[Intro Music Starts Playing]

Tony: Hello and welcome back to another episode of Microbe Matters, presented by ID Pitstop,

where we discuss, dissect, and demystify topics in infectious diseases with our experts here at UPMC and the University of Pittsburgh.

 I’m your host, Tony Morrison, media specialist here at Pitt ID, and I’m just as curious you may be about navigating through a world full of microscopic organisms. Please join us as we examine both the dangerous and beneficial microbial microcosms that surround us, promote public health, and showcase research and treatment of modern infectious diseases.

[Eerie music accompanied by sounds of people yelling and screaming starts to play]

[Tony talks in a mysterious and serious tone]

Tony: A deadly fungus has begun to infect the human population. Cities and towns evacuate.

People loot storefronts, and there is panic in the streets. The world has descended into chaos.

The only thing more terrifying than the mass hysteria is what the infected people have become. Zombies.

[Zombie noises start to play]

 The fungus that possesses their bodies not only feeds off of their host but controls them too. The victims of this malignant fungus are called cordyceps. Named after the group of fungi that infect them. A horror movie made reality.

[Sound of record scratch]

[Tony is no longer talking in a mysterious and serious tone]

Tony: Well…perhaps not reality. But that is the premise of the HBO hit series The Last of US.

Modeled after the video game of the same name produced by Naughty Dog.   All right, so a zombie fungus apocalypse isn’t anywhere on the horizon for humanity. But what if I told you that this kind of fungus does exist? The group of fungi called cordyceps do populate our earth, but they only specifically target insects, at least for now.

Cordyceps have been used as remedies in traditional Eastern medicine for centuries.

Although our day to day lives aren’t in danger of being thrusted into survival horror, there are some fungi infections currently on clinical radar. 

With me today to talk about modern fungal infections is Dr. Cornelius Clancy. He’s the director of the Mycology program at the University of Pittsburgh, as well as the associate chief of Veteran Affairs, Pittsburgh Health System and Opportunistic Pathogens and the chief of their Infectious Diseases Section. Thanks for joining us today, Neil. I can call you Neal, right?

Neil: Yeah, please do. My U.S. government name is Cornelius, so I’m usually in trouble when people refer to me by that.

Tony: In recent years, there has been an increased interest in stewardship programs concerning opportunistic pathogens, And one major field of study that facilitates that is genomic epidemiology. I think that there are a lot of people out there who may have heard of the field,

but aren’t exactly sure what it entails. Clinicians and myself included.

And so, to help us understand epidemiology and its role in health care, we’re also joined today by Dr. Alexander Sundram, an assistant professor of medicine here at the University of Pittsburgh. He works very closely with our labs to detect and investigate hospital outbreaks using genomic sequencing technology from clinical isolates. Thanks for coming on the show, Alex, and helping us better understand this emerging field.

Alex: Thanks, Tony. It’s a great to be here, too.

Tony: I’m sure both of you have at least heard about the popularity of the series The Last of US.

But Neil, are emerging fungal infections a real threat to human health? If so, what are the most pressing issues in the field we should be aware of?

Neil: Yes. So, Tony, I’d agree with you. I don’t think we really need to worry right now about a fungal apocalypse. But I think three things for people probably to be aware of and that they may have heard a little about already. First, I think, is the emergence of resistant candida species. So Candida are yeast that normally colonize the body, but occasionally they can get beneath colonized surfaces and cause invasive infections. 

And the common causes of infections among immunosuppressed and other hospitalized population is what we’ve seen over the past decade or so are increasing emergence of these candida species that are resistant to our existing antifungal drugs. And the species has gotten most attention recently as Candida Auris, which has gotten quite a bit of play in the popular media. And this is a previously unrecognized Candida species that emerged about 15 years ago,

seemingly out of the blue, and it’s caused outbreaks of resistant candida infections. in hospitals, you know, in the four corners of the globe.

Secondly, I think there’s been an emergence also, particularly in Europe, of antifungal resistant mold species, in particular Aspergillus. And what we’ve seen in Europe is with the use of fungicides in agricultural practices, these molds which normally infect plants and crops, become resistant to the fungicides. But in becoming resistance to the fungicides, they’ve also become resistant to antifungal drugs that we use to treat, [stutters] um, patients. So CDC are quite concerned about the potential emergence, in particular of what we call ASAL resistant

Aspergillus in the United States. Similar to what’s been seen, say, in places like Holland or the United Kingdom. And as yet in the United States, we’ve not detected an awful lot of these. But certainly over the next 5 to 10 years of the prospect that we may see more and more of them.

