This Podcast Will Kill You - Ep 119 Marburg virus: Too fast, too furious

Episode Date: June 27, 2023

In early February and late March of this year, separate outbreaks of Marburg virus were declared in Equatorial Guinea and in the United Republic of Tanzania. For several months, news of these outbreaks and other sporadic cases made headlines globally, as public health officials watched the number of cases and suspected cases climb, calling to mind previous outbreaks of Marburg virus's relative, the deadly Ebola virus. Fortunately, the WHO declared both outbreaks over in early June, but the threat of this hemorrhagic virus remains. In this episode (recorded in April 2023) we explore why the biology Marburg virus makes it such a deadly pathogen, what its evolutionary history and the history of its discovery can tell us about the changing landscape of pathogen spillover, and how the recent outbreaks reveal how much we still don't know about this virus. Tune in for everything you ever wanted to know about Marburg virus and more. See omnystudio.com/listener for privacy information.

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On August 18, 1967, malaise and myalgia took place. On the following day, she developed fever up to 39 Celsius. On August 20th, the third day, for the first time, vomiting occurred. One day later, burning and reddening of the conjunctiva. The temperature now rose to 40 Celsius. On the fifth day, she was admitted to our infectious ward. At this time, there appeared in the face, on the trunk, and on the proximal parts of the extremities, a macular-papular rash, a red anathema of the soft palate that reached to the hard palate.

There were enlarged lymph nodes at the neck, along the sternocladomastoid, and in the axillaries. On the sixth day, the conjunctivitis decreased. The vomiting went on, and a watery, not mutiny, or bloody diarrhea occurred, which made an intravenous substitution of fluid and electrolytes necessary. On the eighth day, a diffuse, cutaneous erythema developed over the whole body. The diarrhea went on. The vomiting stopped. On the ninth day, the state of health improved significantly. The diarrhea decreased.

In the 27th day, the skin began to peel off, especially in the face, the palm, and the lower extremities. On the 36th day after the beginning of the illness, the patient left the hospital. She did not show any more clinical signs, but the reconvalescence was delayed, and she continued feeling weak for several weeks. Yeah, not does not sound good.

No, that's a long course. But she did survive. She did survive. Yeah. Yes. So that was a case history of Marburg virus disease. in a chapter titled Clinical Syndrome by G.A. Martini in a book called Marburg virus disease published in 1971. So it was like the first and still in many ways is like the definitive textbook of that outbreak in 1967 that we'll talk about.

Yeah. Wow. Yeah. Hi. I'm Erin Welsh. And I'm Aaron Olman Updike. And this is, this podcast will kill you. Today, if you haven't clued in, we're talking about Marburg. We are. Yeah, there are a lot of reasons to cover this disease.

Most pressing is that it's been in the news lately. Yeah. There is an ongoing outbreak as of the day of recording, which is April 4th, 2023. The outbreak remains ongoing. So we'll get there eventually. We will. We will. Yeah.

Yeah. But first. It's quarantining time. It is. What are we drinking this week? We're drinking in honor of Ebola, still spilling over. Yep. If you are a long-time loyal listener, or you're just someone who happened to listen to our Ebola episode that came out over five years ago, five years ago in 2018.

Five and a half? Yeah. You may remember that in our Ebola episode, we titled our drink spillover because of the fact that like many other viruses and other pathogens, Ebola virus spills over into humans. And guess what? So does Marburg virus. So we're still spilling over here. And also they're closely related, which like maybe that's jumping to gun. Yeah. In any case, what's in still spilling over, Aaron? In still spilling over. It's kind of like a variation of the original spillover. And so it contains mescal and maple syrup and sparkling lemonade and I don't know like a slice of an orange or a lime I don't know

but the point is you fill it to the very top so that it almost spills over but you don't want it to spill over because it's not great when that happens oh I like it we'll post the full recipe for that quarantini as well as our non-alcoholic plissy barita on our website this podcast will kill you dot com and all of our social media channel We certainly will. Okay, podcast business, we've got website. Check it out. Check it out. It's got lots of good stuff. Transcripts, you know, links to many things. It's a good resource. And in other podcast news, we will be back to our regularly scheduled programming next week. So we will be releasing one of our special episodes, our book club episodes. The following week,

week, there will be a normal regular season episode, and we'll do a little bit of that until we wrap up our bonus episode series. But from this point on, we are back to at least one new regular season episode every other week. Bim-Ber-da-Bow! I think that about does it for business. I think so, too. Shall we get into the biology of Marburg virus? Let's do that, please, right after this short break. Dinner shows up every night, whether you're prepared for it or not.

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Marburg virus is very closely related to Ebola virus, which we covered in our very first season. Ebola virus is a pathogen whose name still makes people, usually unnecessarily, absolutely lose it with terror. And Marburg virus is a very close relative. So it's probably unsurprising that a lot of what I'm going to talk about seems very similar. Let's get into it. Marburg virus, it's an RNA virus in the family phyloveridae, which includes essentially just Ebola virus and Marburg virus in terms of human viruses.

I did learn there's a newly discovered phylovirus called Yovue virus. It's in the genus Cueva virus. Yeah. It was discovered in 2011 in Spain in bats. That's all I know about it. So moving on. Literally, just didn't know about it until today. Okay.

So Marburg looks under the microscope a lot like Ebola virus. It's kind of that filamentous, curvy, long shape. And while Ebola virus has several different species, Marburg virus is literally just one species of virus. It's Marburg-Marburg-Marg virus. It does have several different lineages, and there are two classification. of virus, R-A-V-N-R-Avon virus and Marburg virus. Virus phylogeny is very confusing, but in short, they're both the same species of virus. They both cause disease in humans.

And from now on, we'll just be called Marburg. Cool. Sounds good. So this is a virus that, thankfully, as you will see as I continue through the description of its symptoms, has caused relatively limited-scale disease in humans and very limited-scale outbreaks for the most part. It is not something that has, to this point, very commonly caused disease. Primarily, disease in humans is happening, like we mentioned in the intro from spillover events, from zoonotic reservoirs. A lot of times bats, and in some cases non-human primates,

though it seems that this has really only happened in laboratory settings and not in kind of non-laboratory settings. But it can and does also spread person to person. And transmission tends to be like with Ebola virus via direct contact with bodily fluids. That means blood, saliva, sweat, stool, urine, literally any and all bodily fluids as far as we have studied. The incubation period, the time between when someone is exposed and starts to show signs of disease, can really range between 2 and 21 days. It's such a huge range. It's so interesting. I know. And I think, I mean, there's a lot that goes into that, you know, like what's the infectious dose, but also how much data do we have on this? Right. Not much. Not much. On average, it seems to be like five to 10 days for the most part.

