. Tragically, A Koyo had once fought against the disease that eventually robbed him of his sight by volunteering to distribute drugs that help prevent transmission of river blindness.
The River Onane runs through Babagulu and is a perfect breeding ground for the black flies that swarm through the village, infecting people with filarial worms that cause river blindness. A Koyo is one of the many living in the village with the disease. Community leaders think that up to three percent of the community is blind. A Koyo felt the need to help, so he volunteered to help distribute ivermectin. These programs rely solely on unpaid drug dishries readers to
work within their communities. He would travel to neighboring villages, often deep in the bush, to distribute the drugs. He was often bitten during his travels. One day, his village had a stock out of the drug and he stopped taking it. I was told to deliver all the drugs and then I would take it later once I started to have symptoms, he remembers, but then there were no more drugs to take. He then ended up missing distribution programs in his village because he was out fishing in
forest streams. In twenty ten, a Koyo started to have difficulties seeing, and in twenty eleven he went completely blind. His son, Ato, does not go to school and had to quit his job because of the stress of caring for his father. Itto has a number of nodules on his torso and forehead. The adult worms that cause river blindness live in these fibrous nodules. Taking care of his father is a full time job. Ito also suffers from
epileptic seizures about four times a month. Researchers have noted a potentially causal relationship between UNCO Sarkaiais infection and forms of epilepsy found in Africa. I depend totally on my wife. She feeds and dresses me, says a ko Yo. Even my wife doesn't have a job. After I lost my sight, we couldn't send any of our children to school.
That's horrible.
Yeah, it's a tough and unfortunately not uncommon story.
Yes, so that was adapted from an article titled Revealing the Neglect river Blindness from March thirtieth, twenty eighteen on the website for Drugs for Neglected Diseases Initiative, and we will link to that story on our website. And you should definitely check it out because not only is there more story to it, but there's also a really cool video which is the story animated along with a traditional song recorded in a Koyo's region about river blindness. So
definitely check that out. Hi, I'm erin Welsh and I'm erin alman Updike and this is this podcast will kill you. Welcome, Welcome to another parasitic disease episode of our podcast.
I'm very excited about another parasitic disease, another vector born disease.
Yeah, me too. It's super complicated, which gives us an opportunity to talk about all kinds of different aspects of this parasite, of this vector, of the human side of disease, of the history it's I think complex is one word.
I think it's I think it's classic TPWKY.
Aaron, Yeah, it actually it really is. It is. Yeah, So what are we even covering this week?
Erin we are covering oncossarchiasis.
Aka river blindness.
Yeah.
Yeah.
It is truly a very classic TPWKY episode in so many ways.
And speaking of classic TPWKY, we have to start this episode with a quarantiny A quarantiney. What are we drinking this week?
We're drinking as the worm turns.
This is one of my favorite quarantine names.
We went we went back and forth for a long time, but Aaron went out, it is very good.
Well, and so I think that we were like, well, we should save this because we're gonna do more wormy parasites in the future, and this is a really good name. Should we do something else for this? But I found a quote from a researcher who was describing these that describes the worms as being undulating and turny, and so, like, you know, it was just too good to pass up.
I mean, they are very turny worms, Like, definitely they are.
And also I really feel like now that we're getting into the whole like worm and world. Swapping out those two words and idioms or whatever, We've got a whole host of opportunities for future quarantine names exactly.
This is not going to be the end of the worm me world phrase at all.
It's a it's a small worm, after all, I can't remember the other ones sitting on top of the worm.
Keep an ear out, Aaron. What is in as the Worm turns? Okay, yes, let's let's do that. In as the Worm Turns is cognac ginger, simple syrup, lemon juice, and a splash of sparkling water, and you garnish it with some candy ginger. It's actually really refreshing and good.
Yeah, it sounds really good. It sounds both like warming and refreshing somehow.
Yeah. And we will post the full recipe for this quarantini as well as our non alcoholic plus sy burrita on our website This podcast will kill You dot com as well as on all of our social media channels, so make sure you follow us there.
Excellent. Any other business that we should attend to before we dive into this very interesting episode.
There's the usual stuff. Go to our website. It contains links for merch for bookshop dot Org affiliate account for Goodreads reading list, for transcripts, for alcohol free episodes, for anything. Any source you ever want to find on that we reference on this podcast, you can find it there.
Yeah, definitely check out our website.
Okay, is there anything else, Sarin?
I think that you pretty much covered it quite well.
Wonderful, wonderful. Well. In that case, should we dive into the episode.
Yeah, let's take a quick break and then we'll dive into the biology. So, Ancosarchiasis is a disease that is caused by a nematde around worm named Anco circa volvulus, which is a type of worm known as a filarial worm, which means it's a nema toad transmitted by an arthropod vector. In this case. Oncopsychiasis is also the second leading cause of infectious blindness worldwide, after trachoma, which is a bacterial
disease caused by chlamydia trichomitis. So, since this is a arthropod vectored worm, let's jump straight into talking about the transmission and life cycle of this parasite, shall we.
Let's do it.
So, the overall life cycle of this parasite is not very dissimilar from a number of vector born diseases that we've covered on this podcast, but it is a different vector species than we've seen before. In this case, it's a black fly in the genus Stimulium. The black fly
bites your skin generally much like mosquitoes. It's female blackflies that bite a human, take a blood meal, and in that blood meal ingest microfilaria, which are the earliest teeny teeny baby newly hatched larval stages of Onco circa volvulus. These microfilariae travel through the fly's gut. This is where it gets weird. They penetrate the gut walls, which we've seen other parasites do, but in this case they migrate to the flight muscles of the fly like very weird,
very weird. I just have to imagine there's a lot of glucose happening, because those are important, powerful muscles, but I don't know. So in these flight muscles they live for a short time and in that time they mature into a second stage larva, and then from there they make their way down into the salivary glands near the proboscis.
