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[00:00:07] Angela: Hello and welcome back to Communicable, the podcast brought to you by CMI communications ESCMID's open Access Journal, covering infectious diseases and clinical microbiology. My name is Angela Huttner. I'm an infectious disease doctor at the Geneva University Hospital in Switzerland, and editor in chief of CMI Comms. I'm joined by my co-host, Josh Nosanchuk, fellow editor at CMI Comms, an infectious disease clinician and professor of ID and medical microbiology at Albert Einstein College of Medicine in New York, where until recently, he was also Dean of Education.

[00:00:40] Josh: Thank you, Angela. We're excited to welcome two guests today to discuss the World Health Organization's fungal Priority pathogen list. The first is an early friend of the podcast, Dr. Hatim Sati. Hatim is a medical doctor who hails from Sudan. He's the project lead of both the bacterial priority pathogen list and the fungal priority pathogens list, and a technical officer in the WHO's Antimicrobial Resistance Division.

[00:01:05] Josh: Hatim, welcome back to Communicable.

[00:01:07] Hatim: Thank you. Thank you for having me. Pleasure to be back, with you, Josh, and uh, good to see you again, Angela.

Thank you. Our second guess is Professor Dimitrios Kontoyiannis. Dimitrios is also an infectious disease clinician and the Robert Hickey chair in clinical care and Deputy Head of Research in the Division of Internal Medicine at the University of Texas, MD Anderson Cancer Center in Houston, Texas.

[00:01:32] Josh: His group studies various aspects of fungal biology, fungal diagnostics, and antifungal discovery and immunotherapy. He is currently the president of the Mycoses Study Group Education and Research Consortium. Welcome, Dimitrios.

[00:01:46] Dimitrios: Thank you very much, Angela and Josh. Hi Hatim I'm honored and happy to be here.

So as our listeners know, we always start with a get to know you question. What is the strangest or most memorable plane or train or boat ride you have ever had? Josh, you first.

Josh: So I'll go with a canoe trip. In college, a friend of mine and I would go up into the Adirondacks and, pick a different chain of lakes. in one case it was the Fulton chain. And so we had about four or five days where we had our backpacks and our canoe and just went out in the wild and took our time and it was incredible.

[00:02:26] Josh: It was very peaceful. How about you, Angela?

[00:02:29] Angela: Oh, I love that. I have a thing for night trains. When I was 14 years old. I was traveling from Trieste in northern Italy to Rome, which I had not yet seen with my big sister Julie. So Julie is 10 years older than me, and I worshiped her as little sisters often do. So I was really happy to share this train, ride into the unknown with her.

And it was twilight when we left Trieste. Did the train tracks go around the whole Gulf of the Adriatic. So watching the sea change colors and the stars come out as this train made this clattering noises along the tracks. It was just really magical. And I still remember the smell of the salt air, the chill as it got dark.

[00:03:09] Angela: We had the windows open and just the excitement of this unknown thing ahead of me, but the pure comfort of having my sister go with me. , I think that was my seminal night train experience, and that is why I love night trains.

[00:03:22] Josh: That's terrific.

[00:03:23] Angela: Hatim, you're up.

[00:03:24] Hatim: Well

[00:03:25] Hatim: mine was more, along the funny lines. I was in a mission in Saint Kitts and Nevis in 2018, I think, with another colleague of mine.

[00:03:34] Hatim: And we arrived, for the connection and the plane was very small we were told that they have to weigh each of us before we get on board to determine where people should be seated what.

[00:03:46] Hatim: Yes. we were asked to go on the scale. the flight attendants for extra measures. Looked you up and down and they're like, you sit there, you sit here. It was, it was kind of nerve wracking, but also funny at the same time.

[00:04:01] Angela: I hope everyone was sort of like, of a standard body habitus, shall we say. Definitely

[00:04:07] Hatim: become self-aware suddenly, right? When, when you're told Oh yeah. You know, in a way everyone's life is dependent on it in the moment. Yeah. Yeah.

[00:04:15] Angela: I'll say you don't forget that. Oh my gosh. Yeah. I wonder if in the states, like people would be sued for that.

[00:04:21] Josh: actually there's an airline, Cape Air, that flies, for example, from Boston to Cape Cod, and they do the same thing, New York to Hanover, New Hampshire, and they weigh you, they weigh your luggage and they distribute you. So it, it happens in the states too.

[00:04:35] Angela: Wow. Okay. Good to know. And finally, Dimitrios,

[00:04:39] Dimitrios: that was a good question. It make me go back and I have this memorable, anxiety provoking, nerve wracking boat.

[00:04:47] Dimitrios: ride. It was almost 40 years ago, I was in my mid twenties. I was in the military before I came to us. We have compulsatory military service in Greece, and I was, supposed to go as the military doctor along with 30 other soldiers to replace a garrison in middle of the nowhere, Aegean sea.

We went there, there were 30 soldiers with all their gear and cargo to replace supplies on a small boat, and we found high seas. And in the middle of the high seas, I realized. At least 10 people did not know how to swim. And they became very panicked, start grabbing my leg arms. He said, I don't want to drown.

[00:05:26] Dimitrios: And , the boat was at the risk of capsizing I did some hard prayers. I'm not a praying person, but I did some very, very, very hard prayers. Said, if we're gonna capsize, I'm gonna drown. I cannot swim with three other people holding me.

