Thank you all for attending the session this morning. This is the Endemic Fungal Infection State of the Art of Diagnosis and Treatment. We have a great session lined up for us and we're going to get started with Dr. Ryan Maves from Wake Forest University and he's going to talk to us about the Shifting Maps of Endemic Mycoses. Please be sure to have your phones handy for this session as there will be some talks that are utilizing the audience response system. Although not this one. We will be saving questions for the end for the sake of time. All right. Hey, thanks for coming out at 7 a.m. session. My name is Ryan Maves. I'm an infectious disease and critical care physician at Wake Forest. These are my disclosures. None of them are relevant to fungal disease. So this is just to sort of set the stage for what we're going to be talking about today. And the bottom line, the take home message is that the maps, if you will, of endemic fungi certainly in North America have shifted. They are changing and they're going to continue to change likely. And we're going to need to improve our ability both to recognize and to definitively diagnose these incredibly important pathogens moving forward. So when you look at endemic fungi, we're really talking about four major pathogens in North America proper. So coccidioides, histoplasma, blastomyces, and cryptococcus. Cryptococcus often doesn't get sort of mentally put onto our list of endemic fungi, but it very much is. It very much is and has similar behavior. It's just we've thought of it more as an opportunistic pathogen over the years. More recently, it's been clear that there is an incidence of cryptococcus in immunocompetent hosts, however. Now globally, there are other important endemic fungi, pericoccidioides in South America, tailoromyces previously called penicilliosis in Southeast Asia, emergomyces, which is on some level a newly identified or newly recognized genus, which is on multiple continents. So these are common, but these are underrecognized entities, and delays in diagnosis tend to be common. If you look at the annual burden of endemic mycoses in just the United States, so not Canada, not in Latin America, not in Europe, not in Asia, not in Australia, the total annual burden is about 13,000 hospitalizations per year. Six to 700 deaths I appreciate in the post-COVID time. Six to 700 deaths feels like a statistical blip, but the burden to patients both in direct medical expenses, lost productivity, and in early death is up to about $1.3 billion per year. So this is, the morbidity of these diseases considerably exceeds their mortality, but their mortality is not zero. So in terms of historic experience, so I was in the Navy for many years practicing in Southern California, and COX-E kind of paid my mortgage. A lot of the early national attention actually rose to valley fever as an entity. Part of it was due to the construction of bases and airfields in COX-E endemic regions, particularly in the San Joaquin Valley during World War II, where you had a lot of people who were not from the COX-E lands, moving into the COX-E lands, getting exposed, and developing valley fever. Later attention with endemic fungi, particularly histoplasma and cryptococcus, increased with the emergence of the HIV-AIDS epidemic in the early 1980s. Now what we're seeing is emergence of them in previously non-endemic regions. So what do we have now? Increasing rates of diagnoses, and I should probably hedge my statement earlier to say it's not necessarily all increasing rates of infection, it's increasing diagnoses. There is a true increase in range, but there is also on some level the increase in diagnoses is, should we say acute recognition of a chronic problem. We are seeing some changes in distribution due to travel, migration, and land usage, and I'll talk about that in a little more detail in a second. And then we would be remiss to ignore climate change as a consideration here. As the environment changes, the range in which these fungi exist in nature also changes and expands. And we'll talk a little bit about the role of immunosuppression, and I know my colleagues will talk about that in greater detail as well. I would say the role of increasing immunosuppressive medications and the increase in the size of the immunocompromised population, it's a little bit variable in how much it's actually relating to the increase in disease. So when we talk about land use, you know, this is a, in certain cases, this is related to alterations in the human-animal interface, right? So as we saw again during COVID, you know, changes in the interactions between humans and animals will affect transmission of previously zoonotic diseases. So histoplasma and cryptococcus would be two good examples. With environmental changes, that changes where birds go. And where birds go different places and birds transmit histo and crypto, that's how it changes the incidence in humans. Also, human incursion into new areas, right? And so we'll see that when we talk about cocci construction, new house construction, affects the incidence of coccidioides. Now with travel, this is even more notable at the end of the pandemic, obviously. People acquire an infection in Arizona and then fly somewhere and get diagnosed on the East Coast, for example. And then just a side note about climate changes, this is not obviously just a phenomenon with endemic mycosis. We had a case of locally acquired malaria in Arkansas recently, right? Now this happens periodically, right? There's, you know, malaria gets on an airplane, flies an airplane, patient with malaria gets off a plane, a competent vector bites that person's malaria, transmits it. It generally doesn't propagate, right? But still, locally acquired malaria in Arkansas. Dengue cases in Texas, right? Some of that spread is just transmission across the border where there is more endemic dengue to the south. So this concept is not unique. All right, so when I lived in California, this was how I viewed the country and how I viewed risk factors for cocci. There's California and there's everywhere else. It's a Tupac reference. I'm happy to review it for anyone. Okay, so this is the map we probably all learned in medical school. So, you know, cocci, histoblasto, and cryptococcus gadii. And, you know, this isn't bad. These are the areas where the risk of acquisition is the highest. But if we look at, there's some more recent data looking at where dimorphic fungi plus cryptococcus, which is not a dimorph, are actually diagnosed, 94% of states have seen diagnoses of histoplasma, right? 