They mature one more time into a third stage larva and are now infectious, so that when the black fly takes its next bite of human flesh, they can be out spit out those third stage larva just under our skin. So that whole process in the blackfly takes about a week, give or take. And now in the human these larvae that have been injected just under our skin will worm and twirl. As the worm twirls the worm turn, they'll worm their little way into our subcutaneous tissue and that
is where they will live. They'll make a little home for themselves in these little subcutaneous nodules that they kind of build and create, and they are pretty well protected from our immune system, which will become important later on. They feed off of our blood and both by actively feeding but also just by soaking up nutrients through their cuticle, and over a period of about ten to fifteen months
or so, they mature into adult worms. They mate and then begin really leasing thousands of eggs which quickly hatch into microfilaria. Every day during the day, these little microfilaria worm their way back up to the skin's surface, where they can then be ingested by blackflies, which coincidentally bite during the day. Thus completing their life cycle.
Question. I know, so you said that the when the L three larvae are injected into a person and they form this little subcutaneous nodule that in which they're fairly protected from the immune system. How like, why are they fairly protected there? Because a lot of things could be injected into our skin and not be protected from our immune system.
It's a it's a very good question, and it's a it's a question that I don't have a good answer to. I will talk in a lot more detail about what causes an immune reaction to us, but the question of why is it that living worms don't provoke much of an immune response in us is a very good one and not one that I have a good answer to.
And is that universally or are there people that do show immune responses and are like more protected from this parasite than others?
So people don't tend to show immune responses to the living worms aside from the formation of these nodules, which you could think of as some kind of immune response, because it's kind of like, you know, making a little fibrous sheath around those worms and kind of walling them off from the body in some ways. But otherwise there's not much of an immune response that's provoked by the presence of the live worms themselves.
That's wild I know, it gets wilder and so like the immune system isn't even showing like elevated antibodies or it's not is it suppressed? Like are people who are infected with this worm? Are they more susceptible to other infections? Of going like down the rabbit hole of questions here.
You're going so many miles a minute. Let me, let me keep going, and I'm not sure if I'm really going to answer your questions or if I'm just gonna bring up even more questions. Let's find out.
Okay, I'm along for the ride either way.
Excellent, good, I'm so glad. Okay, So these adult worms that are living in these nodules, they can live for years. We're talking ten to fifteen years or more. Oh yeah, okay, and this whole time they're producing thousands, if not millions, of microflaria that whole time, not continuously. They kind of cycle, like every two to four months or so, they'll have a cycle. But anyways, ten to fifteen years.
I have an estimate that I wrote down that because I was so horrified. So, the number of microfilaria released from one female adult worm during its life life of ten to fifteen years is estimated to be greater than ten million.
Yeah that seems about right, because it's like two to three hundred thousand per cycle. Yeah. Yeah, that's a lot of lost, it really is. Okay, And so before we get into what the symptoms of this disease are, what I want to tell you. You're going to get mad at this. All of the symptoms that we see stem not from the worms themselves, but from our immune response to the worms.
Oh but hold on. You made a very strong point of saying the living worms. So I'm guessing these are dead worms.
You are exactly right.
But you're right. I was like, wait a second, errand then I remember.
I know.
So it turns out that they do not trigger these intense immune reactions until they die. So of course we have to answer the quiet why the heck? And how the heck? So it's thought that the immune response that is triggered is in part due to proteins and other like inflammatory markers that are released by the dying worms themselves. So proteins and things that are inside the worms, but
then not accessible to our immune system until that worm dies. Okay, but far more importantly and interestingly, it's also thought to be due largely to the release of the bacterial endosymbiants that they harbor.
Say what, it's so strange. Wolbachia has so many mysteries that surround it.
So many mysteries. So we have talked about wolbachia on this podcast before, briefly in I think our dengay episode, because they're important in the context of mosquitoes that transmit dungay and other arboviral diseases. As a recap Willbakia are a genera of bacteria that often inhabit the guts of
insects and other invertebrates. But it turns out that in filarial nematodes like oncocercavolvulus, but also Wucheria bancroftyi, which is the coosative agent of lymphatic philoriasis and other nematodes, these bacteria are essential endosymbionts. So without these bacteria, the nematodes cannot survive or reproduce. We still don't know exactly what it is that they are doing necessarily, but we do know that they are essential to the process of embryogenesis.
So eggs can't develop into worms without the presence of these bacteria which are transmitted transovarially.
That is so interesting.
I know.
And it seems that based on a lot of data, the release of these bacteria from dead worms is thought to be a major part of the trigger for our immune response.
And so how does this trigger look different compared to like other parasitic infection triggers.
So that's what's so interesting is that what we see is still a lot of eosinophil response, which is what you would expect with a parasitic disease, not solely though. Antibodies have a large role as well in the inflammation and the immune response to acopsychiasis, as do neutrophils and other lymphocytes, and these are all different types of white blood cells. But you still do see a really large
eosinophil response, which is interesting. So maybe those are responding to the worm parts, and it's the neutrophils and lymphocytes and antibodies that are responding to the bacteria. Who knows, We don't fully know. But I'm also going to put a pin in that, and I just want for us to remember how important while bakia are because we'll talk more about them in the current events section. Oh yeah, yes, all right, So then what does this disease actually look
like in its mildest form. It's possible that the only symptoms that you would have are these nodules that we've talked about. So these nodules are very kind of hard, deep subcutaneous lumps, I guess is the best word, often around the hip girdle, but you can also have them really anywhere throughout your body. They tend to be most prominent where you have like a bone, just because then you have less subcutaneous tissue between your bone and your skin.
But in terms of symptoms that we see in the mildest symptoms present as a skin rash, which is usually what we call maculo popular. That means a flat area of rash with a lot of little bumps on it that is incredibly itchy. Right, I think it's it's hard. The word itchy. I feel like it doesn't do. It doesn't right, it doesn't invoke I think the response that that this really deserves no. Yeah, so it's yeah, I wish I had a better word than just incredibly itchy.