And then finally, I’d point to as a global phenomena, the emergence of either existing fungi

in new geographical locations outside of where they were previously encountered, as well as the emergence of wholly new fungi that previously infected plants and animals but were not known to infect humans. And people may be familiar with an outbreak of a Blastomycosis that’s been ongoing in Wisconsin surrounding a paper mill. And these are the type of fungi that were geographically restricted to particular parts of the United States or other parts of the world. And the geographic boundaries with climate change, with changes in human migration and agricultural practices, the geographic balance of these fungi have expanded.

So they’re seen in places where previously we didn’t think of them, where we didn’t detect them. So I’d say those are three general trends that have been in the popular media and that listeners may have heard about.

Tony: We’ve mentioned on the show before how Candida Auris outbreaks are almost exclusively localized to hospitals and other facilities. Alex, could you briefly describe epidemiology and how you use genomics to look into Candida Auris? How is it getting into hospitals and how do you prevent it?

Alex: Yeah, so epidemiology is essentially just study of human diseases from a public health perspective. So, a very broad perspective. And then when you look at genomics, it’s really looking at the DNA fingerprint of different pathogens and diseases that we see. So when you combine them together, it’s really looking at the population level of spread for certain types of diseases that we see going around into different communities.

So genomic epidemiology in terms of Candida Auris shows us like Neill just mentioned,

that we had this sudden emergence in every area of the world of Candida Auris that just started

independently of each other. There wasn’t spread from one single area to a different part of the world, and that’s what we’re able to use [stutters] um, uh, genomic epi to track Candida Auris. You can see where certain clades are moving in about the United States, how they’re getting into hospitals. Canada Auris particularly is very difficult to eradicate from hospitals. A lot of the studies show that, you know, once it gets into a hospital, you can essentially expect it to stay there.

It stays on contaminated surfaces for so long it colonizes patients, it’s difficult to detect and it causes a lot of disruption in these health care facilities. But by using genomic epidemiology,

we can determine, you know, did, did this come to our hospital from somewhere else? Are we actually seeing spread within our own hospital from patient to patient. Um, so looking at the United States, we see this large clade coming out of Nevada and these patients that are in Nevada, they don’t stay there, they moved across the country to different health care facilities.

And that’s how we see a lot of spread actually occur within the United States. And using genomic epidemiology and tools like this allows us to be better prepared and actually better intervene and understand how a pathogen is particularly spreading within health care.

Neil: I’ll just say quickly as a follow up to that, Alex, uh, Candida Auris is a complete paradigm shift among yeast and Candida infections, one because of its propensity to antifungal resistance. 

But the other it’s the first Candida species where people like Alex who have these powerful new tools have shown actually spreads from patient to patient, or from patient to staff within a hospital. Other Candida species, they colonize our body. You become infected with the strain that you carry on your skin or in your stool. But this is a whole different model where I may not carry this at all, but because of hand hygiene and other practices in the hospital, it can go from patient to patient, patient to staff and then to another patient. And that’s wholly new for candida species.

Alex: And we have a lot of high morbidity too, especially you go from someone who’s just colonized to then actually developing an infection. There’s a lot of morbidity associated with those infections. So it’s both extremes, essentially we’re seeing.

 Neil: And colonized people don’t know they’re carrying. [Alex: Exactly.] until people start developing bad infections from it. Then you work backwards and find, oh, we’ve got a population of people who are carrying this. 

Alex: Right.

Tony: Wow. Yeah. It sounds like this could really change the course of hospital stewardship for the better. Simply put, epidemiology examines infection control from a public health perspective

by means of understanding the DNA or genetic makeup of pathogens. This tool is particularly groundbreaking in the sense that it more accurately identifies the source of an infection,

which is important to know for when it comes to treating patients. So, Alex, you use this technology to find outbreaks in hospitals, but how do you search for other things? How can it be used to bust an outbreak?