[00:05:40] Dimitrios: But thanks God, Poseidon, or whatever, the boat made it, and here we are.

[00:05:47] Angela: Oh wow. That is also clearly unforgettable. My goodness.

[00:05:51] Josh: Well, we'll take your prayers anytime, Dimitrios. So one of our very first communicable episodes was on the WHO's, then newly updated bacterial priority pathogen list.

[00:06:02] Josh: But we knew we also needed to talk about  WHO's fungal priority pathogen list. We had a recent episode with Dr. Arturo Casadevall that discussed our warming world and how that's making fungi ever more relevant and more unavoidable, especially as pathogens. So we're delighted to have Hatim who is the project lead on the list to give us the inside story and Dimitrios to give us his independent expert commentary.

[00:06:29] Josh: So, Hatim, can you give us the context? How did the WHO Fungal priority Pathogen list come to be and what are the key components of that list?

As, you, all know, fungal diseases are causing far more harm, than most people realize. Millions of, people impacted globally in terms of, not only mortality, but also morbidity.

[00:06:54] Hatim: on top of that, the rise of antifungal resistance was of a major concern, and it was in the radar of the WHO for a while now. but what's surprising, despite that burden, fungal diseases have largely been missing from the global health conversation. Overall the area is under recognized, underfunded, and almost invisible in terms of the, policy discussions, particularly around the AMR where we, are focused.

[00:07:23] Hatim: the WHO we have developed in 2017, the first bacteria priority pathogens list. That list has been, really instrumental in, drawing attention and, shaping and guiding, the conversation and also the, investments towards, unmet needs in terms of research and development of new medicines and tools.

[00:07:46] Hatim: in 2022, we set out to do something similar for fungal pathogens. I was tasked at the time by my, uh, colleague Peter Beyer he's now in GARDP who was unit head at the time to explore, the, possibility, and the value. I had the privilege to, start the conversation with the group of stakeholders.

[00:08:09] Hatim: And we engaged, a wide group representing all the, different sectors, different disciplines, clinicians, scientists. we tried to, assess gaps and understand how a prioritization exercise could support more, coordinated action. early on in the conversation it became very clear that, uh, this is different in terms of scope and scale.

[00:08:32] Hatim: than with the bacterial priority pathogens list, because quickly you realize this is not, only, uh, about resistance that, the mycology field at large is chronically under, resourced treatment options are limited, often associated with, toxic side effects. Diagnostics are largely also, variable in terms of, their sensitivity and availability and accessibility also in different settings.

[00:08:58] Hatim: And so we established, a formal WHO advisory group through an open call. we received a fantastic, number of applications. And after the initial assessment, we embarked on the list. 45 senior experts were involved, but also a broad, group of experts from across. the world helped us in prioritizing these pathogens.

[00:09:23] Hatim: First coming up with the preliminary list, it was a longer list, but was the collective's consensus to start with 19 pathogens, of public health importance. some of them are globally distributed, some are endemic in nature, and few are even rare molds. Of course, the guiding principles were burden of disease, the public health impact and the implications across the One Health, spectrum.

[00:09:48] Hatim: the selection also, reflected this broader environmental, ecological, drivers that impact or come to play when it comes to fungal, diseases or antifungal resistance. And so finally, [00:10:00] these were, ranked and grouped into 3 tiers of priorities as, we always do, critical, high and medium.

[00:10:07] Hatim: And, was published in 2022 with a report and number of, recommendations at the time, to draw the attention to, this, uh, increasingly, important area

that's really so important and. When you talk about the stakeholders, you mentioned a couple in passing, but to really drive it home, who are we trying to, get these components to?

[00:10:29] Hatim: Top of the list was decision makers, of course, also, we, were targeting, drug developers, diagnostic developers, people who are interested in investing in r and d pharmaceutical sector, and the general public as well. 'cause awareness is, key. The evidence through the consensus of these experts from different disciplines, clinicians, microbiologists, even basic, uh, biologists, to, uh, establish a prioritized framework, through which we could anchor the conversation with decision makers around the impact, the burden and the cost of, action, but also more importantly, the cost of inaction.

if I may interrupt there, Hatim, I do notice that on your list of your audience, let's say those drug developers are quite low on the list.

I think in contrast with the bacterial pathogens list, if I remember correctly, does this therefore reflect a willingness on the part of WHO to say, look, first things we need to do here are decrease transmission, clean up a little bit before moving to actual drug development?

[00:11:37] Hatim: I think you are, right in that, order was not random. Our first goal was to bring this to the attention of policy makers first and foremost. unlike, with the bacterial priority pathogens list, we had the political declaration, the Global Action Plan, which was largely focused on bacteria.

[00:11:56] Hatim: By the way, we are in the process of renewing the global action plan now and will revamp the language around, fungal, diseases or antifungal resistance. When we started the bacteria pathogens, we did have some, already, solid, commitments, if you would, from decision makers.

[00:12:13] Hatim: And so our main focus was to develop a list to inform, research and development of, antibiotics antibacterials, traditional non traditional. In this case, uh, our strategy was first and foremost to, draw the attention to this area, across the board. fungal diseases, some of which are, quite complex.