And when is someone first contagious? Great question. First contagious potentially as soon as symptoms start, but like Ebola, the most contagious towards the end of convalescence as this virus builds up in those bodily fluids. Okay. And in some cases, potentially contagious for quite some time because like with Ebola virus, we have found this in bodily fluids even after somebody recovers from a Marburg virus infection. Right.

which is like part of the question around ecological sources of infection. Exactly. Yeah. Right. It's difficult. Yeah. I couldn't get a sense of what the R not is, the reproductive value of Marburg. Largely, most likely, because there have been relatively few outbreaks.

And with two exceptions, all of these outbreaks have been very small in size, which is a good thing. And I'll mention more about this, but the World Health Organization has like, a PowerPoint that they developed recently on ring vaccination strategies. And in that, the World Health Organization at least estimates an attack rate of 1 to 2 percent. So that means that in, say, close contacts, 1 to 2 percent of close contacts of an infected person, in their models at least, are susceptible to infection or are likely to get infected. That's lower than I thought. That's interesting. Yeah, yeah, which is a good thing. That's great, yeah. But again, very limited. limited data on that, so grains of salt aplenty.

In terms of reservoir hosts, bats are thought to be the primary reservoir host of Marburg virus, as with Ebola virus. Specifically, the common Egyptian fruit bat, Rosettus Egypticus, I think, seems to be a really big contender, at least from the data that we have so far, though it has been detected in other bat species as well, and can infect non-human primates and possibly others. that we just don't know about. So let's get in to the symptoms, shall we? Mm-hmm.

The symptoms have been broken down into three major phases of disease. An initial phase, sometimes called a generalized phase, an early organ phase, and then either a late organ phase, which is not good, or a convalescent phase, which is better, but as we heard in the first hand account, can be very prolonged. Yeah, okay. So this initial phase tends to start with a fever, often a pretty high fever, 39 to 40 Celsius, so that's like 102 to 104 Fahrenheit. Oh, dang, that's high. It's pretty high.

Often a severe headache, chills, muscle aches, malaise, and sometimes kind of a prostration, like not really being able to move beyond just laying down because of. all of these body aches and kind of general symptoms. Most of the time, like 50 to 75% of the time, this then is followed within the next couple of days by pretty significant gastrointestinal symptoms. So lack of appetite or anorexia, abdominal pain, nausea, vomiting, diarrhea, the whole shebang of GI symptoms. This then often progresses to sores in the mouth and, essentially, soars probably in the throat because a lot of pain with swallowing and some difficulty swallowing. And all of that is happening over the course of four to five days. So days, you know, zero to five. That is a rough four to five days. It is. And people are clearly very, very sick at this point.

But all of those symptoms are also pretty non-specific. Yeah. It's called generalized because it's really just affecting, your kind of whole entire body. After this phase, usually after about day five or so, there might be a rash. And this rash is called maculopopular. We've talked about this type of rash a lot of times. It isn't very specific, but in the case of Marburg, it tends to happen on the back, the trunk, and the neck, and kind of relatively limited to those areas, at least at first. And maculopopular means it's little spots with maybe little raised bumps in the middle. And this type of rash might be the first thing that makes it seem less like a malaria or an influenza

and more like a phylovirus infection, an Ebola or a Marburg. Okay. These symptoms then continue to progress to things that are resulting more directly in organ damage. And this is when we enter the early organ phase. you're likely still experiencing all those other symptoms that I already mentioned, but now new symptoms are starting to arise like neurologic symptoms, encephalitis, confusion, behavior changes. You might also start to see signs of vascular permeability. So that means leaky blood vessels.

So depending on where blood vessels are leaking, that might look like difficulty breathing. if your lungs are starting to get fluid in them. It might be generalized edema or swelling if it's kind of just underneath the skin in your arms or your legs. And then it may and often does progress to some kind of clear evidence of hemorrhage. Marburg virus is a viral hemorrhagic fever.

So this evidence of hemorrhage bleeding could be patikii, which are little pinpoint purplish spots that you see underneath the skin. Or it might be mucosal bleeding, like bleeding from the nose or the gums. It might be bleeding into the eyes, so conjunctival injection,

or bloody diarrhea, bloody vomiting, or even just easy and large bruises that appear with seemingly very little pressure. So all of this is going on from about day five until about day 13. And it's not just these signs that are easily visible. What's happening inside of the body is also this direct damage to the organs. So in terms of what we see on laboratory values, we see evidence of kidney damage,

we see evidence of liver damage, pancreas damage, even discrepancies in blood counts, like increases or decreases in white blood cells and platelets, etc. At this point, people either succumb to this overwhelming infection, their organs cease to function, they develop even worse neurologic symptoms, and eventually progress to severe shock, multi-organ failure, and death. And this tends to happen between days 8 and 16 after the onset of symptoms, so kind of towards the end of that early organ phase. and death most often is coming directly from shock and from organ failure, from all of this leakage from the blood vessels and just your organs not being able to keep up.

And again, that usually happens by about day 16. If people don't die, then this is the time period in which they start to show signs of remission and then have a pretty prolonged course of convalescence as they slings. recover. This can happen over weeks to months. What is the virus doing? Yeah. Replicating and replicating and replicating. In what cells? Yeah. So how can this virus make us so sick? Yeah. So the answer, I mean, as always, as we don't fully understand, blah, blah, blah. We know that. But we do know that the way that this virus makes us so sick is at least in part due to its tropism, the cells that it's infecting.