Alex: So when we think about outbreak detection in hospitals, the traditional way we think about it is we call it reactive. So you often have clinicians or the infection prevention department who suspects they have some type of outbreak because they said, look,

we have a few of these infections within a short timeframe, let’s investigate. You do the whole kitchen sink of interventions, try to stop it from spreading, and at the end, we’ll often do

whole genome sequencing to like say, you know, is this a true outbreak or was it just,

you know, independent infections that uh happened to be detected by us? And what [stutters] what we’re seeing is oftentimes they are they are, [stutters] uh, often not outbreaks, They’re not true outbreaks from a clonal spread. You might still have outbreaks of polymicrobial organisms, but they aren’t  true outbreaks that we’re transmitting with the health care setting.

On the contrary, what some of you know our research is trying to do is doing this whole genome

sequencing prospectively. Regardless of that, we actually have a suspicion of an outbreak. And the point of doing that is because typically when we find these outbreaks, we’re already ten plus 20 patients into an outbreak. But if we were doing sequencing, you know, prospectively, not waiting for the outbreak, you detect the outbreak essentially, at you know, the second patient within the hospital. And that allows us to actually intervene faster and prevent the spread and prevent the outbreak from getting any bigger. In some of our preliminary findings

have actually shown that, you know, this is an effective method at preventing outbreaks

from getting bigger in our hospital. 

But then from, you know, more national scale. I think whenever you do the amount of sequencing that we do and you start sharing that data with other institutions, you’re better able to detect national outbreaks that are multistate multi facility outbreaks that we’re seeing. So, for example, there’s this ongoing national outbreak of extreme drug resistant pseudomonas aeruginosa that, you know, the CDC eventually, after many, many, many cases traced back to contaminated eyedrops that were being produced at a facility in India that didn’t have the proper sterile procedures in place. And this bug got into those eyedrops, was imported into the U.S., distributed mostly across many states and started to infect people, causing, you know, very severe, hard to treat infections, that none of our antibiotics really work against it. 

And when we looked at our data, eventually we had a cluster of this pseudomonas aeruginosa early on, but without any, you know, public data available, we weren’t able to compare it to national data. But eventually the CDC shared this this genomic data that they had from their investigations. And we found that we had some of the patients  in our hospitals and one of the patients actually did have eye drop use that was most likely one of those contaminated eye drops. But when you think about that, too, if multiple hospitals were using this approach, we might have been able to detect this outbreak nationally much earlier than we did in the reactive sense.

Tony: Yeah, I remember hearing about the eye drop story in the news the week that it was a big, big story and I immediately ran into my bathroom to check in, make sure that it wasn’t the [Laughs] brand that had been recently blacklisted. 

Neil: Well, if it was, though, you could have brought it to Alex and

 [Alex interrupts Neil]

Alex: Oh, we would have tested it [Neil: the sequencing.]

Neil: You’d either be alarmed or you’d rest comfortably.

Tony: Neil, I’d like to ask you something. While we’re on the topic of outbreaks. We worry about viral outbreaks because of their community ability, but fungi are found natively everywhere in the environment. Is it plausible that there could be fungal COVID 19 scenarios?

Neil: I’d say not, Tony. [Stutters] I mean, for two reasons. One, most fungi are not spread from human to human. They’re out in the environment and you get exposed. And if you’re susceptible, you may develop an infection, but you don’t transmit that to someone else. Now, we just spoke about Candida Auris and why it’s so interesting as an exception to this rule, and it can be transmitted within hospitals from patient to patients, patients to hospital staff. But even then, even there, fungi grow very slowly compared to the way viruses replicate or the way, or the way bacteria replicate. So even if you had person to person spread the scale and pace at which it moves, is just so much lessened that you generally do have time to eventually detect

that the outbreak is going on and, and break it. Um, so I wouldn’t really worry about a COVID type event. The analogy I often use is if you think of viral, respiratory, viral COVID like pandemics as the hair, something that’s very fast

[Sound of car taking off, and tires screeching}

Neil: bursts out of the gates and does what it’s going to do and moves very, very quickly.

You know, things like fungal infections are more like the tortoise. They’re going to move

at a more [Voice is slowed down] deliberate, plodding pace.[Voice picks up at regular speed] But as has been shown with Candida Auris, if they get into a particular environment,

they can persist, they can linger and they can go on for a long, long, long, long period of time. And they exist in our environment as spores for months to years. So [Stutters] it’s more a long

term endemic, slow moving type of thing that that I’d be worried about with fungi rather than explosive pandemic.