So this rash can resolve in some cases, although the disease itself does not resolve, like we said, these worms can live for years. But more commonly, this rash can become chronic and can actually generalize across the body instead of being present in just discrete patches. And this, as you can imagine, leads to even more severe itching. And then as our immune response ramps up, the way that our skin kind of heals results in very severe scarring.
It's what's called like henification, like a like a lichen that grows on a tree. Yeah, so it's like our skin becoming really thick and leathery. At this stage, it can lead to hyper pigmentation of the skin, so it
becomes very very dark in patches. And like we talked about in our leshmaniasis episode, these type of skin manifestations can be associated with a lot of stigma, and so they can be debilitating, not only in the physical sense, like the amount of itching I saw it described where some people couldn't even sleep except for on their knees and elbows because of the pain of the itching.
Yeah. I saw some descriptions of people literally like burning their skin because it was so horrifyingly itchy.
Itchy, but it can also be debilitating in the way that it is stigmatizing as well. And then over years of this infection, the changes can become even more chronic, and the descriptors of these changes in the literature I think are also pretty stigmatizing. But basically what can happen is the skin can end up with its elasticity completely destroyed because of all of that damage to the kind
of mid layers of the skin. So then the very top layers become really thinned out, they become atrophied, they're quite wrinkily, and they can just sort of hang off of the body. You can lose pigment entirely in those areas because of all the atrophy, and so the skin manifestations can be severe and this whole time, even as it becomes chronic that itching persists.
And okay, question real quick again about the nodules when like where those nodules exist is where the blackfly has bitten you, or like how much how much variation is there?
Yeah, there's quite a lot of variation, which is so interesting. So from what I read, black flies often like to bite on lower extremities, so they really bite a lot on legs, But these nodules tend to be present on the hips or even the forehead and on the head. So that would suggest that these adult worms can travel and decide where they're going to make their nodule home. But it also means that the microfilaria which are traveling to the skin surface can also travel a really long way.
They can go pretty much anywhere in our body, right, Yeah.
And I also thought I read somewhere too about like because and I know you haven't gotten to this part yet, but the Americas versus Africa in terms of the location and frequency of the skin nodules blackflies have different biting patterns right on, Like, they bite more on the upper half of the body and the America's compared to Africa, where it's on the lower parts of the body.
I would believe that because I did read about a lot more forehead nodules and things in the Americas compared to in Africa. Yeah, okay, okay, So that's kind of all of the skin manifestations, which is one of the most important parts of this disease. The other is, of course, the ocular or the eye manifestations. Well, that's where it gets the common name river blindness. So as these microfilaria travel out of nodules and towards the skin, some of
them can travel to the eye. In the eye, the microfilaria that die also cause a localized inflammatory reaction and this results in a number of different manifestations kind of The most common one is called sclerosing keratitis, which is where the cornea of your eye, which is the part that covers like your iris and your pupil that becomes
inflamed and then will scar over. So this starts with a haziness around the edges of the cornea and then will eventually go in to encompass the entire thing, causing complete blindness. Oh yeah, it's not only sclerosing keratitis, because you can have these worms that end up in the posterior part of your eye, which can cause inflammation of the retina and similar kinds of damage due to inflammation
in all parts of the eye. And I think it's also important to point out that these microfilaria can travel kind of throughout the body and invade, for example, our lymphatic system, and they've been found in a number of different organs. Like, if you sample organs from someone who's died who was infected with ancosirchiasis, you can find microflaria in a number of different organs, but we don't really have a good handle on what kind of disease might
be caused by that. It's really the skin and the eye that are the two most common organs affected, right, So yeah, I also want to mention because it's important, but also because it was brought up in our first hand account. There does seem to be increasing evidence that infection with unchosirchiasis is also associated with an a increased risk of epilepsy.
Is there any suggestion as to what the mechanism could be?
None at all, which is the hardest part. So there's a lot of epidemiological evidence of association, but there's not really any data on what could be the cause or the mechanism. So we don't really know if it is in fact oncosyarchiasis or something else. But there's epidemiological evidence for this association, so I thought it was important to mention.
Yeah, definitely.
Yeah, So yeah, that's kind of the basic overall picture. I think it's interesting that there does seem to be some strain differences. So in parts of West Africa, it's long been noticed that in the savannah regions the rates of blindness due to Anco circa were much higher than in forested regions of West Africa. And in those savannah regions, the rates of blindness really strongly correlate with the intensity of infection. So the more heavily infected somebody is, the
higher their risk of ocular complications. But in other areas, like in forested regions, that that doesn't seem to be the case. And so it turns out that there are different strains of Anco cercovolvulus. But what I think is so interesting about this is that there's also some evidence that part of the differences in these strains is how much wolbakia they carry erin.
It's well, and it's not it doesn't seem to be just that, as I'll get into, but it's really Yeah, that's definitely an interesting component for sure.
Oh my gosh. So that's pretty much the whole biology, aside from treatment. Do you have any questions arin before I talk briefly about treatment.
Did you say already how long these worms are?
No, I was just about to Okay, these worms that adult females get to be up about thirty centimeters thirty to eighty centimeters long, which is over a foot.
That is two very long, and yeah wow.
And then in each nodule you'll also have one or two males. But what is fascinating is that these males travel around nodule to nodule. They go like beg boop boop boop, traveling along because the females have to be reinseminated every time they have a reproductive cycle.
Hmmm. Interesting. Cool.
By the way, the microfilaria are so so so tiny. They're like two to three hundred microns, which is about the length of two sheets of paper is wide, that makes sense.
Very tiny, Yeah, it's very.
Small, and then they grow up to be quite large. Yeah yeah, okay, So what do we do about it? Yeah, we do have something that we can do, which is phenomenal treatment. Though, like I said, we can't just kill all of the adult worms outright because that would trigger a huge immune response. So treatment is actually via a drug called ivermectin, which is an anti parasitic that is very effective at reducing the load of microfilaria in the skin.