So we are being exposed. This virus is getting into our tissues and our bloodstream either through our mucus membrane or from breaks in our skin, right? From direct contact with infected bodily fluids into our mucus membranes or breaks in our skin. From there, this virus tends to infect cells first like our macronet. Phasias, our dendritic cells, and other of our white blood cells. But then they have a tendency to infect our endothelial cells. These are the cells that line our blood vessels, right, in all of our various organs, which means not only can this virus spread anywhere, cell to cell, as they replicate,

but they also can then, as they break out of these cells to go on and infect other cells, cause that leakiness of the blood vessels, right? Because they're directly damaging, especially the basement membranes, the bottom part of these endothelial cells that line all of our blood vessels. It's not only our endothelial cells. Marburg virus can also infect our liver cells themselves, so they can cause direct damage to our hepatocytes, our liver cells. And they infect a lot of other lymphatic tissues besides just our macrophages and other white blood cells. So in doing that, they're causing damage to our spleen, our lymph nodes, and that's just making it even harder for our body to fight off this virus. Jeez, okay. But in addition to the direct damage to our cells

and our endothelial cells, Marburg virus, much like its cousin Ebola, interacts very heavily with our innate immune system. So it causes an additional and kind of of spiraling inflammation in ways that we say it with me don't fully understand but we know that they're really important in the overall development of that severe organ dysfunction and shock and death right it's the damage to the tissues themselves caused directly by the virus and it's the way that this virus upregulates our own immune system to then cause this spiraling inflammation. Okay. Yeah. This is interesting. Yeah. And in non-human primates, does the course of disease look fairly similar? As far as I understand, yes. Okay. Pretty similar. Non-human primates are

definitely the kind of model species because of that, because it infects non-human primates and causes very similar disease. It's been difficult to find good animal models for Marburg virus and Ebola virus. in other animals other than non-human primates, which are really difficult to work with in the lab for a lot of reasons. So if you are fortunate and you enter the convalescent stage, do you have lifetime immunity? Great question. Or at least any immunity. That's a really good question. I didn't read that specifically, but I know there's pretty good immunity that comes from Ebola virus. And there's a lot of being done on vaccines. So I suspect that you develop pretty robust immunity if you do survive a Marburg virus infection. But I don't know kind of the longevity, how forever it is kind of a thing.

And do we know anything about like, again, in the people who recover from Marburg virus disease, are there long-term effects? Or is it just like, again, we're dealing with such few numbers that it's, yeah, yeah. That's what it is. We're dealing with such a number number. few numbers that we don't have data on it. Probably. Wouldn't be surprised, but we don't have the data to say it. So can we talk a little bit more about the hemorrhage part of this? Yeah. So not everyone who is infected with Marburg virus develops hemorrhaging, and that hemorrhaging can look very different. Yeah. Yeah. Can you say more about that? I think that the word hemorrhage, in this context is very different than in the context that a lot of people are maybe more used to hearing the word hemorrhage.

So in the case of things that are sometimes called viral hemorrhagic fevers, probably more accurately not called viral hemorrhagic fevers, but viruses like Marburg, which can cause disruptions in our coagulation cascade, they can cause disruptions in the way that we're able to clot our blood and therefore put us at risk, higher risk, for bleeding, especially from our mucosal surfaces, which are already more prone to bleeding than just like your skin, for example. In the case of Marburg virus, this could look like a lot of different things, like I mentioned. It could be bleeding from the nose. It could be bleeding in the eyes. It could be bleeding in the GI tract, which would come out in a lot of ways. But in all of these cases, it's not as if someone had like a massive wound and is, you know, bleeding out or hemorrhaging from a very large wound.

It's more slow bleeding and just not being able to stop and clot that bleeding that we tend to see with this type of viral infection. And it's not specific to Marburg by any means. And you're right. Not every person who has Marburg virus is going to necessarily have either the same types of disruptions and the same types of bleeding or any signs of bleeding necessarily. Okay. Yeah.

Yeah. It's just based on the damage to that coagulation cascade. See our hemophilia episode for D. We refer back to that a lot. It's a really good episode. I mean, the coagulation cascade is kind of important. It's pretty crucial. It's pretty crucial.

But kind of along those lines, I think a thing that's interesting about Marburg virus is that when this virus first emerged, and Erin, I can't wait for you to walk us through that story. And for quite some time after, it was thought to be not as deadly, not as virulent, not as scary as its cousin Ebola virus. Because Ebola virus has a case fatality rate as high as 90%, which is terrifying. But as outbreaks of Marburg virus have continued and have grown in size, what we have seen is that, in fact, the case fatality rate of Marburg is as high as Ebola, 80 to 90% if you average across all of these outbreaks. So I think that that's very interesting. And I think that it kind of just shows that even though this is a virus that thankfully hasn't caused thousands of human cases, it is still something to be very wary of in kind of the broad sense of how we think about zoonotic viruses and spillover events.

Yeah, it indicates a lot. And the case fatality rate indicates a lot beyond just, you know, the characteristics of the virus. And you mentioned how it was thought that Marburg had a lower case fatality rate than Ebola initially. And then that later was sort of like, yeah, maybe not. But part of the reason for that, and I'll get into this more, is that when Marburg first emerged, it was in Germany. Right. And the case fatality rate was like 21% or something like relatively low compared to later numbers. And a big part of that reason is probably treatment, which I know there's no Marburg specific treatment, really. But what is supportive care look like that's driving these differences? Yeah, exactly. Exactly that. Supportive care is supportive care. We talked a lot about it in our sepsis episode because this. progression to shock and organ failure is really very similar to what we talked about in our sepsis episode. And it involves access to hospital level care. It involves aggressive fluid resuscitation. It involves being able to identify which organs are being affected the most and how to support those particular organs, whether that means maybe dialysis or maybe just fluids or maybe less fluids, maybe, you know. So it's a lot of different things. But it's,

it really is access to high level, ICU level of care, especially as it progresses to these, you know, late stages of organ damage. So yeah, that's going to look very different in different parts of the world, whether or not people have access to that kind of care. Yeah. I feel like that's a piece that often gets left out. It always gets left out, especially of the discussion around, you know, case fatality rate. Yeah. But in any case, that is the biology of Marburg. Okay.

So it's, I mean, it's still scary. Oh, yeah. It really is. I mean, it's, it's amazing how much havoc a virus can wreak. Yeah. Really. I think that that's what it comes down to. It's just, it's incredible how this virus can just absolutely wreck a body.

Yeah. So, Erin, tell me. How did we get here? Tell me about these first outbreaks and what we know about this virus and how it started infecting us. What did we do to deserve it? Just kidding. Yeah, I'll do my best right after this break. Anyone who works long hours knows the routine.

Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands. hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented, and absorbs quickly. A little goes a long way. Moisturization that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving

environments. It's been relied on for decades by people who wash their hands constantly or work in harsh conditions because it actually works. O'Keefs is my hand cream of choice in these dry Colorado winters when it feels like my skin is always on the verge of cracking. It keeps them soft and smooth, no matter how harsh it is outside. We're offering our listeners 15% off their first order of O'Keefs. Just visit O'Keef's company.com slash this podcast and code this podcast at checkout. Bethany Frankel from Just Be with Bethany Frankel. Listen, I have a bone to pick with these dog food brands calling themselves fresh, natural, healthy. Sounds great, but a lot of these, quote-unquote, fresh dog foods in your fridge are not even 100% human-grade, which is why feed your babies.

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So I do care about the food I feed Biggie and Smalls. So go to Just Foodfor Dogs.com for 50% off your first box. No code, no gimmicks, just real fresh food. So Santana, won this tour, 2026, the power, the energy. Come celebrate your favorite hits from Woodstock to Supernatural and Beyond with very special guest, the Doobie Brothers. So we've already talked about how we covered Marknation.com. the teeniest tiny bit in our Ebola episode from all the way back in February 2018. And if you are a TPWKY listener with like just the world's best memory, then you may remember

exactly what I talked about. I did not. So I went back to our transcripts to see like, okay, what like what did I say? What do I need to recover stuff, you know? And no. Basically all I talked about was that when Ebola virus was first observed in 1976, people initially thought that it could be Marburg virus, which had shown up nine years before in 1967, when workers at a lab in Germany came down with this hemorrhagic fever. That's about it. That's like all I really talked about. And we even joked about how like, oh, now we don't have to do an episode on Marburg virus. Ha, ha, ha. We were so naive. Right? Right? Because we even. That is far from the full story of Marburg virus.

And even if there weren't currently an ongoing outbreak, this is still a really important virus to cover. And I think that remains true despite the fact that Marburg has kind of been, I think, overshadowed by Ebola in recent decades. Totally, totally, totally. Yeah. Okay. So we're recording this on April 4th, 2023.

As we speak, like we've mentioned, there's an ongoing outbreak of Marburg virus in Equatorial Guinea as well as Tanzania. That's the first ever cases observed there. And this is, of course, part of our reason for choosing to cover this topic to give a little context to what's happening today, or at least close to today, because this will be coming out, you know, quite some time in the future. And we'll go into these current outbreaks in the current events section in a bit. But along with providing this additional context in answering where this thing came from and how do we get here and all those questions you asked, I also wanted to talk a bit about Marburg virus in history. As in what impact did this virus's emergence have on public health or epidemiology or disease ecology? Because it really did mark a sort of turning point in the history of infectious disease. Huh.

The story of Marburg virus hits on some themes that at this point in the podcast and at this point during COVID, we are all probably very familiar with. One in particular being the spillover of a zoonotic pathogen from wildlife to humans. Even before COVID brought this concept to a much wider audience, things like SARS-CoV-1, hendrovirus, Nipavirus, which we still need to cover both of those. I can't believe we haven't covered it. Listen, there's a lot of ground. There's a lot of things out there. Sinombre virus, West Nile virus, and others had shown that as humans, as our domestic animals and as wildlife, interact with each other more and more. As habitat is destroyed, as the climate changes, pathogens will be unavoidably exchanged.

As global travel continues to become more widespread, those pathogens will more easily cause outbreaks that turn into epidemics, that turn into pandemics, rapidly spreading to all corners of the world too fast for containment. Too fast, too furious. Too fast, too furious. But we know this, right? We've lived this. Scientists have warned about this. Possibility doesn't seem like quite strong enough of a word here.

this inevitability, this reality for a long time, long before COVID, so long that it seems like ingrained knowledge. Like we've always been waiting for the next pathogen, probably a virus, to spill over. But it hasn't always been that way. Oh, okay. Of course, the circumstances for pathogen spillover have always existed. That's how we got so many of our old friends. But the number of emerging infectious diseases has risen over time, even controlling for reporting bias. And the majority of these emerging pathogens have their origins in wildlife. It's taken us some time to notice this pattern. As the mid-20th century approached, things were looking pretty good in the war against infectious disease. We had antibiotics.

We had pesticides that had drastically reduced rates. of arthropod-borne disease. We had vaccines for many diseases that had been the biggest killers historically, including most recently polio during that time. And it seemed like only a matter of time before we got a handle on the rest. But this starry-eyed optimism would be short-lived. First, with the rise of antibiotic resistance chipping away at our confidence to handle bacterial infections, and then the emergence of extremely deadly, never-be-forcing viruses that seem to serve as this reminder that humans hadn't quite conquered the natural world. The first of these viruses to make an appearance was Machupo virus in Bolivia in 1962,

which causes Bolivian hemorrhagic fever, and which we will cover someday. And the second was the topic of today's episode, Marburg virus. Wow, second, okay. Yeah. Like I mentioned, first described in 1967, after 31 laboratory workers in Marburg and Frankfurt, Germany, and Belgrade, Yugoslavia, now Serbia, became extremely ill after handling African green monkeys with seven people ultimately dying. Both of these viruses, Machupo and Marburg, they sort of marked the beginning of a new chapter in the history of infectious disease. One that we could reasonably call spillover, thanks David Quammon, and one that we're still deep in today. Although I feel like we may be shifting to like even more like spillover to more intense spillover than ever before.

Still spilling over? Still spilling over. I mean, yeah. And the emergence of these two viruses kind of served as a wake-up call, that we actually weren't close to shutting the door on infectious disease, that our increasing contact with wildlife and the ease of global travel had potentially deadly consequences. Let's get into what those consequences looked like in late summer and fall of 1967. Okay. In August, 1967, Marburg, Germany was not the place to be. Oh, oh dear.

Even before the outbreak of a deadly virus. Oh, gosh. The heat wave had driven anyone who could get out of town up to the mountains or over to the sea, while anyone left behind, had to suffer through the unrelenting heat day after day. And a handful of those, unfortunate enough to not have a means of a skis. out of Marburg, we're about to get a whole lot more unlucky. Oh dear. Because within a few weeks, about 20 people living in or near Marburg began to get sick.