70% have seen blasto, 69% have seen cocci. And that 37,000, for example, in cocci, and my colleagues will talk about this in greater detail, that is a gross underestimate. Right? There's probably, you know, 200,000 cases of cocci a year. These are just the ones that get recognized. And when you look at where cocci is diagnosed on a county by county, so this is from mycoses.org. I assume you all have that bookmarked. These are the cases of where cocci. But, you know, you notice way up there, up in the upper Midwest where I've circled, there's this, so darker colors, purples, more cases diagnosed per 100,000 population. That is a phenomenon from snowbirds. That is people who live in, like my grandparents, they live in Minnesota and then spend the winters in Arizona. Right? So there is this, that travel phenomenon leading to increased diagnoses of cocci in Minnesota where it is not endemic, is an interesting phenomenon. And since we're in Hawaii, this is the incidence of cocci in Hawaii. Right? It's not zero. These are, of course, largely people who are traveling to the southwest, southwest of the mainland. But it's not zero. Now, we'd be, this is a global meeting and it would be, we'd be remiss to focus entirely on the North American experience. This is where histo is endemic in the world. And that's probably an important thing. Histo is a global disease. Right? Histo is everywhere. It's just in North America, it has a regionality. In the rest of the world, it really doesn't. Okay. And same thing for cocci. We think of cocci as a disease in the southwest U.S. But cocci was actually first identified in Argentina. Right? And the coccidioides in Posadasia is named after an Argentine physician, Alejandro Posadas, who first identified it. Okay. So there have been, we talked about shifts in endemic regions. So for example, there's cocci in Washington State. I grew up in Washington State, kind of in the top middle of the state in Okanagan County. It's very desert-y out there. Right? It's very desert-y. And it doesn't, if you look in eastern Washington and you look in kind of the desert regions of California, they're not that different. Increased temperature may reduce fungal competitors in the soil, which gives more opportunities for cocci to reproduce. You do need occasional rainfall for cocci to grow. Rainfall is a thing we have in Washington. And then increased construction. Right? And this area of the state, like around Yakima down there, which is the bottom middle, has a lot of construction going on. Same thing in Utah. Utah has all, southern Utah has always had endemic cocci. Cases are starting to creep up. The graph on the right there, the top is cocci incidents. The bottom is construction permits. And you see in the upper northeast corner a lot of construction and a lot of cocci. So these things are interplayed. So some of this may, again, be new identification. The organism has been identified in the soil in these new regions, and that is a change. What about other things? So blastomyces. Blastomyces historically was not identified in Canada. There are cases of blasto identified in Canada now. This is sort of a well-established thing at this point. But cryptococcus gadii was largely a disease of Australia previously. Then made its way to the Pacific Northwest, specifically Vancouver Island in Canada. And then made its way south all the way down to California. So that's actually sort of a reverse of the normal sort of climate change moving away from the equator. It's actually moving towards the equator. That may be in part related to bird migratory patterns, though. And also where people plant eucalyptus trees. So there are new pathogens, right? And the great part about being an ID doctor, I say to my cardiologist buddies, you guys get a new stent, I get a new disease. Ermergomyces is five species identified thus far. Often previously misidentified as histoplasma or as blastomyces. Some were reclassified from a genus called Ammoncia. This is currently the major dimorphic mycosis in southern Africa, and specifically in the Republic of South Africa, right? This has become a major specifically HIV and AIDS-associated dimorph. The ermergomyces looks very blasto-like with pulmonary and cutaneous manifestations. Blastomyces, though it's not helices, I'm sorry, it's a typo, it's helicus. Blastomyces helicus was also previously classified as an Ammoncia species. This is in western Canada, the United States. So the blue, I'm sorry, the green there is where like blastomyces dramatidis is. It's kind of the traditional blasto lands. And the cases of the people and the animals are identified with blastomyces helicus, again, in the western part of North America including up to Canada. Only a handful of case reports, relatively small numbers, but very high reported mortality. Admittedly, this is being identified in profoundly immunocompromised patients. So what its actual performance is in immunocompetent hosts is unknown. So what about immunocompromised hosts? So the interesting thing is that, you know, donor-derived disease and reactivation after solid organ transplant are pretty rare for these with the exception of COX-E. And my colleague from Mayo, Arizona will discuss that in greater detail. We do screen for COX-E in the transplant setting. There are very few cases of endemic mycoses identified in after bone marrow transplant. Only 18 published cases in review that came out this month. This is probably likely prevented by routine antifungal prophylaxis though. De novo infections, however, in the immunocompromised hosts are common and frequently very, very severe. All right, so what are our challenges? So obviously we have the delays inherent to culture, right? Fungal cultures can take many weeks if they're positive at all. PCR-based assays are still on some level in their infancy. They're not widespread. Certainly at certain referral centers, you can get them done fairly rapidly. But getting a COX-E PCR or a histo-PCR is a drawn out process in most places. Antigen-based assays are widely used. They are largely insensitive, at least in immunocompetent hosts. Urine antigens can be pretty good in disseminated disease. Cryptococcus is the exception to that. The cryptococcal antigen testing is a very reliable test. There is a limited awareness of these diseases outside of endemic regions and often within endemic regions. When I was in San Diego, I would occasionally get a patient transferred down from L.A. And it was striking how, even though we were in driving distance of each other, how little COX-E there was up north, just a short distance from us. And then overlapping clinical syndromes, obviously, these