For several months at a time, which helps not only with symptoms, but it also reduces the risk of complications like blindness. It doesn't, though, kill the adult worms at all, not even slowly. What's so fascinating is that ivermectin is a neurotoxin and it works on channels that we have as vertebrates as mammals, but we have a blood brain barrier, so in us it doesn't have the same effects. Oh, isn't that cool. So it's actually a very safe drug,
which is awesome, yeah for humans, not for worms. But while it causes a flaccid paralysis and eventual death in the microfilaria, in the adult worms, what it does is just kind of block them from releasing eggs for a short period of time, so it's thought to kind of paralyze their reproductive tract, but not much else. Okay, which is so fascinating. I tried so hard to get the like, why why can't this kill an adult worm? But I don't have the answer to that. I don't know.
Yeah, that's very it's so interestrange.
Yeah, but that's the biology of ancosnychiasis.
Oh, it's a it's a big one. It's a big it's so interested, it's so interesting. There's so many steps, and there are so many different components. And that's sort of the theme also that I will talk about in the history.
Would you please, would you please? I'd love to hear it.
Let's take a quick break first, and then I'll dive right in. I feel like I start off most of these histories, or at least a lot of these histories, especially in episodes about parasites, saying that you know, this disease has been around forever, like millions of years forever, and then I go on to talk about how there was this fossilized poop found or evidence of infection in a mummy. And so I was surprised when I started researching for this episode that I wasn't finding any of
that for uncosychiasis. Where were my ancient Egyptian papyri, Where were my coprolites? None of it. Maybe they are out there still waiting to be found, either by me in the literature or by a budding paleo epidemiologist or something
like that. Let us know if you find anything. But most articles I read discussed the early history of uncosirchiasis as starting either at the evolutionary roots of the parasite that causes the disease, or they jumped ahead to the early scientific work classifying this parasite and detailing its transmission route and disease characteristics. And so we'll get to that part eventually, But first I want to go back, of course, to the evolutionary ecology of this parasite. Yes, did it
come from? How did it get to be distributed the way it currently is, and what role does the ecology of this complex parasitic infection play in its establishment and
continued persistence. Okay, here we go. This disease, ancosarchiasis exists in two main areas of the world, Africa, where ninety nine percent of cases occur in Central and South America, where it's a lot more localized and less prevalent, partly because of control efforts that I'll go into later, and partly because of the history and ecology of the parasite itself.
And so based on this distribution, it's probably not that surprising that the parasite evolved in Africa and then was brought to the Americas at some point during the slave trade beginning in the early sixteenth century.
Makes sense, But what.
May be surprising is that although the genus Anco circa is likely millions of years old and also originated in Africa, the species that causes river blindness, Anco Circa volvulus, is a relatively recent parasite of humans.
Okay. I saw that somewhere, and I was like, what, I didn't mean anymore because I wanted to.
Okay, Well, because genetic analyzes that have compared like many different species in the Anca cerca genus show that Anca circa volvulus likely evolved from the ancestor of Anca Circa ochngi, which is a parasite of African savannah bovids.
Okay, but I'm so confused by that, Aaron, because Anco circa volvulus is pretty much a human specific parasite.
Yes, So that is since this this evolutionary pathway, like this speciation is supposed to have occurred only within the last ten thousand years or so, because it's supposed to correspond to the period when cattle were domesticated, and that's when humans would have come into contact.
What are you telling me?
Well, and there's a side note too. Cattle were domesticated between like ten thousand and thirty seven thousand, six hundred years ago in parts of Asia, but domestication is actually thought to take place later in Africa, like maybe between four thousand or fifteen hundred years ago. What And so it might be that this parasite evolved so rapidly.
Yeah, that's bananas.
I know. And there's more on this too, Oh my gosh. So for much of that ten thousand year history, let's just call it ten thousand years, this parasite stayed in Africa. It drove human settlement patterns in such a way that perhaps people would settle near a river or a lake. And then as more and more people developed this horrifically itchy skin condition or they lost their vision, they moved away to land that was further away from these sources of water. So the land was often less arable, it
was more susceptible to erosion. And by the way, this is still happening today, like, for example, in parts of Ghana, where people have moved away from these high anchro psychiasis prevalence areas to more crowded, less arable areas that have led to an increase in nutritional deficiencies and food instability. But I'm getting ahead of myself. So yeah, so let's go back to this remarkably short evolutionary history. This is
an obligately human parasite. Yeah, like they have shown, you know, incidental infections in a gorilla I think I've seen, or in some other animals, but it is human specific.
There's no animal reservoirs for Anco circa volvulis. It's a human disease.
Right, And so within a relatively short time span, like let's say, conservatively ten thousand years, this parasite went from a bovine host to just humans as hosts truly, and so this definitely seems like there were some strong forces that drove speciation. And there's also some evidence that suggests that there might be speciation happening currently within the parasite species on Cacerco vulvulis.
Stop it.
Yes, and you touched on a little bit of this and talking about the strains, okay, and I want to talk a little bit more about that and about the ecology of this system overall. So, as you mentioned, this parasite species is transmitted by multiple species of simuliad blackflies, and the distribution and habitat preferences of these blackflies varies
quite a bit. And warning this is going to be oversimplified, okay, But in Africa, for instance, you have some blackfly species that are savannah dwelling and those that are forest dwelling. And you mentioned that there are vana strains of the parasite and forest strains of the parasite, and these different
blackfly species transmit those corresponding strains of unca cercovulbulus. Yeah, and what happens when researchers try to take a savannah strain of the parasite and put it in a forest dwelling black fly, They found that the parasite developed poorly or not at all, And the same thing happened with the forest strain of the parasite in the savannah dwelling blackfly. What ain, Yes.
And there's some regions that they can be coinfected. So is that maybe like I'm getting too too complicated.