Fever, malaise, headache, vomiting, rash, conjunctivitis. Their doctors chalked it up to summer diarrhea or dysentery. And the patients were instructed to take lots of fluids and, you know, relax and recover at home. But that wasn't working. They weren't getting better. They were getting worse. And about five days after symptoms first showed up,

most of them had checked into the hospital of the University of Marburg, where they were promptly put into an isolation ward for infectious disease. Wow. Just imagine working at that hospital at that time. Yeah, I mean, people still weren't wearing gloves until, like, later, to handle specimens and stuff. Oh, wow. Yeah.

Because it was like, this is probably a. disease that we know about. Yeah, but also you weren't gloves with those. Yeah, well, maybe not in 1967. Maybe not 1967. Yeah. Yeah, but this was looking less and less like a GI infection, less familiar overall, and much more terrifying as word spread that an additional four people with similar symptoms were being treated in Frankfurt. Who? Doctors at the hospital in Marburg ran test after test first looking for, you know, the usual suspects like salmonella, shigella, rickettsias, chlamydia, yellow fever, leptospira, and others. And then when each of those tests came back negative, they enlisted the help of a dozen labs around the world to test for the unusual suspects, things like arboviruses or other pathogens that were known to cause. hemorrhagic fever. And it was looking more and more like it was going to be a rare zoonotic pathogen at the root of all of this, especially since interviews with patients had revealed the one

thing they all had in common. They all worked in a lab either directly with African green monkeys, their organs, or cell cultures derived from these monkeys' organs, namely kidneys. Okay. Why were they working with monkey kidneys in the first place? The polio vaccine. Oh, I was going to say, I feel like I should know this because I feel like we've talked a lot about the African green monkey kidney cells. Yeah. I should have done a search through our transcripts to see where else I've talked about African green monkeys or you have.

Yeah, they've come up quite a bit, probably in our polio episode, to be honest. But yeah, so if you remember in that. polio episode that we also released forever ago at this point, it feels like. Sabin's polio vaccine used a live attenuated strain of polio, and this polio vaccine strain had to be propagated in monkey kidney cells. But why African green monkeys? Well, in the first half of the 20th century, researchers had primarily used rhesus macaques in biomedical research, But it turned out that they couldn't be used for vaccine production because these monkeys are natural hosts of herpes B virus. Whereas the African green monkeys were thought to not carry any viruses or other pathogens whatsoever that could be infectious to humans.

I mean, the hubris. I know, it still happens. Yeah, but that thought, you know, changed once this outbreak happened. And we can look back now and think, okay, 31 total cases. Like, that's not that many. That's, you know, just a few dozen. I mean. It is a lot.

But like- It sounds really scary. It is. I mean, absolutely. But like, in the scheme of things, it's like, okay, 31 and it was done within a few months, that's done. And they all worked at this place. I feel like that's the thing that makes it the least. like, okay, at least we have a source.

They all initially worked at this lab or at a different lab, but then it started to spread to other people. Oh, dear. Okay. So that's when things were getting really scary, right? Yeah. Okay, 31, and that seems like, okay, they were able to contain it. They were able to isolate it. But when cases were still happening and when those cases were not,

not just in Marburg in Germany, but also in Frankfurt. And then when they were also in Belgrade, in then Yugoslavia and now Serbia, also in a vaccine facility that also handled African green monkeys. And then things started to get scarier when it was not just people who had direct contact with those monkeys or monkey organs or cells, but also health care workers. And then a family member or two. Here we go. I started to kind of like, whoa, whoa, whoa, what is the actual limit of what this outbreak is going to be? And in the 1960s, tens of thousands of African green monkeys were exported each year from Ethiopia, Sudan, Eritrea, and Uganda, which is where the monkeys linked to the 1967 outbreak were ultimately traced. I couldn't find an exact number, but it seems that at least several hundred monkeys,

were shipped from Entebbe, Uganda to Germany via London. Normally, they would have been sent straight to Germany, but the direct flight was disrupted due to the six days' war. And this detail would become relevant when researchers were trying to track down where exactly the virus came from, because in London, they were against regulations, kept in a room with other animals from other places. and like one of the animals got sick later, for instance.

And then in the final transport to Germany, two of the monkeys escaped. And then were later captured. But like, you know, just like, did it have to be these monkeys? You know what I mean? Like, are you kidding me? Yeah, yeah. But all this confusion and this contact with the other animals kind of obscured where this virus originated. Did the monkeys have it when they were captured in Uganda or did they get it from another animal that they were temporarily housed with?

Right, right, right. It also, of course, led to fears that if it did come from the monkeys, it would have spread to the other animals, which was a legitimate fear. Yeah. Because when the monkeys arrived in Belgrade for quarantine, three shipments of 100 monkeys each, 21% of one shipment, 32% of another, and 4%. 46% of another died during quarantine. Oh, my goodness. Yeah. And because of the super high mortality rate, a vet at this facility was assigned to do necropsies.

That vet ended up getting infected with Marburg virus. Huh. And about 10 days later, his wife, who was taking care of him, developed symptoms. Oh, dear. Mm-hmm. They both survived, fortunately. And later on it would be revealed that there had been a major outbreak of a deadly disease in the monkeys in the places that they were usually caught before being shipped to Germany. Oh, gosh.

But at the time of this 1967 outbreak, no one could say for sure that the virus was from Africa. It was only later, about eight years later, when a 20-year-old man from Australia who was traveling in South Africa was diagnosed with Marburg virus disease. and later his companion and a nurse caring for them also got sick. But that suggested pretty strong. He had picked it up in his travels, likely in a cave where he slept near bats. Yeah. But I'll get to these later cases of Marburg virus in a second, but I want to head back to 1967 for now.

So by mid-September, seven of the 31 infected individuals had died of their infections. So a 23% case fatality rate. But the disease did not seem to be spreading, which was a huge relief, as you can imagine. And less than three months after the first cases, the responsible virus had been isolated, characterized, identified, and named. Wow. Marburg, of course. after where the cases occurred, most of the cases, I should say. The last case of Marburg virus in 1967 developed in November, the spouse of someone who had

recovered from the infection a couple of months prior, so thought to be sexually transmitted in that case. Oh. Yeah. But yeah, I feel like all of that was over a fairly short course of time, right? Right. Just over the period of a few months. But the impact of this outbreak would last a lot longer and spread much wider than the virus itself did.