Tony: So the short answer is no. The way fungi survives and reproduces does not put it

on the same playing field as pandemic level pathogens, but it is quite resilient in varying environmental ecosystems, and that’s what makes fungi still a looming threat.

Neil: So, you know, one thing, along, [Stutters] along your line, Alex, is, you know, one thing that’s very interesting about fungi is that they’re eukaryotes. So genetically they’re probably disturbingly close to humans and they’re much more closely related to humans on a genetic level than they are to bacteria or viruses or viruses or bacteria related to one another.

And this on the clinical and makes it really challenging to come up with treatments or diagnostic tests that are going to detect these fungal eukaryotes but not cross react or cause damage to human cells. It’s a reason there’s only really three broad classes of antifungal drugs, for example, rather than the dozens that we have with antibacterials. But does this present, you know, challenges for you on the genomic epi front? Is it is it harder to do these studies with fungi than it is with [Stutters] with bacteria or viruses? 

Alex: Yes. So the the genome of fungi are so much bigger. So the analysis is so much more in-depth and requires different methods to actually analyze it. And even then, determining, you know, what’s, what’s related in the end. When we look at bacterial genomes, which are much smaller, you can look at the mutation rate, which for us is really easy to describe because these bacteria mutate at a, you know, pretty well agreed upon rate within the patients that allows us to determine thresholds of what you know, what’s the same strain causing an infection.

So whenever we do these investigations, we can have that threshold handy for bacteria, but we don’t really have that for fungi yet. Even, even for viruses, which are genomes are much smaller too. You don’t have these really big mutation rates, and especially for viruses, these patients, you know, they get ill, they have their contagious period for like COVID, you know, which is a few days, and they spread it. You’re able to look even within a certain time frame with another patient that might have a low threshold. So they might be related to that, uh, other patient.

You have more confidence in determining that.

When we go back to bacteria, though, these patients, they can get sick, they can hold on to it in a colonization after their infection, and there’s that mutation over time. So determining transmission within, you know, genomic epi for bacteria can still be kind of complicated whenever you have similar pathogens over the course of a few years. But, you know, nothing’s

been really common among these patients.

Neil: Yeah. One thing we see in the research lab, among the fungi that infect humans, most of them have incredibly plastic genomes as well. So it’s, [Stutters] it’s not simply that you develop a mutation in a particular gene over time, but with Candida in particular and molds that infect humans, you can see large scale chromosomal changes where there’s [Stutters] there’s chromosomal duplications or chromosomal loss and this plasticity is what gives Candida

and these other molds the ability to exist in so many different environments. You can find Candida in almost any surface or organ of the body. 

You can find these molds in almost any environmental niche. And the genomic plasticity, in addition, just the simple point mutations that occur at specific DNA sites, uh is [Stutters] is, you know, one of the mechanisms these have evolved to be as successful as they are in the environment and as, [Stutter] as human pathogens. And that probably also presents challenges for understanding relatedness when you do a whole genome sequencing.

Alex: Yeah, actually determining where did it come from, which patient are they related to? Uh, 

We always say whenever you look at these outbreaks, you can’t look just at genomics, you can’t look just at epidemiology. You have to weigh both of them in determining, you know, what makes sense in the scenario.

Neil: Yeah, it’s a great point. I remember as this was emerging, you go to meetings and I think for me outside the field there was an idea this is just going to unlock all the mysteries. You’ll be able to just look at the sequencing. You’ll say, this bug is the same as this bug. Therefore these patients are related in terms of transmissibility. And what you realize is that the good old , what? In your line of work [Alex: shoe leather] shoe leather epidemiology, right,  Is it perhaps even more important now so that you don’t misinterpret or misuse or mis apply these genomic data.

Alex: Right. I mean we so often we see that in some of our research which we publish on where, you know, we have gene patients with genetically related isolates in the hospital. So you think there’s an outbreak, but you look among these patients and nothing is common between them.

So either you’re missing that additional data to actually say, you know, maybe we didn’t sample patients or sometimes you’re just restricted by the investigation. That might be community spread, it might be some environmental reservoir that you just don’t know about and you’re restricted by. So again, you always have to weigh both those factors when we do these types of investigations in any type of pathogen.