[00:12:34] Hatim: some are, resistant, some are not. Some are, simply difficult to treat. And so we wanted first to raise the awareness, around the importance and around the gaps in terms of funding, et cetera. one of our goals, of course, was also to encourage, investments in this area. Knowing that perhaps, from a pure market, point of view, this area has been, unattractive to investors, that infectious disease at large, but, particularly mycology.

[00:13:04] Hatim: And that there is not only a value in these investments, but also there is a true societal need, for such, innovation and such investments in new treatments, in diagnostics.

[00:13:16] Josh: So one of the things that I think is so important is that it is a global list, but at the same time. There are areas like you were mentioning, that may have issues that are significantly higher. So sporotrichosis, for example, in Brazil and Sporothrix is not one of the organisms on the list. So one of the conversations I've heard is, should there be more of these lists?

[00:13:42] Josh: Should you have the global one? But then should you split down and say, okay, but for this region, and again, for political purposes, in terms of public health and information and heightening the understanding of that impact, should you also have some regional, perhaps priority pathogens?

Absolutely. in fact, these are, some of the lessons learned from the first list. of course we stress in the report. That this list is meant as a global list and must be contextualized to the local context, the regional context, but we definitely understand that leaving some pathogens out of the list have implications also in terms of funding and in terms, of the, impact for the, populations affected by these pathogens.

[00:14:29] Hatim: we are now embarking on two projects or tracks to sort of remedy this gap. The first is, we are going through. Series of, exercises with some countries and with some regions to contextualize the list and develop regional, list. And one of these is the Latin American and the Caribbean region.

[00:14:50] Hatim: Currently, we are working with a group of experts from Latin America and the Caribbean to, develop their own, fungal priority pathogens list with the aim of, starting with a manageable and a feasible, list, of pathogens to be, addressed. the second is, our, report, was recommended by the steering group that the list, must be revisited every five years.

[00:15:16] Hatim: So, towards the end of, 2025, we have, planned already the start of the review of the fungal priority pathogens list. and in this time around, we will, address some of these lessons learned and keep, in mind some of these, unintended consequences that we saw in the first, list.

Angela: So Hatim, why was the one health approach so important for this list?

[00:15:39] Hatim: Thing about fungal pathogens is that, the, epidemiology of fungal disease is shaped by complex interactions between human animals and most importantly, the agriculture sector.

[00:15:51] Hatim: In fact, one of the major drivers of antifungal resistance, as you know, is, massive use of fungicides in the agricultural sector. scientists like Arturo and Dimitrios are telling us that, an emergence is driven by factors like climate change. Deforestation, urban expansion, antifungal use in plants.

[00:16:13] Hatim: And so these, forces are reshaping ecology in ways that, directly affect, human health At the same time, in health systems, in especially in limited resource settings, are not often equipped to deal with such a threat that, requires high level of funding and high level of coordination across sectors.

[00:16:34] Hatim: And so in these cases, you know, one health approach, here is not just, a concept. it's a needed practical framework really to address, these types of threats. also it's a must to not only inform the priority setting, but also inform the interventions and the action.

[00:16:52] Hatim: this kind of, systems level of thinking is really, really needed in medical mycology.

[00:16:58] Dimitrios: In the next reiteration would that be interesting in the future to link or tag the burden of aspergillosis with the burden of tuberculosis and target post-tuberculosis cavity disease That's One. Example. The second in the context of the bacteria resistance and very complex interactions between bacteria and fungi.

[00:17:18] Dimitrios: For example, you go to cystic fibrosis when you see a lot of bacterial infections, common disease, a lot of antibacterial multidrug resistant bacteria, and then aspergillus or Scedosporium .

[00:17:29] Dimitrios: can we go to more geographic or sequential bacterial. Fungal or more specific priority list to make it more nuanced the second interation list?

[00:17:39] Hatim: These are all fantastic ideas and, they reflect the complexity of, fungal diseases and antifungal resistance.

[00:17:46] Hatim: I think, one suggestion was also, looking at this from, global versus endemic lens. Like you suggested also, was, you know, looking at this in terms of association and I think during COVID-19, this idea of a super imposed endemic on top of an endemic.

With COVID, 19 fungal associated infections. the context of, cancer treatment, such as the work you lead, there is the question of, the underlying, population at risk in terms of, the social determinants of health. And this is something I've been thinking about and you and I had collaborated, on, one paper, to try to, pose these questions. What does it mean, to have more conflicts in the world, the impact of climate change, the mass migration, and the, impact in terms of certain occupations.

[00:18:37] Hatim: And so there are a number of ways you could dice or slice this. Of course, our hope is through the next, iteration is to have, again, a, strong multidisciplinary group of scientists who could help us in, perhaps framing this in a way that, makes sense.

[00:18:52] Josh: Yeah, I could see the transplant society having their own priority pathogen list.

[00:18:56] Josh: It would be very interesting. the fungal priority pathogen list is under three years old. It's still really young, but Hatim, could you share any examples of a direct impact of this? Well, I, I think one of the most important, impact was, shifting the conversation really before the fungal priority pathogens list. In my opinion, communicating about fungal disease often, felt like an upstream battle.

[00:19:22] Hatim: there was limited awareness. Largely the, issue was reduced to number of neglected tropical diseases.