things look like a lot of other things. COX-E, TB, histo all look very much alike. And, of course, also resemble community-acquired pneumonia in the majority of people. So what are some approaches for us to take? So, again, travel history is important. Although I said the ranges are expanding, those ranges are still a useful tool in assessing risk, right? Improved screening of premenopausal depression and transplant donor populations. We have seen donor-derived infections from these. That's a little bit separate. We need to get better diagnostics. And my colleagues will talk about that in better detail. Improved therapeutics. And then just a little plug for climate mitigation. Now that I'm not in the military and I can say whatever I want in public now. Work to reduce the climate impact of healthcare, right? That's one of the things that's driving these changes. So reusable PPE. Be nice during the next pandemic. We not throw everything away and then get caught with our pants down with having to rotate N95 through paper bags for a week at a time. I would like to not do that again. Reusable medical devices. Disposable bronchoscopes make baby Jesus cry. Energy efficient construction. And then obviously leading by example. Thank you very much. We'll take questions at the end. Thank you so much for that great overview, Dr. Maves. We're going to move on now with discussing blastomycosis from nodules to ARDS. My name is Kelly Pennington and I am a lung transplant and critical care physician at Mayo Clinic in Rochester. I have no financial disclosures for this discussion today. This will use audience response questions. So if you have your phone handy, go ahead and get that out. I have several learning objectives that we're going to get through in this talk today. One, I hope that you can recognize the spectrum of illness caused by blastomycosis and interpret common tests used to diagnose blastomycosis. Understand therapeutic options. And then lastly, we're going to talk about some new research or updates in the literature regarding blastomycosis. We're going to accomplish these learning objectives by walking through three unique cases. First, blastomycosis is a systemic pyogranulomatous infection. Infection occurs following inhalation of canidia. I don't know if you guys used first aid to study for step one, but this is one of the popular quotes I remember from first aid is that it's a mold in the cold and a yeast in the beast. So it's a true dimorphic fungi as Dr. Maves had previously alluded to. Infection can really occur in any body system. However, it's most common in the lungs because the initial inoculation is generally through inhalation. The second most common site of infection is the skin followed by bones and genitourinary system. But it really can also cause meningitis or meningoencephalitis and any organ system can be at play here. As Dr. Maves highlighted, most cases occur in North America and he highlighted sort of what regions in North America are pretty common for blastomycosis, including us up in northern Minnesota and Wisconsin. So let's get started with our first case here. We have a 73-year-old farmer from southern Minnesota who presents with an incidentally noted 10-millimeter right lower lobe nodule. He has a remote history of prostate cancer that's been in remission. He's a 40-pack year smoking history and he has a pretty significant family history for cancers. Looking at the mediastinal windows on his chest CT here, we can see that there's no definite lymphadenopathy and on lung windows all we see is this right lower lobe nodule. He underwent PET-CT where we can see that there's strong FDG avidity in his station 11R, 4R, and station 7 lymph nodes with lesser FDG uptake in the primary nodule itself. So this is going to be our first polling question here. Do these PET-CT findings influence your differential diagnosis? So yes, this is highly concerning for a primary cancer. Yes, this is most likely benign. No, we need more information. Or D, I'm not sure this PET-CT was helpful at all. I'll give you guys a couple minutes to answer this question, or a couple seconds I should say. So it looks like most people said no, we need more information and I can see why that would be a popular answer. But I'm going to make an argument how this PET-CT is slightly reassuring although we did go on to biopsy this nodule. The idea that this PET-CT finding represents a benign lesion comes from the study of 209 patients at Mayo Clinic. And what they did is they looked at the PET-CT findings of patients who underwent evaluation for incidentally noted nodules. And what they identified was this phenomenon called the fungal flip-flop sign. This is the idea that the primary nodule has less FDG uptake than the ipsilateral draining lymph node, in which case they argue in this paper that this represents a benign fungal lesion in contrast to a cancerous lesion where the FDG uptake will be more intense in the primary nodule than in the draining ipsilateral lymph node. In this study, they highlighted sort of the time course for FDG avidity of nodules caused by cancer versus fungal nodules. And you can see for fungal nodules, they have increased FDG uptake in comparison to their lymph node early on in the disease course, but that FDG avidity wanes with time while the draining ipsilateral lymph node increases. As you can see here with the cancerous nodule, that FDG avidity remains high and greater than the ipsilateral draining lymph nodes over time. They developed certain criteria to identify the flip-flop fungus sign. And when they applied this to patient characteristics or patients in their cohort, they found that the overall sensitivity for this was about 60% and specificity of about 85%, which is pretty modest. However, when you combined that with positive fungal serology, that specificity did increase to 100%. I'm not suggesting that we all implement this into our practice because this is a one single center cohort study, but it may be reassuring for you as you're seeing patients and see this sign. After shared decision-making with our patient, we decided to ultimately pursue EVUS with FNA and a biopsy of the primary nodule, in which case we identified a necrotizing granuloma and GMS stain-indicated blastomycosis infection. And so for our patient here, according to the 2019 ATS guidelines, how do we manage this or treat this? And for simple infections here, for mild to moderate illness, the recommendation is to undergo a draconazole treatment. Now, unlike histoplasmosis, if you identify blastomycosis, treatment is generally indicated. There are some nuances from