Neil: Yeah, that gets us back to the environment, right? I mean, generally speaking, people

coming into a given hospital are coming from the same geographic area [Alex: Yeah] outside the hospital. So is what’s going on in the community, outside of the hospital in some sort of environmental niche, or is it in the hospital itself in an environmental niche? And this can be incredibly difficult, I imagine, to tease out when you’re actually looking at clusters of cases.

Alex: Yeah, yeah. We’ve had some evidence too where we actually see, you know, genetically related isolates, but they have a community exposure that we’re able to identify. But you think about that, you know, if you weren’t able to identify that through a chart review then yeah, like you would you toss that up too? We don’t know. So I mean, it supports your point that, yes, you know, a lot of these get circulated in the community and then the patients come to the hospital with the same strain.

Neil: Yeah. So it goes to show you as with all these technologies, right, they’re incredibly powerful. They answer a lot of questions, but in a way, they sort of open up even more questions and

[Alex interrupts Neil]

Alex: It’s like it’s like AI, they’ll never replace us, Neil

[Neil laughs]

I always have a job.

Neil: I’ll tell you what, they’re less likely to replace me than you

[Alex laughs]

because you’ve got a lot longer still to go

[Neil laughs]

Tony: So, Alex, I guess that brings me to my next question. How do you see this technology evolving? Do you envision it becoming more generally available and applied both within and outside of health care?

Alex: Yeah, I think so. So in the past few years, because of COVID 19, we’ve saw a huge investment for genomic sequencing, for mainly for public health departments to get a better understanding of, you know, the COVID uh, variants that are circulating. So whenever you see in the news, you know, like new COVID variant Omicron, and I don’t even know what name that we’re on at this [Chuckles] moment, but that’s because of genomic sequencing. So there’s been billions of dollars invested into that. And, you know, our [Stutters] our work and looking at hospital transmission and others where others as well within the world have shown, you know,

the contribution it could actually give to health care settings.

 So I think as we see the evidence emerge, a lot of that COVID and investment can actually be shifted to the health care setting where we realize that, you know, we’re having this growing

AMR crisis, we’re seeing lots of transmission and we see the value of genomic sequencing.

We can slowly shift those resources to a hospital setting. That can actually be feasible, though,

right now in its current state. We you know, a lot of these places that do sequencing takes them,

you know, weeks, months to actually get those results back. But in order to be anything actionable, you have to get it, you know, results quickly. In our hospital right now, we can get results from the time that, you know, the physician takes the culture at the bedside to actually having the genomic results in hand takes about two weeks. And that’s only going to get faster,

as you know, the more that we do this. But I think, you know, infection prevention departments across the United States see the value in this technology, see that it detects these outbreaks

that otherwise go undetected.

It’s just a matter of looking to these professional societies to try to create some types of standardized guidelines and recommendations on actually using this technology. Because right now, you know, it’s not recommended by anybody where, to our knowledge, the only people in the U.S. that are actually doing it to the scale. So how do you convince other hospitals, hospital leadership, at least to actually invest in this technology that will uncover outbreaks that you don’t currently know about? It’s a very hard ask to do.

Neil: Yeah, it’s an interesting point because you’ve already got enough challenges to, to deal with. There may be a mindset out there that I don’t really need to look for challenges that I don’t know exist right now. Um, you know, one thing, Alex, that, that we’re excited about in the mycology world, sort of on the research front at this point, but down the road may have clinical applicability is taking your genomics work and melding sort of genomics of the host the human genomics with the microbial genomics. And you know, one thing we’ve learned in the fungal world is we know general risk factors for these fungal infections. If I get a bone marrow transplant and, you know, my immune system is effectively obliterated, I’m at risk for aspergillosis and other mold infections. But even there, not every patient in the same environment develops an invasive mold infection. So there’s other things going on.

And with with human sequence, it’s become apparent that there are a lot of very subtle defects

in specific arms of the immune system that probably in particular predispose you to certain fungal infections. So it may be possible down the road based on your own genome sequence

to understand what your susceptibility to specific types of infections might be. And it may be that in the future you’ll be able to get your snapshot or your fingerprint and understand combined with other factors, my relative risk of this infection or that infection might be high, might be lower or what have you. We might be able to, you know, use drugs or us diagnostic test more rationally in conjunction with this. So maybe it’s at this point kind of pie in the sky.