[00:19:30] Hatim: I think, uh, the narrative was missing from the global health, agenda. But with the fungal priority pathogens list, we finally, had, uh, a structured, evidence-based tool to, anchor this conversation around. And also it gave us a way to talk, about fungal diseases. Not as an isolated clinical problem, but rather as a global health, issue.

[00:19:53] Hatim: we were also, able, and now we're in the process of developing a blueprint and we call it the fungal priority [00:20:00] Pathogens to Implementation Blueprint, to, use the list also to, identify gaps and interventions to address some of these pathogens in the list, from a equity access, lens, but also from research and development and policy point of view.

[00:20:17] Hatim: And really, this shift was not, unnoticed. I don't know if you're, familiar with the piece that was written by Denning and Fisher in Nature. They described this as a game changer, and this has been the feedback we're receiving from a lot of, scientists, a lot of clinicians and researchers.

[00:20:35] Hatim: That the list, truly moved the needle in terms of, funding. Nowhere near what, we are aspiring, of course, to, arrive to. but at least now this is part of the conversation. for example, we see, in the uk, number of government and non-government funders, have, issued calls for proposals for, researchers, with research focusing range of R&D, basic research, et cetera. similarly now in Denmark, there's a big push, to fund research related to, fungal infections and narcotic diseases.

[00:21:11] Hatim: In terms of awareness, our communications department actually picked an uptick of uptake, using certain terms and social media and the media. And it's estimated that since, 2022, the list has been covered in over 150 news articles across eight languages.

[00:21:31] Hatim: and this is really a true, impact in terms of. Bringing the conversation also to the public. 'cause, you know, if you bring the conversation to the public, public awareness really often leads to, pressure on decision makers and policy makers in action. And that's what we're hoping really to have.

[00:21:48] Dimitrios: An opportunity also to reach out to philanthropy efforts, and advocacy through non-government entities. For example, they have been a very telling, CDC survey in infection, these practitioners outside academic centers and asked the question, Hey, have you ever heard post influenza aspergillosis?

[00:22:08] Dimitrios: And 35% of them never heard of it as an entity. So I think also opportunities here is to educate the public. And a good catalyst may have been the COVID And mucormycosis explosion in India, when for the first time in my life, a fungal Disease made it to New York Times and to the main press.

[00:22:28] Dimitrios: and also emphasize this is a pathogen also in the WHO list. just, you know, Educate the public and the people who can give money towards fungal disease.

Yeah, I think it's fantastic when WHO, lifts its microphone. I mean, really the world is listening still, even with what's happening today. it's hugely important.

Can we just go back for our listeners, Hatim, and can you just tell us what are the let's just say the top fungi.

[00:22:57] Angela: The way it's ordered, it's just like the bacterial pathogens list, and how were they selected?

Well, as I mentioned, the preliminary list of, fungi to be ranked were selected through a consensus, process. through the, advisory group that was established for this purpose. each of these 19 pathogens were then assessed against a set of 10 criteria covering the burden of disease, both fatal and nonfatal burden, antimicrobial resistance impact, transmissibility, the, trends of, infections, the distribution, treatability, and, the status of the pipeline this followed of course, a multiple criteria decision analysis approach, that allowed us to, fill in gaps in evidence with, the expert's consensus. And then to determine the weights of each of these, criteria, we, conducted a global discreet choice experiment, survey, with the participation of over 375 experts from across the world.

[00:24:00] Hatim: The survey actually was translated to three languages to, ensure, full participation. And then accordingly, the, list was scored, and then a group of, 55 senior experts who constitutes the core group. Determine the public health weight of each of these pathogens versus the R & D needs through a best-worst scaling approach . Accordingly. . We have 19 pathogens in the critical list: cryptococcus neoformans, candida auris, Aspergillus fumigatus and Candida albicans The high group contains a mix of, pathogens that are endemically and globally distributed, including candida glabrata histo plasma, species, and eumycetoma and Mucorales, Fusarium, Candida tropicalis and Candida parapsilosis.

[00:24:52] Hatim: in the last, category, we have pathogens, some of which are very rare, some of which are endemic, like, Coccidioides mycosis, Paracoccidiodes, as well as, Talaromyces. Some of these pathogens are very relevant to, certain populations like people, living with HIV in certain areas, Southeast Asia or in Latin America and the Caribbean and then the, list of course came with this caveat that it is a global list, that the list is diverse, the pathogens in terms of their distribution impact, and that it is extremely important to, stress the need for contextualization, but also to stress that this list is not exhaust.

Now, if you examine the, pathogens in some of these, categories, perhaps for some regions, some of these, rankings will shift. in terms of the priorities, but we thought that this is, an okay balance. The critical list are, globally distributed, and we try to strike that balance, I think, to the extent we could. For example, candida auris, for the emergence of these pathogens and the impact of these pathogens globally and the impact of climate change and, how these pathogens are also, emerging, not in isolation of environmental drivers.

[00:26:08] Hatim: first isolated in 2009 in, Japan. Fast forward, it is, reported in over 55 countries. With some devastating, outbreaks, in many countries.

Dimitrios, Do you agree , with the pathogens that made it to the critical versus high priority?

[00:26:27] Dimitrios: Yeah. I tend to agree with all these caveats , I think the other thing to emphasize, this list also try to capture burden of disease.