experts who may indicate that you don't always need to treat blastomycosis, but I think as a general takeaway from this, because of the risk of disease progression and disease spread, you should probably put in your brains that blastomycosis indicates treatment need. For severe life-threatening blastomycosis, recommendation is liposomal amphotericin, then idraconazole, and then for meningococcal infection, liposomal amphotericin with sequential idraconazole or fluconazole. If patients are not able to tolerate idraconazole, then posaconazole can be used as an alternative. Let's move on to our second case here. This is a 33-year-old homemaker who presented to Urgent Care with 24-hour history of right interior chest pain. She really has no medical history, but her social history is that she lives in northern Wisconsin, recently went hiking with her family and her pet dog. The only finding on her labs is that she has a mild leukocytosis. Her chest X-ray, as you can see here, shows this perihilar fullness and ill-defined infiltrate. She was treated with community-acquired pneumonia coverage by Urgent Care. But as you probably guessed, since this is a talk on blastomycosis, her story doesn't end there. She represents about seven days later with worsening anterior chest pain, low-grade fevers, cough, and sputum production. And this is her follow-up chest X-ray, which you can see now, she almost has a low-bar consolidation. This is definitely expanded, and that's re-illustrated here on her lateral views. On her CT scan, this once again demonstrated dense consolidation with air bronchograms. And then on her soft tissue windows, you can see the heterogeneity within the consolidation there, indicating that there's likely necrosis as well. So this brings me to my next question. As the good clinicians that you are, you're highly suspicious that this may be blastomycosis. And so what would be the most sensitive test of these options to diagnose blastomycosis? Blastomycosis antibody testing by immunodiffusion. Blastomycosis antibody testing by enzyme immunoassay. A histoplasma urine antigen. Sputum fungal culture. Or BAL fungal culture. All right, so it looks like we have a spread here. It looks like some of you are indicating enzyme immunoassay with the majority indicating BAL fungal culture. I agree with those of you that selected BAL fungal culture. And according to the 2019 ATS guidelines for diagnosing fungal infections, there really is no one best test to diagnose blastomycosis. So tests should not be ordered in isolation from one another. But the gold standard for the diagnosis of blastomycosis really is culture and histopathologic visualization. There are a lot of limitations to whether or not culture or histopathologic visualization can be done on your patients. For example, in a patient like this, culture can take one to up to five weeks to perform. And time to initiation of appropriate therapy is linked with improved survival outcomes. So that's a huge limitation. Sensitivity of culture does improve with lower respiratory tract cultures. The sensitivity for a case like this with pneumonia is somewhere around 92%. For sputum, it would be somewhere around 85%. However, you may be asking yourself, well, can't we just use fungal smears? That's really operator dependent on how the fungal smear is prepped. And so the sensitivity for fungal smears can actually be pretty low for blastomycosis, somewhere in that 30 to 40% range. As Dr. Maves alluded to earlier, there is the option for PCR tests for both histoplasma as well as blastomycosis. This has limited availability depending on where you are. Overall, the sensitivity is pretty modest for PCR-based assays for blastomycosis, somewhere around the 70% range. This can be performed on any respiratory secretion specimen, though. There's low cross-reactivity, though, with PCR to other endemic fungi. What you're gonna see is really a limitation of our antigen and antibody testing. So for antigen testing, this can provide a rapid diagnosis, can be ran on urine or serum. The sensitivity of antigen testing for disseminated blastomycosis can get pretty high, somewhere in the low 90% range, but for a fungal nodule can be relatively low, somewhere around 75%. There is cross-reactivity with other endemic fungi, specifically histoplasmosis. We run into similar issues with antibody testing. Now, there are limitations with antibody testing, specifically in patients who are immunocompromised, because they may not have the ability to mount appropriate antibodies. You can obtain antibody testing through three different mechanisms for blastomycosis, complement fixation, immunodiffusion, or enzyme immunoassays, and these have ascending sensitivities, with complement fixation having the lowest sensitivity and enzyme immunoassays having the greatest. Traditionally, these assays have been for antibodies against the A surface antigen on blastomycosis. In recent years, there have been further development of antibody testing using EIA and BAD1 serum protein on blastomycosis that is showing promise at having increased sensitivity and less cross-reactivity with histoplasmosis. So for our patient, we were actually able to obtain the diagnosis from an induced sputum, so this is a fungal smear using KOH and calciflora white, showing our traditional broad-based budding yeast. We treated her with ambazome until clinical improvement, and then transitioned her to itraconazole, and she made a complete recovery. I'm gonna finish up now with our last patient case. This is a 26-year-old man who presented with cough and shortness of breath. He was initially treated by his family medicine physician with this chest X-ray, with different repeated courses of antibiotics. Unfortunately, he really demonstrated no clinical improvement. He had no significant medical history. He had just returned from a mission trip in Tanzania, and also prior to that, had went on a Boundary Waters camping trip. So for those of you who aren't familiar with Minnesota, the Boundary Waters are the lakes that border between Canada and northern Minnesota, and is an area that's endemic for blastomycosis. If you looked at his physical exam findings, you would notice that he had these nodules that he didn't even notice on his extremities, indicative of the skin findings consistent with blastomycosis. When he presented to our emergency department because he wasn't improving, this was his chest X-ray, with almost complete whiteout on the right, and you can start to see patchy infiltrates over here on the left. Because we were highly suspicious of blastomycosis, he was started on Ambizome, and