Well matter, what it seems is that that's fairly uncommon, like it's happening more today, possibly because of control efforts and how that sort of changed the landscape of disease in this case, but at least like historically, it really does seem that there has been sort of this something, some sort of barrier preventing the mixing of this like
savannah strain and this forest strain of the parasite. What and so, what some researchers think is that these different parasite strains may actually be diverging from one another.
So we're gonna end up with two species.
Mm hmmm, possibly, Oh my gosh. I mean. And it also makes sense because these parasites rely so heavily on these flies for their transmission and development that they may become in a sense, reproductively isolated quite easily. So basically how I was thinking of it is that like the adaptations that these parasites have to survive and develop in one black fly species might not be the same ones that would allow them to do the same in others.
And for what it's worth, these parasites don't seem to be harmless hitchhikers for these flies, like at least for some of the species or vector parasite complexes. And there have been some studies confirming that some blackflies show innate and acquired resistance to filarial infection.
I love that. I love when insect vectors have fight responses.
Oh yeah, and so because there's such like let's call it a tenuous relationship between the parasite and vector. It might be that putting all of your like, you know, adaptive eggs in one blackfly basket might be a favored strategy in terms of evolution.
Yeah, you get really well adapted to that specific immune response.
Mm hmmmm hmm. In any case, this diversity of blackfly species and the complicated interactions between different strains of the parasite and different species of fly is just one example of the incredibly complex disease ecology of this parasitic infection. And I also think that this episode is a great
opportunity to talk a bit about disease ecology in this context. Yeah, because we get a lot of emails from people asking us the difference between epidemiology and disease ecology, and I feel like, even though I technically have a degree kind of in both, I still don't feel very qualified to go into those differences same, but I'm gonna try. So there's a lot of overlap between these two fields, and I think that this disease is a good way to show at least some examples in ways that the approaches
or research questions could be different. And so overall, epidemiology is often defined very broadly as the study of patterns of disease and health in populations, and disease ecology is more concerned with the role that the environment and evolution play in the interactions between host and parasite. And so, for example, in the case of onchosychiasis, the transmission of the parasite depends on so many things that are influenced
by the environment. Which vector species is present, how abundant is that vector species, what are the things that determine its abundance, what season it is, what habitat it's in, and within a certain season or even a certain time of day, things like relative humidity, temperature, wind velocity, light intensity, rainfall, all of which could influence transmission in some way, And there's evidence to suggest that a lot of these factors do.
And so a disease ecologist might ask something like, how does the seasonal biting activity of different Simulia blackfly species change across these different environments, and how is that associated with the output of L three larvae by those blackflies?
Like all of these things are sort of what role does the environment play in the transmission and getting a better sense of the different factors at play can help to focus control efforts in a lot of ways to make them more impactful or more efficient, like, for instance, is there a distinct wet season, like a distinct wet and a distinct dry season, and should one of those seasons be targeted more for breeding sites for the flies? And should that time of year be targeted more for
habitat removal or habitat spraying. And an epidemiologist, conversely might ask about the geographical variation in infection prevalence and how these prevalences might be associated with past spraying or ivermectin campaigns, and a lot of these epidemiological questions. The way I look at it is that they helped to get a sense of the extent of the disease, how human behavior or experience plays a role in the exposure, or to
measure progress in control efforts. Aaron, did I miss anything withology.
That was really good? Also? How fun to get to talk about, like just broadly disease ecology and epidemiology.
Well, it's it's really fun because as I was reading about the ecology of this system, and I didn't do like, I didn't do a very comprehensive job of explaining it. But I was struck by the number of questions that you could ask about, how is the black fly, you know, feeding, like at what time of day, what part of the body is it feeding on? What time of year? How does that? How does the current filarial load in the fly influence behavior? Like all of these things, I know another PhD PhD Take two.
It's just so funny erin because as you're talking about all that, like I can hear how excited you are, and I'm also getting so excited, and so it's just so funny that like, of course, this is a disease that would get us so like excited to be asking these questions, and like that's why we did the degrees that we did. Like it's just it all comes full circle, like yep.
And I love too, Like this is such a good example of, you know, the ways in which that that barrier between epidemiology and disease ecology isn't really a barrier at all. It's a very fluid you.
Know, eco epidemiology. Yo, there we go.
And so it's really cool to see how, you know, the data derived from these two different fields in terms of research questions could be used synergistically or in the same in the same like applications.
Well, I'm also love it. Can we get some immunologists to join this party too, because I still can't get over that this is a newly evolved human specific parasite that is so good at evating our immune response, Like, are you kidding me? I know we should get back to ancos chiasis.
Let's get back to anchoerchiasis. Yeah, we do need to do a career's episode one day, we have. We want to have other people to find what an epidemiologist does
and what a dizzas ecologist does. But yeah, I just wanted to kind of go through this because I think ancoserchias is with its you know, three player cast of human parasite vector and its super close ties to environmental factors, is a great way to think about how the environment ends up shaping transmission patterns leading to human disease.
Absolutely.
Okay, So I've talked for a very long time about evolutionary history and disease ecology in general, but I haven't even started on the written history of anchoschiasis.
Well let's get started.
But don't worry. I mean, it's a pretty straightforward story so much. It's much more straightforward than it's ecology. I'll say that before I begin. I also want to acknowledge that before the quote unquote discoveries of Western scientists regarding this disease, the people who lived in Africa among this disease for thousands of years were already well aware of several aspects of anarchiasis, including the association with rivers or bodies of water, the role of the blackfly and transmission,
and both the skin and blindness manifestations of disease. But you know, this long standing knowledge is rarely, if ever noted in the official histories of scientific achievements, not just in terms of uncles psrachiasis, but in terms of many many diseases that we have covered or will cover. So taking that into consideration, where do these official histories begin?