[00:26:36] Dimitrios: And, fungal infections are not bacterial infections. There are sub acute or chronic infections. So if you see there with exception of some kind of acute illnesses, like candida auris that tends to behave like bacterial infections. A lot of the fungi that made to the list are chronic disease like coccidioidomycosis, mucormycosis, aspergillosis.

[00:26:55] Dimitrios: So if you look for the public. perspective, burden of disease patients, thousand days and resources. That's another way I think this list is relevant. Not only the morbidity and mortality, but also the resources needing to study them, diagnosing them, and treating them. So if I wear my public health hat that I don't have, that I think is a very appropriate first Step.

Yeah, I would also highlight that eumycetoma. That's something that in developed countries, high resource countries, you don't see a lot of that, but it doesn't take much if you travel to some other places. and even within a, space like Brazil, they have very different distributions of mycetoma.

[00:27:39] Josh: The causative agents are different in different spaces. The diagnostics are terrible and the treatments are terrible. So having this complex distribution is really rich, I think.

[00:27:53] Hatim: Yeah. and Josh, just to add, you know, the example of mycetoma also, the outcome is devastating. I come from Sudan and, you know, Dr Ahmed Fahal was one of the pioneers in this area. The Mycetoma Center of Sudan, Sudan is not a very rich country, as you know, it's a low income country, and yet that center used to receive patients from, all over the horn of Africa. and unfortunately since the conflict started in Sudan.

[00:28:19] Hatim: that center has sustained major damage and now they're operating, from Cairo, . And so, yes, some of these are devastating, but I wanted to also point out, that one of the limitations of the list is that we, focused on, pathogens, that can cause invasive fungal diseases.

[00:28:37] Hatim: That doesn't mean that some of the pathogens that were not included, here are not important. Dermatophytoses, for example, dermatophytes especially multi-drug resistant  Dermatophytoses, is something in, our radar and something that we are actually, working to, in the short term, even before the update on the list to try and address formally, particularly, in areas, where, these.

[00:29:02] Hatim: infections tend to be multi drug resistant India, Pakistan, you know, population dense areas. And what's really, scary about this, situation is that this seems to be the tip of the iceberg. And as the understanding evolve, the burden seems to be even more and, far reaching.

[00:29:20] Josh: But even regular dermatophyte disease, Onychomycosis, it's multiple billions of dollars are spent globally addressing this.

[00:29:29] Josh: And the treatments are awful. So even, even things that are not drug resistant, but are incredibly common, and they wouldn't make this type of list because of the morbidity, although there is even morbidity with onychomycosis in terms of mental health and other, potential, super infections with bacteria and things.

[00:29:48] Josh: It's, amazing what fungi do. Dimitrios. From your vantage point, how have you seen this priority pathogens list used in communications about fungal diseases, [00:30:00] talks, papers, grants?

[00:30:02] Dimitrios: First of all, if you see discussion about investigation drugs, a lot of them are presented in the context of they address some. Priority pathogens in the WHO list.

[00:30:15] Dimitrios: Like, say Rezafungin for Candida auris. Fosmanogepix for mucor. So a lot of these discuss about drugs that are being investigated are in the context of do the work for the WHO Fungal list . Second. having published a lot in this area, all the papers mine and everything had the same boring start.

[00:30:38] Dimitrios: Fungal infections are important cause of morbidity, mortality in cancer patients. So now there is another modified you say, blah, blah, blah is very important for the WHO pathogen list.

[00:30:51] Dimitrios: And all the presentations typically , slide two or three in a presentation. They throw the list before they talk about their fungus.

[00:30:58] Dimitrios: So it's a standard slide over everybody has and throw it in the presentation. Either gonna talk about aspergillus mu And having had the pleasure of just having gotten a PO one for Mucormycosis, we started our thing. You say it's a bad disease and WHO has it in the important pathogen list.

[00:31:18] Dimitrios: So it really has permeated to the academic endeavors in a major way and help us.

[00:31:23] Josh: I actually have a talk on the impact of the fungal priority pathogen list, which I've given, in many places. I'm actually giving it at the, Paraguayan Infectious Disease, society meeting later on this month.

[00:31:35] Josh: And it, it really is a great foil to talk about these things that are so critical in terms of policy, in terms of communicating science, and it's been just fabulous to have in hand. So, Dimitrios, what are you most concerned about with fungal diseases?

[00:31:52] Dimitrios: yeah. I, I think we can talk hours about concerns and fungal disease in the future. I will try to make three broad points. One is, global warming and climate change it's gonna affect in a predictable and unpredictable way.

[00:32:09] Dimitrios: the geoclimatic aspect of fungal disease. Something that actually we have published before the global warming about 20 years ago when we looked into aspergillis cases in Seattle versus Houston, and we realized that Houston areas were flat and in Seattle was connected to the precipitation , by the rains.

[00:32:30] Dimitrios: so I think we're gonna learn a lot about climate change and I think what people start realizing is, much more complicated than we think. It's not only the thermal adaptation, but also the, co-evolutionary framework fungi have a lot of plasticity in their genomes to adapt.

[00:32:47] Dimitrios: For example, what do we know about precipitation? How it affects dark light cycles, soil changes because microbiome that have been some nice papers and science, how the microbiome of symbiotic fungi changes with, thermal adaptations. What do we know about predators and their behavior in the soil like amebas?