within 24 hours, significantly deteriorated, requiring endotracheal intubation, lung protective ventilation, prone positioning, and paralysis. So my question for you is, in this patient with blastomycosis ARDS, do corticosteroids have a role in treatment? Yes, they may have a role to help reduce the hyperinflammatory response. No, they will worsen the infectious syndrome. Or C, I really don't know. I like the way y'all are thinking. This is definitely what I would say. The answer is, I really don't know whether or not corticosteroids have a role in treatment. And I would say that that's what the literature tells us so far. However, I'm gonna make an argument that corticosteroids in a patient like this may have a role. So we know that ARDS caused by infections or atypical infections like blastomycosis, histoplasma, or even PCP, that there's a robust inflammatory response driven by T helper cells, secondary to this invading microbe. Severe infections with a heavy microbe burden, once you start appropriate antifungal medications can cause a cytokine storm. Corticosteroids may have a role to dampen this excess inflammation and reduce the permeability of blood vessels and limit leakage of fluids into the lung tissue. This really isn't a novel idea, although corticosteroids for blastomycosis ARDS has not made its way into any guidelines. However, we do use corticosteroids for ARDS for histoplasmosis, tuberculosis, as well as severe PCP infections, and that is endorsed by guidelines. Blastomycosis ARDS has a very high mortality rate. If you look at the literature, it's anywhere from 50 to 90%, especially when we get to the point that this patient here was in. We don't have clinical trial data to support this practice and we probably never will. Blastomycosis ARDS happens in about 10% of patients who are diagnosed with blastomycosis. Now the counter argument to using corticosteroids in this patient is that you use corticosteroids that can promote fungal growth through dampening the immune system, preventing the host from being able to fight off the pathogen. But I think, honestly, the risk of mortality is so high in these patients, and some of it is because of this hyperinflammatory response that corticosteroids could play a role, although we don't know the exact dosing that should be used, and that this really should be a treatment reserved for those with blastomycosis in severe disease. We'll just review our take-home points as we wrap up here. Today we have talked about the different presentations from blastomycosis that this can really present as an indolent nodule in someone, all the way up to unresolving pneumonia from antibiotic therapy, and then developing into ARDS. For diagnosis, there's really no single best test to diagnose blastomycosis, and there's a lot of cross-reactivity on antigen and antibody tests with other endemic fungi, specifically histoplasmosis. Treatment, I'd say the takeaway should be that in general, blastomycosis should always be treated, and that severe infections require ambazone, and corticosteroids may have a role in ARDS for blastomycosis. Thank you so much. We'll take questions at the end, but please feel free to email me with any questions or comments from this presentation. I'm going to hand it over to our next speaker, which is my colleague, Dr. Cyril Varghese. He's going to talk to you guys about coccidioid mycoses. And Cyril is coming to us from Mayo Clinic, Arizona. All right. Good morning, everybody. Thank you for coming to the morning session. I moved from Arizona, from Rochester to Arizona about three years ago. And ever since I moved, my wife tells me that I'm obsessed with cocci. Every time she coughs, I look at her, it's ready for testing. But hopefully by the end of this talk, you will side with me more than her. All right. So these are the lesson objectives. I'm just going to pause there for a second. I'm sure you're all very good readers there. Just take a look at that. We will try to cover all this in 15 minutes. All right. So cocci, like the other endemic fungi we talked about, is truly a dimorphic fungi. There are actually two species, imetus and postidaceae. And because it's a dimorphic, there is a filamentous form that occurs in low temperatures, ambient temperatures, and then they produce Arthur Cornelius spores that I learned that can even get through an N95 mask. So when I wear those to do gardening, I'm still kind of cautious. But once they enter, they become spherules, about 120 micrometers. And as you can see there on the right, there's a giant cell that's kind of captured it. And there are numerous endospores in there, which are about two to four micrometers. About 30% of community-acquired pneumonia in endemic regions can be coccytomycosis pneumonia. And therefore, there's a lot of under-diagnosis and delays in diagnosis. Per current cap guidelines, we don't treat people with antifungals, even in endemic regions. So usually they come to us after several weeks to months of failed antibiotic therapy. The disease itself, the symptoms can be very mild. People may not even remember. They may remember a rash. That's something that I'm learning more that people talk, oh yeah, I did have a rash three weeks ago. It can be just a generalized rash, or it can be like, I don't know why it keeps advancing, but I'll go back here, erythema multiforme. Or it can be a vegetative ulcerative plaque like this in disseminated cases. The natural course, the symptoms last for one to three weeks after exposure and majority resolve. Sorry about that, guys. Without treatment, but complicated, disseminated, aggressive local infection can even happen in immunocompetent hosts. For some reason, infection is higher in men. And this is thought to be maybe because men are more involved in construction and things like that. But we are, even in dogs, in non-primate animals, you see a higher incidence in men for unclear reasons. Immunocompromised, as we talk about, including pregnancy. For some reason, there seems to be an ethnic predilection to black and Filipino patients, which we don't understand fully why. Here I'm going to show you an empyema by one of my colleagues. And this was in an immunocompetent host, a young person. And it's literally this plural rind that we had to kind of extricate. Hope nobody throws up breakfast. So the changing landscape of coccidioidomycosis, I'm going to advance through that really quick simply because Ryan already talked about it. But I'm sure you guys have seen these news articles where they talk about, you know, debilitating fungal infections, probably global warming is causing this