Because first, this outbreak showed that these monkeys, these African green monkeys, were not as safe to work with as had been previously thought. For instance, before this outbreak, lab employees would handle the brains of these monkeys without any PPE. Oh my God. PPE was limited at best, like it didn't protect against aerosols, for instance. And even initially, like I mentioned, the samples taken from infected people were handled without any extra precautions by hospital staff. Obviously, all of that changed because of Marburg. Right.

Secondly, the remaining monkeys that had been imported in the same batches as the infected ones were called. Future imports were super-referrous. restricted, and tons of monkey kidney cells had to be thrown away, along with the polio vaccine produced from them, all of which led to a pretty big shortage in polio vaccine in Germany, which then led to in increasing cases of polio. Wow. It's amazing, like these cascading effects. Yeah, seriously. But fortunately, having the virus identified and described meant that existing batches of vaccines,

could be tested, and future monkeys or kidney cells from those monkeys could be checked for presence of the virus. Side note. Some vaccine manufacturers switch to using crab-eating macaques from Southeast Asia for vaccine production because they were thought to not carry any potentially harmful pathogens. Or at least, that was the belief until 1989 when Reston virus, and Ebola virus, was discovered in macaques in a research facility in Reston, Virginia, near Washington, D.C. I just, I mean, we learn, but we don't learn, but we learn, but we don't.

It's like a little bit of absence of evidence is not evidence of absence. Mm-hmm, mm-hmm. And also, like, we know this. Mm-hmm. And it's like, well, we screened for everything that we know. Yep. That's how we find something we don't know. Yeah. I mean, fortunately, rest in virus, like this is a huge dodge, right? It does not, it's not

pathogenic to humans. Right. Or at least doesn't appear to be at this point in 2020. 20, 20, yeah. Okay, but I wanted to just throw that in there because I thought that was a, come on. Do we need to keep learning this? Yes. Yes, we do. Yep. All right. But, okay, back to Marburg. After the 19th 67 outbreak, Marburg virus was not detected again until those three cases that I mentioned in 1975. The next year, 1976, was when the first recognized outbreak of Ebola occurred, which was initially thought, like I said, to be Marburg virus. And since then, Marburg has mostly been overshadowed by Ebola virus, partially because by the mid-90s, Ebola virus had caused sizable outbreaks involving hundreds of people with a super high case fatality rate.

Like you mentioned, you know, on the order of 65 to 80 to 90 percent. Right. Whereas Marburg virus had really only caused one or two cases at a time outside of the 1967 outbreak. I counted like eight cases total between, you know, 1968 and 1997 or something. Yeah. And a couple of those eight cases. were lab accidents from like a needle stick. But things would change in 1998 because that year, an outbreak of Marburg virus began in Durba, a gold mining village, with an estimated population

of 25,000 in northeastern Democratic Republic of the Congo. From October 1998 to September 2000, a total of 154 cases were detected or suspected and 128 people died. Wow. That's a case fatality rate of 83%. Yeah. Very high. Yep. And very different again than most of the cases that we had seen prior.

Yes. Yeah. This was, this seemed unusual at the time. We now know that it is not. unusual. Because in October 2004, there was another big outbreak, but this time it was in northern Angola in West Africa, where the virus had not been detected before because all earlier outbreaks had origins in East Africa. So that alone was sort of like, whoa, what's happening here? Why is this? Why is this going on? And the size of this outbreak in Angola and the case fatality rate

was also unprecedented, a total of 252 cases and 227 deaths. It was 90%. Yeah. It's, yeah. One of the things that I found really interesting about these two outbreaks is comparing the viral genetics between these outbreaks because researchers observed two pretty different patterns. So in the DRC outbreak, they found at least nine genetically distinct viral lineages during the outbreak.

Wow. So that suggests multiple introductions from a natural reservoir. Ooh. Suspected to be those Egyptian fruit bats that you mentioned. So that's like multiple spillover events. A bunch of different people were exposed to a bunch of different bats in that outbreak. Yep. Whereas in the Angola outbreak, researchers found what looked like a single introduction of Marburg virus.

That is so important and interesting, Erin. Yes. Right. Okay. Because the other thing that this outbreak did was challenged not only like, oh, it is geographically restricted to this area. But also there was, I mean, it was hard to say because there were so few cases still. and case histories were really difficult to get and like all of that. But there was sort of this prevailing idea that secondary infections,

so if somebody picked up the virus from an infected person rather than from a natural reservoir, that it was going to be less deadly. Right. Less virulent. Yeah. Yeah. And that obviously was not the case in Angola. Well, I think it also just can show this.

scale or the potential scale of person-to-person transmission to begin with because previously we hadn't seen any outbreaks on that scale. And so knowing that it could have been potentially from a single introduction means that all of the other cases are from person-to-person transmission. Yes. And it gets even more kind of like interesting because, so we've talked a lot about RNA viruses on the podcast before as being highly mutagenic. They mutate. They mutate. frequently they mutate a lot. I don't know, and I probably should have looked up the mutation rate of Marburg compared to something like influenza or SARS-CoV-2 or something. But in some of the genetic analyses from this Angola outbreak, they found that the virus didn't really same to

change very much, even after going through like two to three human-to-human transmissions. where you would normally expect at least some changes to occur, the genomes were identical. Fascinating. Yeah. So I think that that suggests that the mutation rate in general for Marburg virus is pretty low. Right. But why that is is a fascinating question. Yeah.

I don't know. What causes mutation rates to be different? I don't know the answer, but I now want to know. Uh-huh. I do. So since the first outbreak in 1967 and excluding the current outbreak that I'm sure you'll talk more about, Erin, there have been approximately 474 cases of Marburg virus. But that's probably an underestimate.

Oh, certainly. Yeah. Number one, there have probably been, like very, very probably. additional cases that were contacts of confirmed cases that never developed disease or were never tested in the first place. And second, because Marburg virus has probably been around for quite some time, causing infections before we knew what to look for. For instance, before the outbreak in Derba in DRC, there had been cases of something called hemorrhagic syndrome of Durba, associated with living near the mine. and one person who had survived this disease was later found to carry antibodies against Marburg virus. Ooh.

Mm-hmm. Research into the evolutionary origins of Marburg virus and other phyloviruses tells a similar story, although definitely not a consistent one by any means. I'm not surprised about that. Some papers put the origin of philoviruses at 10,000 years or so ago, or at least, at least, least several thousand. Okay. While others say that it's more like millions of years, since phylo-virus-like elements have been found incorporated into mammalian genomes, which is pretty intriguing.