[00:33:08] Dimitrios: All of these things we don't know. So I think it's gonna be a very fascinating scene in the following decades to know how that's gonna change. Second is because I've seen that here in a cancer hospital, we're seeing now beyond the classic risk factors, prolonged neutropenia, corticosteroids. Lower risk patients like lymphoma patients, chronic lymphocytic leukemia, who get a design drug like a Bruton kinase inhibitor, and they come with aspergillus in the brain.

[00:33:37] Dimitrios: Two 3% of them, not a lot of them. Who are they? What is their immunity? I think it kind of challenges us to understand a little bit better fungal immunity and what governs it. And the third is, I think, is gonna be a big push in the context of WHO and policy about lay person's education, policy education.

[00:33:58] Dimitrios: How do we position fungal disease in the future? And this is something we're trying to do, not only us ASM is trying to do that, mycoses study group, try to educate a little bit of patient, bringing patient stories that are very powerful about what it is to have a chronic fungal disease. So I think a lot of geoclimatic changes, surprises about fungal immunity and new risk factors, new niches.

[00:34:23] Dimitrios: And also a lot of push for education and policy. So we shared earlier that you're the president of the MSG right now, and I don't think most people listening probably know what that is. Can you share a little bit about what the big points of that society is?

[00:34:38] Dimitrios: Yeah. This is, an historical, organization started in the seventies, funded by NIH, so, focusing on clinical mycology and clinical trials.

[00:34:48] Dimitrios: Actually, most of the vota clinical trials in psychology have been done under the auspices of my study group. it was, , a society of US based scholars on clinical mycology, trialists, new drugs , very active crypto cocus in HIV era, et cetera.

Now the organization has changed a little bit, has become more global, more also focusing on education, patient advocacy. we have working groups about, intellectually attacking other problems in modern mycology. For example, we have a working group for host transcriptomics to prognostication how you do smart pragmatic studies and other working group women in mycology and other working group.

[00:35:31] Dimitrios: Working in new diagnostics, how you mine data from Epic or ai, you know, trying to put some kind of intellectual context beyond the classic trialist. and dangers that are still there. So it's a global organization of scholars, most of them, academics, but obviously , a lot of CDC interactions with, colleagues from, policy making institutions, patient advocacy.

[00:35:55] Dimitrios: And it's a very active in different ways. this gives me the pleasure to say we're gonna have our biennial meeting next year in Colorado, September 19. And it's gonna be a very rich program, attacking different areas of modern mycology.

It's really terrific in the, things that they have done. As you said, the Cryptococcal work was transformative in care, and they continue to do a lot of. Packed full studies that really change practice, which is so important. Dimitrios, you've not only worked on best practice for use of antifungal drugs, but also on novel therapeutics.

[00:36:30] Josh: To me, one of the fascinating areas that you're working on is harnessing the host to combat fungal invaders. Can you share what you are doing and why this is a rational approach to dealing with mycosis?

[00:36:41] Dimitrios: You know, I, think I'm not to be credited for these areas entirely. I just witnessed the two revolutions working in a cancer hospital of modern oncology, which is basically cellular therapy and CAR T therapy and, checkpoint inhibitors for oncology.

[00:37:00] Dimitrios: Actually, one of the first paper is credited to Josh, who has been an inspiration with his nice paper. In Histoplasmosis, published in the PNAS. So what we thought was, wouldn't it be nice to get things that are already approved by FDA and we were focusing on non cellular therapeutics, typically, checkpoint inhibitors.

[00:37:22] Dimitrios: That was the thing to study in a cancer hospital with or without traditional, immunotherapies like GMC interferon and see if those somehow augment immunity in the setting of immunosuppression. Initially we came with this hypothesis when checkpoint inhibitor were very hot in leukemia.

[00:37:43] Dimitrios: Now they're not very hot of an intervention. And we put this double hit hypothesis, we give checkpoint inhibitors to leukemia. Leukemia gets better and if they get aspergillosis, also aspergillosis gets better because the checkpoint inhibitors. So we have done animal models when we treated immunosuppressed animals with a fraction of the dose used in oncology in attenuated schedule without anti-fungals.

[00:38:07] Dimitrios: And we found we have proven protection and survival benefit by just given G-M-C-S-F in the past and now checkpoint inhibitors. When we combine checkpoint inhibitors with drugs that alter immune system for the better immunomodulatory, the drugs like echinocandins, we saw synergy. So what are the things we are still very hot on we have a mouse model of leukemia.

[00:38:31] Dimitrios: When we raise the bar and try to say how much this interval work in the leukemia microenvironment, we're having this very active. product and worth pursuing. We're much more hot with the non cellular therapeutics. We can work with CAR T cells with dectin-1 recognition to attack aspergillus.

We just realized it's a little bit more cumbersome. It's not real life. It takes 20 days to develop, basically product. It is a lot of donor variability. this technology exploded in oncology. We studied second generation CAR T-cells and other studying feed generation CAR T cells, and we were not impressed by the outcomes doing better than non cellular therapeutics.

[00:39:15] Dimitrios: So we have done some work also with CAR T. Specific for fungi, but this work is a little bit on the back burner now, and we're more focusing on non cellular, therapeutics. We're gonna use them for mucor. It's a part of this PO one we're gonna have with or without G-M-C-S-F. The other thing we are doing, and we just published, just a couple of months ago, comes, I'm a clinician by nature, so a lot of ideas come being , in the floor.