stuff. And then I looked at this. Is this the last of us? Is this what's happening? I don't think it's too far from the truth, you know, looking at some of these maps. So the initial maps that were drawn were based on skin tests for endemic fungal infections in the 1950s to 60s. So these are not based on, you know, real sample from soil data. Regardless, I think, Ryan, we have you beat in Arizona from California right now. So about 144 cases per 100,000. What are the causes for increasing incidence? Population growth is thought to be one of the reasons. Maricopa County in Arizona is one of the fastest growing counties in the United States. That's where I am. And many people who are immune naive are moving to Arizona. So one thing good about cocci is once you're exposed to cocci, once you have a mild infection, then you are pretty much have protection for the rest of your life, unless you're immunocompromised, which is another problem. We are keeping many immunocompromised people, elderly individuals alive for longer. Urbanized land is getting urbanized, so any time you go in and start digging into the soil and you have aerosolization of these organisms, you see that problem. These are, on the bottom, you see a graph from the 1990s all the way to current times. You can see a general increase. In 2011, there was the spike because there was a heavy rain period, which allowed mycelial growth, and then arid period, where cocci kind of dominated as a fungal species, and then you had a very dry period after that, which allowed the spores to spread, which is why you see that spike. But in general, I hope you can appreciate that trend there. The expansion is determined both by precipitation and temperature. So you need both to have cocci. So low precipitation, so you have to have some. You cannot have zero precipitation. Low precipitation, but then aridity allows the fungus to spread, the spores to disperse. And you can see on the top, you have a magenta. Sorry about that, guys. The magenta is kind of where you have low temperature and low precipitation. The red is where you have high temperature and low precipitation. In the right, you have high temperature, but precipitation is fine. In the top, you have low precipitation, but low temperatures as well. So you can see that you need that magenta or both factors to happen. And as you go through time, you can see that this climate model show that the magenta regions are increasing. In other words, precipitation is decreasing and temperatures are increasing, which is bad news for cocci. You see that spread happening. And by 2095, you see pretty much much of the north of the United States is going to have cocci. All right. Question. Please select the correct answer. In serological testing with high complement fixation, 1 is to 32 helps in diagnosing cocci, microbiological evaluation including finding spherules has high sensitivity in diagnosing cocci. Capillary lesion in the lungs are an uncommon manifestation of cocci. Cocci pulmonary nodules tend not to calcify like histo. Satellite nodules are not useful in discriminating cocci pulmonary infections. All right. I think that's a good number. Okay. So some teaching can happen today. So D is the right answer. Okay. So let's go through the imaging. So there is a lot of diversity in imaging findings in cocci. So you can have incidentally discovered solid nodules like you see in the left up. And then you can see which is very actually I'm learning important in cocci is that you have this nodule with daughter nodules right next to it or satellite nodules. Cavitary lesions are very common in cocci. And then you can have cavities that actually rupture and go into the plural space. So as you can see, especially in the images in the bottom, this can be easily mistaken for neoplasms, other endemic fungal infections and granulomatous diseases, which is why cocci is very hard to diagnose correctly. So how do we do it? There are lab testings. They're not great. So for proven disease, you need confirmation for spherules, either in tissue or fungal growth in medium. Probable disease, you have to have evidence of exposure and characteristic symptoms and positive serology. Cultures, the problem is, sorry about this, guys. The sensitivity is quite low because depending on the immune status, fungal burden, and sites of infection and empiric use of antifungals, you may not see the organism in tissue. And again, depending on where you get the sample, you may or may not see the organism. So respiratory samples are the highest. CSF is next. And as you can see, even in that empyema situation, you can get plurifluid and may not see cocci. The lab testing, there's kind of like an algorithm there of how we do it. So essentially, you get EIA or lateral flow assays. The lateral flow assays are much quicker than EIAs. But again, the sensitivity and specificities are not great, especially if you have an immunocompromised host where the sensitivity can drop in the 60 to 70 percent. Complement fixation, as one of the question options, is not used for diagnosis, right? It is used for prognostication and to monitor treatment monitoring. So once you give antifungals, you see if the complement fixation decreases. Immunodiffusion and complement fixation is the benchmark. So once you get an EIA, you want to usually, if you see that algorithm there, you want to get immunodiffusion and complement fixation. The problem is, it's a very complex test, and even in Mayo, we take about five to six days sometimes before those tests can come back. As a result, most of these patients, we are already starting them on empiric antifungal coverage. This is a chart on the right, if you guys want to take a look at all the different assays. But in summary, cultures microanalysis, although specific, are not sensitive. Antibody testing have variable sensitivities and specificities, particularly the IgM, EIA. We are seeing a lot of false positives with those. Negative tests does not mean that the patient does not have disease. As you can see, as you guys know, the antibodies can form later, so usually we repeat testing in a few weeks. Most patients require confirmatory testing, which are hard tests to do, and take several days to come back, and patients are getting sicker, so you need to treat them. So what do we have? Do we have improved diagnostic methodologies? And that's what I want to focus my talk on is, yes. So this group, I believe they are in California, they looked, and this paper was published in 2023, they looked at what can we see in radiographic appearances of COX-C that's separated from cancer. And what they