But do you foresee medical practice being able to go that way? Would something like that ever be feasible where you could combine, you know, patient and microbial data?

Alex: I mean, that would be great to see. I know just from a, you know, broader perspective, you have patient level risk factors like you just said, you know, high….lots of co-morbidities makes you predisposed to having those types of infections. But to have that genetic human data, I’m

sure, you know, it’s probably out there that there’s certain things that will make you more predisposed to infections. And like [Stutters] like we see certain types of predominant strains in the hospital that are successful. You know, creating an environment that they can persist in and infect our patients even over the course of many years. We see that genetic shifts that, you know, the strains change because they’re out competing other strains.

If you can combine that with the human genetic data and show, you know, maybe these types of patients with this genetic risk factor are more susceptible to these infections that we see that are dominating, we can predict and give some risk level for our patients. So, you know, they’re

they’re at more risks than other patients. That would be great to see for an infection prevention standpoint.

Neil: So Tony can have you back next year and you can talk about the ethical considerations around this 

[Someone lets out a light whistle/sigh]

because it’s really going to present, you know, I think challenges for bioethicists and and [Stutters] and those of us practicing, you know, in the future.

Alex: Right, Right. Well, even in the sense of outbreaks that we detect to in a bioethics standpoint, if you have two patients with genetically related isolates, meaning they’re part of an outbreak, but you can’t find what’s between them, is that something that they need to know about? Is that a risk factor versus, you know, an unknown outbreak that you’re able to notify them how it happened? You know, these are things that even just from the pathogen perspective need to be discussed before we see this rapid expansion.

Tony: So I think that perhaps the future of genomic sequencing could be an invaluable part of an infection prevention toolkit for curbing whatever the next pandemic could be. And maybe if we can sequence human genomes, we can help prevent these virulent infections in those who are more susceptible to them. With this medical research and development, possibly in the near future, how do you hope both of your work can impact communities outside of human medicine?

Neil: Well, you know, it’s all one health, right? And I think this is this is one thing that’s become increasingly apparent over the past decade. And a lot of ways, perhaps even most apparent in mycology. You can’t separate human health from environmental, animal, other ecosystem health. And what you see is the bacteria, the viruses. COVID is a perfect example. The fungi,

they’re not singling out humans. They’re just looking for a place to, you know, live, raise a family, do what they want to do. And whether it’s a bog, you know, in the north of Scotland or it’s a human body to them and in a sense is immaterial. So, you know, this this historic Balkanized ocean of veterinary medicine, agricultural practice, human medicine, you know,

 I think is obsolete. And I think we’ve got to think, you know, globally about how do we combat the emergence of new pathogens, how do we combat antimicrobial resistance?

And, you know, how do we bring the tools that Alex and others are bringing to not only improve human health, but improve the way we just exist within, within our environment, with the way we raise our food or, or how we handle our animals. 

Alex: I think putting my, my public health hat on to,  you know, scaling it in a way that is equitable to all populations that certain parts of the world or certain parts of the U.S. that we don’t see, you know, have more advantages than others, whenever we think about this

genomic type of medicine, this genomic approach, there’s you know, there’s a big call out for that. Essentially, even within outbreaks, you know, there’s probably a lot of social determinants of health that make people more susceptible to having these types of infections and being parts of an outbreak. So how do we equitably go forward in that sense to make sure that, you know,

we’re not discriminating against different populations, different areas of the world in the U.S.

and that everyone have proper access?

Tony: Yeah, well, I hope that we can eventually put more of our faith into this breakthrough technology. It sounds to me like it’s certainly worth the investment. 

[Music starts playing]

Thank you again, Alex, for pulling the curtain back on epidemiology and genomic sequencing.

Alex: Thanks, Tony. It’s great to, It was a great talk. Always fun talking to Neal too, as well.

Neil: Yeah, yeah. We don’t see each other enough, Alex uh.

Tony: and Neal, thank you for reassuring us that a zombie apocalypse is still just something of science fiction. It was a pleasure to have you. 

Neil: Great. Thank you, Tony.

Tony: Please join us next time as we dive deeper into microscopic topics

on microbe matters. Thanks for listening. If you enjoyed this episode, make sure to subscribe to the show wherever you listen to podcasts and be sure to check us out on social media at ID Pitstop.