And if that is the case, then it's possible that philoviruses have played a pretty big role in mammal evolution overall. Marburg viruses as a group probably emerged much more recently as long. as 700 years ago or maybe in the mid-19th century. What? I know. There's ranges with estimates. I feel like this may seem like a small detail.

Like, why do we care precisely when or where this thing emerged? But it's important because it helps us predict and contain future outbreaks. It helps us understand how this virus might change during an outbreak. how those changes could be related to the severity of disease that a specific variant causes and for developing an effective vaccine. And all this is important because one thing is certain. The outbreak that we're seeing now is not going to be the last time that this virus makes headlines. And before I hand it over to you to talk about what's happening today, Erin,

I want to take a quick moment to talk about those headlines. Both Marburg virus and especially Ebola virus have fascinated people, terrified people, and intrigued people since their discovery. They've been the subject of awful fiction, such as The Virus by Stanley Johnson, aka Boris Johnson's dad. Really? Yeah. Okay. I know, I could not believe it. I'm like, is this, am I, is Wikipedia fooling me here? What's happening? Not to mention the movie outbreak, which is terrible, but also kind of great in some ways.

And also egregiously exaggerated nonfiction books like The Hot Zone by Richard Preston. And don't get me wrong, the Hot Zone is definitely one of the books that got me interested in the history. history of infectious disease. But it is borderline fiction. I grabbed it off my shelf for researching this episode because I was like, okay, I know that there's a part in here about Marburg virus. Where did he get his sources? Like, are this going to be good places where I can learn about like the sequence of events and stuff? Yeah. There are no sources listed anywhere. Love that. None. There's a list of main characters and a glossary at the back. But, you know, giving benefit of the doubt, at least in my copy, there are not, there's not a single source.

Huh. Which was very jarring. And, you know, the hot zone did get people interested in epidemiology and so on, and that's great. But I feel like we really should aim higher when it comes to transparency in science communication and reporting. Mm-hmm. Anyway, Marburg and Ebola viruses are scary. We've talked about case fatality rates as high as. 90%. But a frustrating amount of news reports play on that fear, stoking it, describing grisly

symptoms and chaotic hospital scenes, suggesting that the virus appeared out of nowhere, encouraging you to imagine what if it happened here? These news articles rarely talk about why that case fatality rate might be so high, especially considering, like we talked about, that first outbreak in Germany didn't come close to that. They rarely mention that perhaps things like inadequate health care infrastructure, inadequate pathogen testing, inadequate isolation facilities, inadequate access to PPE, and other sociopolitical factors that could play a role in driving that number far higher than it should be. They rarely mention that we know quite a bit, actually, about the ecological circumstances leading to spill over events, meaning that these viruses don't just

come out of thin air. These outbreaks don't just happen out of in a vacuum. They sometimes mention that we do have vaccines in the works, but they may not mention that we are likely equipped already scientifically to bring those vaccines from the lab to the real world, but we lack the funds. Because these are rare diseases that happen quote unquote over there. Over there, but you should be terrified if they come, quote, over here. That's, I think, the part that is just on top of everything so frustrating. Yeah. Yep. And the other thing is that part of the reason why these vaccines haven't been completed,

I mean, and a lot of it is logistical difficulties considering that there have been few cases of Marburg and so difficulty in testing and all of that. But there's no profit in making these vaccines. That's a huge part of it. And that may be so. But is that a reason to not make a life-saving vaccine? Or, at the very least, to build up health care infrastructure overall? In the regions where Marburg and Ebola cause outbreaks,

these pheloviruses are rare currents compared to many other diseases, infectious and non. But they are also indicators of ecosystem degradation and possible climate change, these factors that promote pathogen spillover. and they're indicators of how well a region is equipped to deal with a disease outbreak. So I guess my point in all of this is that the sensationalist portrayal of Marburg and Ebola viruses in much of popular media does a disservice by withholding information or misrepresenting what we do and what we do not know at this point. So speaking of which, Erin, what's happening with Marburg virus today? Oh, I'd love to.

to tell you right after a short break. So the outbreak that you mentioned, Aaron, that happened in Angola in 2004 to 2005, still remains the largest outbreak that we have seen, thankfully. And for a long time after that, like you mentioned, it was really just sporadic individual cases or very small single or double-digit outbreaks that happened since then. However, in the last couple of years, There have been outbreaks year after year. In 2021, there was an outbreak in Guinea from August to September with only one individual, but that was the first time that a case was reported in the country of Guinea. And then in July 2022, two cases were reported in Ghana for the first time, both of which were fatal.

And then two more cases were identified, so a total of four cases and three deaths. overall. And again, these are two outbreaks in two countries where Marburg had never been reported before. And then that brings us to 2023. Again, we're recording this April 4th. And at this time, we are looking at two different and thus far much larger outbreaks than we have seen in recent years. One of them is happening in Equatorial Guinea, again the first time that cases were reported in this country. And as of March 22nd of this year, that outbreak is up to nine laboratory confirmed cases and an additional 20 probable cases with seven deaths reported among those that are confirmed Marburg and all of the probable cases have died. So,

that's 27 people who have died so far. And a second outbreak identified in March in Tanzania, which, if you haven't looked at a map of the continent of Africa recently, is nowhere near Equatorial Guinea. These are completely disparate outbreaks that are happening to happen at the same time. In Tanzania, it's a total of eight confirmed cases and five deaths so far, and the first outbreak reported in Tanzania. Both of these outbreaks are considered still ongoing because the incubation period is long enough that the World Health Organization doesn't consider an outbreak over until at least 42 days after the last reported case, just to like really try and make sure that we're

catching every possible case in an outbreak. So these are still ongoing. So by the time you're listening to this episode, dear listeners, there may have been a number of more cases. Or maybe the numbers will have stayed the same if we're lucky. But obviously, one of the biggest natural questions is like, why does it seem like these are increasing in number again? Like, is this an increase in number? This is two different outbreaks that's going on.