In eighteen seventy four, there was a British naval surgeon by the name of John O'Neill who was assigned to the HMS Decoy off the coast of what is now Ghana. He noticed several people living along the western coast of Africa had an itchy and irritating skin disease with nodules and pustules. Locally it was called craw craw, and he
thought at first could this be scabies? And so he examined some of these nodules under a microscope, and quote succeeded at length in discovering a filaria, which I believe to be the immediate cause of complaint, threadlike in form, at one time undulating and now twisted as if into an inexplicable knot, then having rapidly untwined itself, it curls up into many loops. It's a very poetic description of
this hilaria. Yeah. O'Neill's observations of this parasite were followed pretty closely by Rudolph Lukart, who in eighteen ninety received a nodule of worms the size of a pigeon's egg that an unnamed German surgeon had removed from someone also in the Gold Coast. What has now goneah? Actually?
And how big is a pigeons egg?
Actually, that's a great question. Let me look it up. A pigeon egg is smaller than a chicken egg. Looks like to me, it's like half the size to two thirds the size.
Yeah, I would say that.
So, yeah, he received this nodule the size of this pigeons egg from this guy who had sent it to him asking for identification, and Lucart looked into it, and he didn't make any announcement of his own regarding the description of the adult form of this worm, but he did tell the famous parasitologist Sir Patrick Manson, who published a note in which he gave Lucart credit for both the discovery as well as the naming of the worm, which eventually became Oncacerca volvulus on caa circa from the
Greek words meaning barbed tale and volvulus from the Latin for to roll or turn as the worm turns. By this time, several other helmet species had been discovered in Africa and elsewhere, and Oncacerca volvulust didn't really seem to attract any particular interest, which I find interesting. Yeah, I mean, they simply noted it, as you know, it's probably this old disease. And also they seem to think that it was more of a rare curiosity rather than a common occurrence.
But that belief would later be turned on its head. So, despite the much higher prevalence of river blindness in Africa compared to Central and South America. A good chunk of the big leaps forward in terms of understanding this disease
were made by Ridolfo Roblis and Guatemala. In nineteen seventeen, he published a report linking the parasite to blindness as well as the dermatitis that had previously been observed, and the link between blindness and the parasite wouldn't be discovered in Africa for another decade or longer by researchers working there,
which I find very interesting. Yeah, and I wonder if one of the reasons for that is because of the biting preferences of the black flies in Central and South America compared to Africa, like.
That they were more kind of visible.
More visible more no, I mean like in terms of the blindness, that there happened to be more nodules on the face and head compared to Africa. So I don't know. But Roeblis also suggested that Simulidae blackflies might be responsible for transmission of the filaria and that removal of the
nodules might provide relief in symptoms. And speaking of nodules, in his quest to see whether these parasitic worms were the same species as Anca Cerca volvulus, or if they were a New World species, spoiler alert, they're the same species. He was wrong. He had a hard time getting the worms out of the nodule intact, and so he used quote the novel technique of removing the fibrous tissue by active digestion in the stomach of a living dog. Yeah,
that's all the explanation that I found for that one. See, he fed the he fed the dog nodule to a dog who then presumably post worms.
Pooped out worms or did he like induce vomiting or something.
Oh, that's another possibility. I don't know.
I don't know either. Yep. It's weird that it was effective.
Honestly, it's weird that he thought of it.
There's a lot that's weird.
There's a lot that's weird. And the next big jump in Ancaserkias's research was when Donald Blacklock made the link that blackflies were responsible for transmitting the parasites through observations of the guts of simulium blackflies. Roblaze had just suggested it,
but Blacklock actually did the experiments. Although again, this link I want to say was well known among people who had been living there right By the nineteen thirties, interest in ancastrakias's had picked up, and scientists had started to realize that it was much more widespread than previously thought. But they were still missing one big piece of the puzzle, the piece that Roblaze had found nearly twenty years before
the link between the parasite and blindness. In nineteen thirty one or nineteen thirty two, I can't remember, a researcher named Gene Hassett published a report that showed that in a part of the Democratic Republic of Congo, twenty percent of the people with uncoserkiasis were blind and fifty percent of that population suffered from eye troubles. Unlike in many other places in Africa, the nodules and systs were concentrated on the head rather than lower down the body, which
was also kind of the pattern in the Americas. And although Hisssett's work seemed to show a clear connection, including he found microfilaria throughout the eye, the link wouldn't be widely accepted until the mid nineteen forties at the earliest WOW, which also coincided with this period of increased European troop
presence in uncleserciasis prevalent areas, so not unsurprising. Unsurprising. As researchers got a better handle on the scope of the disease and the devastating effects that it could have, campaigns to control or eliminate the disease were started. The earliest campaigns targeted the vectors of the parasite, relying on the use of DDT, which was developed in nineteen forty one and found to be extremely effective as an insect killer and also, as Rachel Carson has made us all aware,
as a killer of many other things. Some of these early control programs seemed to actually be quite effective. So, for instance, in the Coodera region of Kenya, which had been nicknamed the Valley of the Blind due to a prevalence of acosarchiasis of seventy percent. Oh my gracious, DDT applications over a six to seven month period led to eradication of the blackfly vector in that area.
Wow mm hmm, I know.
It's like feels weird to be like wow, DDT worked really well, But it did until it didn't, and then it did until it didn't. Killed a lot of other things.
Yeah.
Yeah, Leading into the seventies, which is when probably the largest campaign began, the WHO on Chris Archaius's Control Program OCP. Still, the strategy for control focused on interrupting transmission by vector elimination.
In this program, which targeted initially seven countries around the Volta Basin of West Africa, with additional areas or countries added later on, insecticide was applied either on the ground or aerially, and the plan was to continue these types of vector control activities for twenty years, the length of a female worm's life like the maximum length.
Yeah, that makes sense.
But there were several challenges that emerged that either interrupted or slowed down progress, and one was that several areas were reinvaded by adult flies from outside the target areas. Studies showed that some flies in the Simuleum damnosum species complex could my grate up to five hundred kilometers Yeah, three hundred and ten miles.