[00:39:42] Dimitrios: So the new phase of opportunistic mold infections in leukemia is not neutropenia anymore. The typical patient is somebody with refractory leukemia for two, three years, who walks around who has 30,000 WBCs with 80% blasts, and [00:40:00] numerically his neutrophils are adequate over a thousand. So we started the impact of blastemia to affect immune cell responses that we found.

[00:40:09] Dimitrios: If you're blastemic, you're as bad as being neutropenic. And if you're blastemic and neutropenic is the horrible group to be. So we've done some trans assays when we exposed blast and effector immune cells. And these interactions bad, the effect immune cells cannot kill the fungus. So, a part, the twist of our cellular therapeutic program is to work in the environment of blast to see how much cellular therapeutics alter immune responses.

[00:40:37] Dimitrios: So I think we need to sense what's going on in your microenvironment of oncology and just make observations and go and, and study those are the exciting things we're trying to do in this space. since we keep changing our patients and we also keep having things emerging from the environment, it sounds like some of us are still gonna have a job in a few years.

[00:41:00] Dimitrios: yes, definitely. It's gonna be more challenging. It's gonna be more niche, more intellectually nuanced, how to do that. the easy things have been described, prolonged neutropenia, steroids, but how you study a patient who comes with aspergillus in the brain, if you got, ibrutinib, you know, for lymphoma, and one of the things we are putting as an idea, and I have a junior faculty join us soon, is to study the idea of tandem immunosuppression.

[00:41:28] Dimitrios: Like people who have a underlying disease or to antibodies or whatever, and then they get like chemo and then they, have a flu blood infection, so they're gonna be a lot of ideas. Or the other thing is, what is the impact of comorbidities? Risk something we don't think about. What does it mean to have diabetes, liver disease and get chemo?

[00:41:49] Dimitrios: You know, so there are gonna be a lot of sophisticated little questions, but I think these easy questions have been already out the door. Now it's the time to see how to personalize risk of acquisition and outcome.

[00:42:02] Angela: Wow. Quite a ride. So Dimitrios and Hatim, question for both of you.

[00:42:09] Angela: Where do you think Medical mycology will be in 10 years from now?

to me, the FPPL was a start, but we are nowhere, where we should be. I think, those kind of, Ideas, this type of science that, Dimitrios was, discussing just, now, needs to be funded, needs to be supported.

[00:42:32] Hatim: I really, am worried, about, , the implications of the global cuts on, medical funding, public health funding across the board, but especially in these areas, I think the assumptions, oftentimes, mostly due to a general lack of understanding, how, these scientific endeavors work that this work is not important.

why do we need to fund this? did answer this question ironically, when we released the fungal priority pathogens list, a journalist asked me, why is this important now? And my response, I said, we cannot wait until we have a catastrophe unfolding before our eyes, like COVID-19, to then put all the funding, all hands on deck.

[00:43:19] Hatim: rather, we need to invest early on not only in the basic research to, understand, the implications and the dynamics and the impact of climate change and the impact of all these drivers, but also in research, that is truly innovative and not just the, traditional, research. That could help come up with truly innovative and impactful, solutions for some of these complex problems.

I hope that we continue to move ahead, but I have to say at this point in time, I am a little bit, concerned, with the global situation.

[00:43:55] Dimitrios: for me, is a timely question because I'm gonna be giving a, talking a week, and I must prognosticate about the future.

[00:44:02] Dimitrios: And, I kind of try to organize a little bit my thinking about, I've been doing clinical mycology 27 years.

[00:44:08] Dimitrios: I think, as we said before, we're gonna see new fungi emerging and expansion of geographical range, of common fungis happening, obviously. And, with the help of WHO and other policy makers, fungal epi will become global and not what US does, or Brazil does or whatever, like a global effort to mitigate resistance and, have better access to care, better diagnostic, I hear the concerns about, the climate, the political climate, but, I remain optimist. That's gonna change long term to the better for clinical because I work in a cancer hospital where there is a lot of excess. Things. And sometimes we do too many things for people who are on the end of the road, for the underlying disease.

[00:44:58] Dimitrios: I think there's gonna be more emphasis about smart care, who gets what when and how. We're gonna look a little bit more into attributable versus contributable versus global mortality. In other words, a patient who dies with end cell leukemia and aspergillus what can be done for him compared to an early, onset of disease before you go to transplant.

[00:45:20] Dimitrios: How often do we do cts? How do we do therapeutics? Combination, new drugs, immunotherapeutics. I think we're gonna see a lot of emphasis to preemptive therapy like we do for CMV. Like a new, blood market and then early before we wait the culture to grow when it's gonna be too late. So those are gonna be interesting things.

[00:45:42] Dimitrios: And also everything becomes outpatient now. We're doing even CAR T therapy, outpatient, a lot of emphasis to non-hospital care, home care, outpatient care. There gonna be a lot of mental shift, how we do things in mycology outside the hospital. then for research, I think a lot of things we already talk about, I think immunogenetic, risk for risk of fungal disease and prognosis.