found, as I talked about, is the satellite nodules is a big deal. So satellite nodules, capillary lesions, and absence of chronic lung disease in the rest of the parenchyma. So by chronic lung disease, they meant emphysema, honeycombing, and reticulation. So if you don't have those things, and you have a nodule, a capillary nodule, there's a probable, in an endemic region, it could be COX-C. But satellite nodules is a big deal. As you can see, the positive likelihood ratios, positive predictive value, and negative predictive value is pretty good. We have published, our group has published many papers on artificial intelligence and using artificial intelligence to look at nodules so that we can prognosticate between benign and malignant without biopsies. And we have actually validated it in, trained it in the NLST cohort, and then validated it in external cohorts. And we have AUC curves in the high 80s, low 90s, even in external cohorts. But what we are noticing is that when we run our AI algorithm on a COX-C nodule, which, by the way, for those of you who are interested in AI, this is actually an unsupervised clustering algorithm that looks at density histograms within each voxel of the nodule there, and also surface characteristics and surrounding lung parenchyma and many other things. But we are noticing that for histo and blasto and many of these other fungi, we are able to differentiate. COX-C, we are having a tough time. And if you see on the right, that is a probability distribution, it's classifying it as malignant. So managing COX-C, last question, current guidelines suggest treating chimeric-acquired pneumonia in highly endemic regions. Empirically, pulmonary cavities caused due to COX-C must be treated with antifungals to reduce chance of local invasion. A high CF titer is grounds for considering antifungal treatment. Fluconazole is usually chosen or retroconazole for treatment of COX-C because it's more efficacious. So fluconazole is a good choice for treating CNS-COX-C disease. All right, all right. So the right answer is C, and we'll talk about that. So when do we treat COX-C? So in general, many COX-C we do treat, okay? The way I look at it is if you have an immunocompetent host, I first try to think, is this moderate disease? And moderate disease is defined as if you have greater than half of your lung involved, if you have persistent constitutional symptoms. So mainly it is fatigue, joint pains, and weight loss of greater than 10 percent from baseline. Or if you have a higher CF titer, that's considered moderate disease. You treat them with a triazole for 6 to 12 weeks. If you don't have moderate disease, then you're probably mild or severe. If you're mild, in general, you can observe. But if you have any of these risk factors, then you consider treatment. Severe disease is where you have most of the moderate features, but also you have respiratory compromise. Then you're looking at the big guns like amphotericin, longer duration. Immunocompromised host, you're going to treat even mild cases. And the duration, again, is based on the severity in the graphic above. You may put patients on lifelong therapy, especially if their ICH is going to continue and they're going to be immunocompromised host indefinitely. Disseminated disease, you treat with triazoles. In summary, fluconazole is first line. Itraconazole is similar in efficacy, but has many side effects. So we don't go to that as first line. For bone and joint disease, it is considered a better option. Voriconazole can cause visual impairments. Once a patient tells you that, you'll never forget. Drug-to-drug interactions with voriconazole, amphotericin is pretty good. But renal injury. Isovuconazole, remember, for board questions, it does not penetrate the CSF, so do not use it for treatment of cocci meningitis. Isovuconazole is probably effective, but we don't have enough studies. The good news is there are many things coming in the pipeline. Olorofim is a drug that kind of inhibits pyridine synthesis. All the rest of them actually prevent cell wall synthesis, and therefore, prevent or treat the infection. I can't pronounce any one of those, probably right. But with that, just to let you know in summary, immunocompetent hosts can get severe or disseminated cocci. Due to climate change, cocci is expanding, going further north and further east because of changing precipitation and becoming hotter in the world. Imaging and serological testing is neither sensitive or specific. We need development of better tools, including AI, especially in imaging, and probably integrating that with poor serology tests to get individualized prognostication. Triazoles, that is the silver lining. Despite how bad cocci is, fluconazole still works, and there's not many resistant cases to fluconazole. There are other drugs being developed in the pipeline, so that's also a silver lining. With that, I apologize for the technical difficulties, but thank you for your time. Well, thank you, and thank you, Kelly, for the invitation. My name is Shadi Haj. I'm at the University of Pittsburgh, and I am a transplant pulmonologist as well. This is like a transplant session here. So my career is in transplant pulmonology. My hobby is in histo and blasto, so this is a good place for me to be. And again, thank you for making this early morning, waiting for this to load. All right, here we go. So I was asked to give a case-based presentation to keep everybody awake after three heavy talks. This is just to try to compete with the amazing Dr. Mays regarding use of maps, but histo is everywhere. Histo is a global disease. It's not just in North America. Obviously, in North America, I used to be in Indiana. I spent most of my career in Indiana, and it's highly endemic in the Midwest, but you can see it's everywhere. So if you have not seen histo in your career, then you haven't looked hard enough. And please do not miss histo or blasto because they're extremely common in our business. So I'm going to start with a quick case, and then we'll come back to it at the end. Just going to wrap it up. So this is an actual case from Indianapolis, a young man, 36-year-old. Believe me, 36 is very young, with HIV and Hepatitis C, came in with two weeks of progressive dyspnea, cough with clear sputum, had fever, splenomegaly, hypoxic on oxygen, CD4 count is extremely low, platelets are low, white count is low, so there's pancytopenia, hemoglobin is low, alveolation outbursts are elevated. So if I was in New York when I did my internship, this would be pneumocystis, move on, right? Well, not too quick. He had histocerologies that were