They're really far flyers, which makes it so much more complicated, so.
Much more difficult. And another issue was insecticide resistance. So the OCP adapted to overcome these challenges by rotating different insecticides to reduce the likelihood of resistance. And there was another development that actually helped to overcome these challenges as well, and that was the discovery of ivermectin, which was developed in nineteen seventy five and provided for free by Murk starting in nineteen eighty eight, and its developers were actually
awarded a Nobel Prize in twenty fifteen. Yeah, Yeah, that was like really changed the landscape of control. This one two punch of insecticide and treatment allowed the OCP to
make incredible strides in Uncas Archias's control. So by two thousand and two, it was estimated that the OCP had rid two hundred and fifty thousand square kilometers of farmable land of Bonker psychiasis, with forty million people having been protected and six hundred thousand cases of blindness prevented in at least seven countries in The incredible amount of work done by this program not only greatly reduced the burden of disease in some areas, but also led to a
huge amount of knowledge being gained about the ecology and the epidemiology of this disease, which could then be integrated into future control efforts. And I just want to make a little note Another bright moment during the OCP era happened in nineteen eighty one with the release of the Jay Giles Band song river Blindness. I'm going to read you the first two verses.
Okay, you're not going to sing them.
I'm not going to sing them. I actually haven't listened to the song yet, which is so bad, but I found it like right before we started to record. Okay, okay, human kindness, river blindness. Blackflies rise as the water flows, human kindness, river blindness. Angels cry as the fever grows. Indications, demographics, control of the basics is all you see. Correlations, disintegrations, cessation of life, expectancy.
We need to ask if we can get permission to play that song on the pod because police.
I know, I know. I I had no idea. It was on like a ten Things you probably didn't know about river Blindness, and I was like, you're right, I did not know about this the Jay Giles Band song. The only other song that I know by the Jay Giles Band is Centerfold. Like my angel is wait, I know that song. Yeah, so I think it's very funny. In their repertoire of songs, one is Centerfold and the other is blindness.
Wow, fascinating, there.
We go, Okay. Anyway, after the OCP ended, Anca Cirkias's control was headed up individually by many of the countries involved in the OCP, and since the mid nineties there have been many other control programs started in countries that had not been involved in OCP, and on the other side of the Atlantic, other elimination campaigns had started up in the Americas, and these were slightly different than those
in Africa due to the ecology of the disease. So whereas in Africa large parts of thirty one countries are affected by ancassrakiasis, in the Americas the distribution is much more limited or focused and has been and so in those areas, mass drug administration with ivermectins seemed to be the ticket, and in nineteen ninety three the Ancasrakiasis elimination program for the America's began and there have been many
success stories there. For instance, and I hope I'm not stepping on your toes errand but rather setting you up to wrap up this story, I love it. Alcast rokiasis was declared eliminated in Colombia in twenty thirteen. In Ecuador, in twenty fourteen, in Mexico in twenty fifteen, Guatemala in
twenty sixteen, and parts of Venezuela in twenty seventeen. And from what I can tell, the areas where the most of the transmission still happens is the southern parts of Venezuela and the northern part of Brazil where they border one another in sort of like the Amazon area. So aerin it seems like there's been a great deal of progress in the control of this disease, but it still seems like we have a long way to go based
on some prevalence numbers I saw. So take me through where we stand and what we have left to do with this neglected tropical disease.
I would love to. We'll take a quick break and then get into it. So World Health Organization estimates, based on data from twenty seventeen, which is the most recent data that they have listed, estimates that worldwide, almost twenty one million people are currently infected and living with Anco Cerca volvulus. It's so many, it's still a very very
large number. Yes, it's estimated that of those twenty one million people, about fourteen point six million of them have active skin manifestations, so they have active disease, and about one point one five million have some degree of vision loss, if not complete blindness.
Will everyone who is infected with this parasite develop blindness? Is it just an inevitability?
Great question. No, definitely not, and not everyone would even necessarily have all of the skin manifestations. But I did not I could not find a solid number on what that percentage or proportion is. I think it largely has to do with disease burden. So the higher the intensity of burden, the more likely you are to have severe disease,
including vision loss. Right, Okay, Yeah, like you said, Aaron, already, it is still the case that over ninety nine percent of those who are currently living with ancosarchiasis live in thirty one countries across Africa. The other one percent are located in Focai in Latin America as well as Yemen. And the thing is that acossarchiasis doesn't kill people outright, but it is no less debilitating and it does reduce
life expectancy even though it doesn't kill people directly. So, like you mentioned, Aarin, before control efforts ramped up in some endemic areas up to thirty five or forty six percent of people would become blind eventually. That is just yeah, yeah, And in many areas where ancosyirchiasis was endemic, up to ten percent of the adult population would become blind, just
depending on the overall worm burden in the area. And even without considering permanent disability like blindness, these skin lesions, I really can't underestimate how debilitating the itchiness can be.
People can't sleep, they can't work. So if we look at the disability adjusted life years, which is an imperfect measure but still a measure of overall disease burden, alcocerciasis is estimated to account for between one million and one and a half million disability adjusted life heres annually, depending on which paper you look at, and the itching and skin manifestations account for over sixty percent of these. So
it's not just the blindness. I think that with a common name like river blindness, it can be overlooked how impactful the skin disease really is as well.
Right, I think that's definitely the case.
Yeah, And also these skin manifestations can result in open wounds, and just as well the aarin you asked really early on whether people become immunosuppressed in some ways. When you have a very very high worm burden, it does cause your immune system to be more likely to have other infections. Okay, on top of having potentially open wounds on your skin, that can be an area where you can become infected.
So overall, it's estimated that oncopsychiasis, though it doesn't kill people, it does reduce over life expectancy by thirteen years.
That's yeah, that's not in substantial at all.