[00:46:07] Dimitrios: How you incorporate these risk to time monitor clinical scorecards of risk, like being old, having comorbidities, having immunosuppression. talk a little bit more, I think something we haven't talked about too much, is beyond MI Cs beyond resistance. If you look. In the exciting data, we just put a editorial with David Perling about hetero resistance and tolerance.

Something we don't look in the lab. What do we know about this in the context of how drugs work, especially for echinochandins problematic fungi Candida auris, I think we're gonna look, because with NIH having all this mandate about mouse models scrutinize, are they really needed? Maybe it's gonna be an explosion to organoids and also non mouse model. Something we haven't talked about. I think there's gonna be also an explosion of nanotechnology for smart delivery of drugs through the skin inhalation vaccines, and also a lot of effort to public policy, patient reported outcomes, what is important at the end of the day. So it's gonna be a lot of excitement.

[00:47:15] Dimitrios: Those questions are more complicated than they sound, and some of them are interrelated questions, but I think it's gonna be a very interesting scene to see. I think overall in 20 years, it's gonna be very close to personalized medicine in fungi and, better outcomes.

[00:47:34] Josh: Wow. Those are some very deep thoughts and it's very exciting to hear. I do wanna acknowledge that we have not talked about certain areas of fungi, which means that we have future podcasts that we can do in terms of antifungal, stewardship and diagnostics. I wanna now sincerely thank Hatim and Dimitrios, because this has been absolutely terrific.

[00:47:54] Josh: It's been a bit unsettling to hear some of the challenges because they are vast and they are many. But we have had a, I think, an illuminating discussion and showed that there are promising roads ahead. And I want to give you both the opportunity to share any last messages for our listeners Hatim.

[00:48:14] Hatim: Sure. A lot of these, infections and the burden remains, unseen.

[00:48:19] Hatim: I really think that this is the tip of the iceberg. I hope that in the coming, years, we're able to have a clear idea about the extent of the burden of some of these, uh, infections across the board in, limited, income settings too. I hope also that the fungal priority pathogens list, is just a start and that we will continue build on it We'll be able eventually, to achieve our end goal and bring it about the paradigm shift, to, the discussion or how we view, fungal diseases and, fungal infections at large. , Dimitrios spoke about, personalized care. And I wanna talk about, , also focusing on some of the, populations that, are now continuing to face, displacement, migration, water scarcity, and the impact of climate change and how that, will, play into the future.

[00:49:15] Hatim: but, for now I think, all we could hope for is to, continue this work. maybe in the future we, will be able truly to look back and say that we did all we could in this moment to address these challenges. So, yeah.

From my standpoint, I remain optimist. I think in the future is gonna be an acceleration of success we had.

[00:49:36] Dimitrios: as I'm getting older a little bit, I know I look like 25, but I'm 62, I kind of reflect what success has been in fungal disease. In this 27 years I've been a faculty here. So when I first came to MD Anderson as a postdoc in 1990, fluconazole has been an investigation drug candida albicans was the dominant bug in leukemia, something we never see [00:50:00] anymore. If you get aspergillosis, you go, forbid the ate in four weeks, six weeks, you had renal failure in two months you were dead. No one was given any chemo back then. Transplant. Forget about it.

[00:50:13] Dimitrios: And listen what we are now having aspergillosis is not a problem. You got transplant no problem. people live with aspergillosis for years. Actually we had some data we haven't published yet, but we'll present it next month when global. Mortality if you get a mold infection has remained stable. Maybe reflecting some improvement in supportive care in leukemia care or transplant care.

[00:50:39] Dimitrios: But attributal mortality, with all the difficulties how to assess attribute mortality, has dropped. In other words, success here is these people live for a long time, months or years, and they keep getting the hope of getting another miracle around the corner to control their disease, go to remission and be cured.

[00:50:59] Dimitrios: So how success is, not how success is defined, for bacterial infection or tuberculosis or whatever. Success here has been living longer with your cancer and fungal disease and keep fighting until you get to a solution to underlying disease. And I think mycology we have 12 drugs, we have better diagnostics.

[00:51:20] Dimitrios: Better understanding of pathophysiology. Not perfect, better understanding. So we have done a lot, a lot, a lot of improvements over the last 30 years, but also we have defined , what are the questions to be answered? And I think in 10, 20 years, we're gonna be even better with more personalized approach, especially if the global climate or funding and policy is conducive to this.

Thank you so much, Dimitrios. Thank you so much, Hatim. Hatim Sati at WHO here in Geneva, Dimitrios Kontoyiannis at MD Anderson in Houston, Texas. many years ago. Saved by Poseidon.

[00:52:00] Angela: And thank you for listening to communicable the CMI Comms podcast. This episode was hosted by Josh Nosanchuk in New York, USA, and myself, Angela Huttner in Geneva, Switzerland. Editors at CMI Comms, ESCMID's Open Access Journal. It was edited and produced by Dr. Katie Hostettler-Oi and peer reviewed by Dr. Andrisa Xhaxha from Elbasan Albania. Theme music was composed and conducted by Joseph McDade. This episode will be citable with a written summary referenced by A DOI in the next eight weeks, and any literature we've discussed today can be found in the show notes. You can subscribe to Communicable wherever you get your podcasts, or you can find it on ESCMID's website for the CMI Comms Journal.

[00:52:42] Angela: Thanks for listening and helping CMI Comms and ESCMID move the conversation in ID and clinical microbiology further along.