I mean, the outbreak in 2004 was certainly the largest. We're nowhere near that scale yet, thankfully. but these are two significantly larger outbreaks than we have seen in quite some time. And because this is happening currently as we speak, we do have to rely on information kind of directly from the World Health Organization as well as journalism articles that are written because we don't have a lot of peer-reviewed science thus far from this particular outbreak or these particular outbreaks. But one article that I read from the New York Times that interviewed a number of people mentioned that since COVID over the last couple of years, a lot of countries have beefed up their capacity for things like PCR testing.

So it could be in part that 2021, 2022, now 23, where we're picking up Marburg not just more cases, but also in more countries than we've ever seen. seen it before, it could be that it's because we're able to actually do the testing, right? Yeah, that's interesting. Yeah. So it could very well be that this virus has been circulating far more widely than we realized and we're just now picking up on it for kind of the first time. Yeah. And that might be part of it.

I think only time will tell. One thing that I do think is interesting kind of that might support that idea is that I read a paper from 2015, which is really prior to any outbreaks being reported in the most western parts of Africa, aside from Angola, that had modeled the potential niche for Marburg virus based on all the prior outbreaks that had happened before 2015. And this paper indicated a much broader potential range of risk for Marburg than the places and the countries where outbreaks had up to that point been previously reported. I'll definitely put a link to that paper on our website because the maps are really interesting

and they now very nicely overlay with places that in the last few years we have started to see Marburg, in fact, appear. Yeah. So that may be part of it, is that we finally are beefing up the capacity to be able to pick up on these viruses that previously were just going, undetected, you know, just generic people are dying from some kind of viral hemorrhagic fever or some kind of unknown, undetected virus, right? Right, right. But of course, as you mentioned, Erin, and as we always get to on this podcast, we'll kill you. Certainly things like climate change, land use change, urbanization, encroachment on natural habitats, and this overall increase in wildlife human interactions,

all of these things are going to increase the possibility and probability of spillover events happening. And Marburg is still predominantly a disease of spillover events. So that piece of the puzzle really can't be ignored. And because of that, I think that in terms of where do we go from here, what is the future research as it comes to Marburg? I think that some of the biggest areas are really in better understanding the biology and ecology of this virus, right? We need a lot more knowledge on the natural reservoirs, a lot more details on why are we seeing these increases in case numbers?

Is it really true increases? Is it better detection? Is it a combination of all of these things? There is a lot, I think, to be done on the general ecology of this virus. but there's also a lot of work to be done and that is being done on both vaccines and therapeutics for Marburg. As of right now, neither vaccines nor any specific therapeutic treatments exist. There are a number of candidate vaccines, at least one of which has made it as far as phase one clinical trials and has been shown to be safe in humans. and a number of others that have had pretty thorough animal testing that have been shown to be very effective in non-human primates

and are ready for human trials but haven't been able to undergo them yet. So the World Health Organization very recently, like March 2023, put out this very interesting guideline that anyone can access. It's just a PDF of a PowerPoint. on what their kind of plan of action is to try and actually do these clinical trials during outbreaks. Yeah. And this is in an effort to both increase the capacity to do this kind of research. Because like you mentioned, Aaron, with a disease that's as sporadic as Marburg, it's really difficult to do clinical trials the way that we typically do them.

This is a very rare disease, which is a good thing. and the better our public health response is in identifying and isolating cases, the less chance we have for this type of clinical trial, right? Which is a good thing for people. Right, right. But it still does limit in terms of the data that we're able to gather on these various vaccine candidates. So at this point, we have relied heavily on these animal studies. But these guidelines are for things like ring vaccination campaigns during outbreaks. So this would be vaccine trials that involve people who are at very high risk, people who are either already exposed potentially or at very high risk of being exposed, like health care workers or family members of people who are identified as infected, etc.

Right. So that's kind of where we stand. Most of the vaccine candidates thus far are viral vector vaccines. So very similar to the AstraZeneca COVID vaccine, people may remember. So they use adenovirus vectors or some other virus vectors. And then in terms of therapeutics, there is research being done on using things like monoclonal antibodies. The word remdesivir might ring some bells for some people because I was used for COVID. Originally developed for Ebola, didn't work great for Ebola, has been shown to be effective.

in non-human primates for Marburg. No idea if it works in humans, but there's at least potential. But like you mentioned, Aaron, a lot of the limitation comes not only in the fact that this is a rare disease, but also in the fact that especially between outbreaks, the funding kind of just disappears. Right. Yeah. And it's very difficult to do vaccine research without funding. Yep. It's kind of like investing in health care and public health infrastructure is a good idea.

But let's just throw money at the problem when we see the problem. You might come to the conclusion that investing in this technology would serve us well. I don't know. Maybe you'd come to that conclusion. One could reason. But that is. is Marburg. Sources?

Sources. I have several. I have a bunch. I'm going to shout out two in particular. One that was helpful with the evolution was by Emmanuel et al from 2018. I think it was a book chapter called Philoviruses, Ecology, Molecular Biology, and Evolution. And then there was a great paper by Browberger at all from 2012 titled 45 years of Marburg virus research. So I love that paper. It's great. It's very thorough. That was actually my number one paper. I relied very heavily on that same paper as well as a paper from

2022 that was called the pathogenicity and virulence of Marburg virus. I had a few other papers with a lot more kind of nitty-gritty detail. And then I will link. to the World Health Organization Disease Outbreak News kind of generic website because this is where when you're listening to this several months from today,

you'll be able to get the most up-to-date information on what's going on with Marburg and also any other infectious disease that are having outbreaks around the world. And we'll post the sources for this episode and all of our episodes on our website, this podcast will kill you.com. Thank you to blakey.

Lubmobile for providing the music for it this episode and all of our episodes. Thank you to Leanna Skulachi for our amazing audio production and editing. Thank you to exactly right. And thank you to you listeners for listening. Yeah, we hope that you learned something. Yeah, I feel like this was a real kind of throwback episode, like very OG TPWKY. So hopefully it was fun for everyone. For sure, yeah.

Yeah. And a special thank you to our wonderful. generous, amazing patrons. We appreciate you and your support so, so much. So much. All right. Well, until next time, wash your hands. You filthy animals. This is Bethany Frankel from Just Be with Bethany Frankel. Listen, I have a bone to pick with these dog food brands calling themselves fresh, natural, healthy. Sounds great, but a lot of these quote unquote fresh dog foods in your fridge are not even 100% human grade, which is why feed your babies, just food. for dogs, it's good enough for big and smalls, my precious babies, so it's good enough for

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