Right, not in the slightest. But the good news is that control efforts have been ongoing for decades now. Early on AARIN, like you talked about, they relied on a lot of integrative approaches, using both vector control pest management as well as ivermectin. Most of the programs that are out there today really just rely on community directed treatment with ivermectin annually. This has worked very very well in
some areas, like in the Americas. It has not worked as well in very very highly endemic areas in Africa, largely because it doesn't kill these adult worms and you administer ivermectin annually, but it really only reduces symptoms and slows the transmission for a few months. So ivermectin alone is unlikely to completely control or eradicate ancos orchiasis.
And in terms of like how it's only given once a year, is administering it more frequently bad for year?
So it's yeah, it's a great question. It's it's a possibility, and there's some data that suggests that maybe in these hyper endemic areas that could be a good option to administer it bi annually instead of annually, But the data doesn't suggest that that would actually result in that big of a decrease, because annually does make a really big difference. It's just that in places where this is hyper endemic, it's just not quite enough essentially.
Well, and I think it's it's also interesting too, going a little bit back to the ecology, is that I saw a few like line graphs looking at the biting frequency and how it does peak at certain times of year, and so if you reduce the microfil area like presence during those times and time the drug administration then then.
Precisely exactly Yeah, so kind of targeted administration as well. But overall, in twenty seventeen, one hundred forty five million people, which is about seventy percent of the estimated population at risk. We're treated with ivermectin through these various control programs, which is phenomenal. It's not quite where we need to be because in every region you would need at least eighty to eighty five percent treatment to really help reduce an
interrupt transmission. But it's good progress. But the big question is like, can we do better? We've been doing this now for decades. Can we do better, especially as it relates to actually curing disease rather than just treating symptoms or halting progression, which requires treatment for ten to fifteen years or more. Right, enter wolbakia. Okay, I told you
we come back to them. So, like I said in the biology section, the more that we know about the disease path of physiology of nco psychiasis, the more it becomes clear that Wilbakia play a very important role. But we already know that we can't just kill the adult worms outright, because then the Wolbachia that are in them would make us really sick. Right, So some researchers have wondered, what if we just kill the Wolbachia bacteria inside of these worms? How do we do that great question, Aaron,
We can do it. Okay, treatment with doxycycline, which is an antibiotic, it's a relatively common one that we use for a lot of diseases, including tick born diseases like ricketsias, which Wolbachia are relatively closely related to ricketsias.
They are. Indeed, so treatment.
With doxycycline can interrupt embryogenesis, stop adult worms from being able to reproduce for at least a year, if not two years, which is far longer than the few months that ivermectin can do.
That's incredible.
So it's unclear whether treatment with doxycycling can fully just kill the adult worms very slowly. I think in some studies it suggests that these adult worms will then die, but certainly it stops their reproduction. It stops the production of microfilaria for years.
That's a wonderful news.
So why aren't we mass administering this? Yeah, yeah, it's a little tough. So ivermectin is a one single dose treatment, one dose once a year, and you have effect. Doxycycline, on the other hand, requires one hundred to two hundred milligrams per day every day for four to six weeks at a time. Yeah, there's also a pretty large range of people, including pregnant people, breastfeeding people, children under nine
who can't take doxycycling for various reasons. So there are groups that are doing research to try and find other compounds and drugs that might have the same effect but be administered in a more practical way, so not needing people to take drugs for six weeks at a time, but also to a wider range of people who are at risk of infection or who are living with infection.
But what's really cool is I saw some papers that were suggesting that this could be something that's particularly beneficial in those areas that are hyperendemic where we've been treating with ivermectin but it doesn't seem to be having the effect, or also in areas where you have a high burden of disease but you also have Loa loa, which is another filarial parasite that if people are coinfected with Anko circa and Loa looa, you cannot treat them with ivermectin
because the loaaloa worms will also die, but they are larger and they can block blood vessels and cause brain damage and death.
Yeah, so that's bad.
Yeah, but loa looa don't have waalbakia. Interesting, so doxycycline and drugs that were like it don't affect them. So that's a pretty promising area of research for that reason as well, because areas where both ankocerca and loaloa are present have been very difficult to do control strategies.
We need to keep a list of like things at the end of these episodes were like, oh, like all these future directions, let's keep an eye on how these things are progressing.
There's a lot I feel like there was a lot in like the Dengae episode where it was like, this is happening now, Okay, right, but it's pretty it's pretty awesome. I think there's some good researches going on. I think that overall things are not great in terms of anchocerciasis, but they're a lot better than I expected. Quite honestly, they're a lot better than I expected.
And I think that like the you know, the past fifty years or so of control efforts have really shown that a lot of progress can.
Be made exactly. Yeah, like we've we've made massive progress. It's just that because the life cycle of these parasites is so long, you still have really high prevalence of disease, right, But yeah, we've come a really long waist, so we can end on kind of a positive note.
Yay for a.
While, like when that happens me too.
Sources sources, So I have a thousand different articles, not that many, but I have a lot of different articles. I'll shout out a couple. One resource that was great is a book called A History of Human Heal Mythology by David Grove. And in terms of papers, I want to shout out a few, one by Basanyas at all two thousand and nine and another by Crump at all twenty twelve, Kruger at all two thousand and seven and Leifs Foulon at All twenty sixteen, and those were all
really great papers. I will post these papers as well as all the other ones I didn't mention on our website same.
I have a very long list of recommended reading, everything from the specific biology and path of physiology to a lot more details on the role of wellbakia and ivermectin. It's a really fascinating drug. If you want to read more about it, you can find all our sources for this episode and every one of our episodes on our website This podcast will Kill You dot Com under the episodes tab.
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And thank you to you listeners for allowing us to make this podcast and for listening even if we talk about like really I don't know, scary subjects or really weird subjects, We're glad to have you along for the ride.
Yeah, this is really fun. We hope you enjoyed this episode.
Yeah, well, until next time, wash your hands.
You feelthy animals. MBA, bum bum bum bum