drawn, immunodiffusion complex fixation, both of which were negative. He had a serum aspergillosis galactomania that was highly positive, 4.6 is actually very high, and he had a beta D glucan of 468, that's also extremely high. So are we dealing with aspergillosis, are we dealing with pneumocystis because of the beta D glucan? I mean, he's from Indiana, is this histo, histocerologies are negative. So we're going to go over some of these scenarios and see what we can come up with. So I'm going to start talking a little bit about acute pulmonary histo. So acute pulmonary histo is the, we call that the epidemic form. So a bunch of guys go dig in a trench in the backyard or destroy an old building or clean a barn, all of them came down sick, one ended up in the ICU, three at home. This would be epidemic form of histoplasmosis. Acute histo, there's an acute exposure, there's a point exposure. One event that you can pinpoint, one to three weeks after the exposure, they get sick, they get a flu-like illness with fever, dry cough, dry cough again. It's not productive, chest pains, sweat, malaise, flu-like illness, and it could be self-limited. Now those who have a heavy exposure, so the front person who gets the heaviest burden of this cloud, comes down with a severe pneumonia, can end up with ARDS on the vent. And you can see some examples of imaging and the skin changes with this erythema that was also characteristic of histo, of acute histo. So what about diagnosing this? Usually serology is used for this, but the caveat is in the timing. So you see that graph on the right, this is a one-point exposure, this epidemic that happened in Minnesota actually, that was a wedding venue with wedding parties going through this area that had a lot of bird droppings, so we know exactly when the point of exposure was, that's time zero. And then serologies were collected at three weeks, four weeks, and six weeks. And you see the vast majority of them at three weeks were negative. And this is when they were ill. So three weeks after the exposure, they're all sick, they got serologies on them, all of them essentially were negative. Repeated at week four, so a week later, you know, number increased, and then the majority became positive later. So the lesson from this is if you suspect the acute pulmonary histo and it's severe enough, serology may not be as helpful. Now if serology is positive, that's actually very helpful, because the background positivity, if you lived in Indiana or you lived in Nashville, and there's no outbreak happening, the odds of having positive serology if you're not sick is actually extremely low. So positive serology is very helpful. And it comes in immunodiffusion, complement fixation, you can see the interpretation there. Usually H-band appears earlier than M-band, and M-band lasts a little longer, and you know, can go up to two years. And then in complement fixation, there's a yeast and a mycelia antigen. And the higher the titer, the more likely the disease is. But again, timing is extremely important, the use of serology in acute histo. This is a newer version of serology, similar to what's been developed for COXIE. Actually this was the prelude to the COXIE EIA assay that was developed later. So this is an ELISA assay, and it detects IgG and IgM. It provides a higher sensitivity in acute histo using data from two big outbreaks. So collected samples from two big outbreaks of acute histo, and you can see sensitivity is 87%. It's highly specific as well. There's some cross-reactivity with blasto and COXIE, and you have an IgG and IgM, so it's helpful in terms of timing. And when compared to the traditional comp fix and immunodiffusion, it was higher sensitivity. So the newer test provides us with a more accurate testing for acute histo than what has traditionally been used, complement fixation and immunodiffusion. Chronic cavitary histo, this is a whole different disease. So this is similar to blasto, essentially, or TB. So it's people who have COPD, usually, and develop this TB-like illness with cavitary disease, upper lobe. This is a sputum-producing infection. So of all the histo syndromes, this is the only one that produces sputum. This is similar to blasto, because blasto is also a purulent infection, sputum-producing infection. So here, sputum culture and stain are often positive, and often are the method for diagnosis. So it's usually, I used to see this a lot at the VA, you know, a patient with severe emphysema, they come in with upper lobe cavitary disease, we think it's TB. It's not TB. We think it's histo, and it's usually histo. Histocerology is actually extremely useful here, because again, the exposure was a long time ago, and they have continued exposure, so more than 85% sensitivity. So sputum culture and serology are very helpful here. And then if you do an induced sputum, this is what you would see, this is a macrophage loaded with these two micron size yeast that are full inside the macrophage, and that would be diagnostic. You can't always do a bronchoscopy, we're bronchoscopists, this is a chest meeting. So if you do a bronchoscopy, you can do an antigen assay on the BAL, that's highly sensitive, and this study was published many years ago, looking at histo and blasto, and was highly sensitive. So this is a summary slide from multiple studies, and we have acute histo, subacute histo is the form that you see, it looks like community acquired pneumonia with no acute exposure, and then the chronic cavitary, as I mentioned, it's like TB-like illness. And you can see serology is very useful in those who are subacute to chronic. Culture is very useful in those who have chronic cavitary disease, because it's sputum producing. Antigen is actually very useful in acute pulmonary histo. So if it's severe enough to land you in the hospital or in the ICU, acute histo is diagnosed more often by a histoantigen, either by the serum or urine testing. And then you can see cytopathology is not very useful in primary samples of histo. This is the big one that you do not want to miss, progressive disseminated histo. So this is the stuff that we used to see a lot in AIDS, but now the most common is not AIDS anymore, the changing epidemiology of histoplasmosis, Bennett paper that was cited earlier, you see that it's more solid organ transplant recipients, patients on biologic therapy, anti-TNF therapy, is actually overtaking AIDS patients. And again, the presentation is acute lung injury, splenomegaly, fever, cytopenia, increased LDH, increased LFDs, I think this x-ray was shown a little earlier, B. mucocutaneous disease, CNS disease, GI disease, adrenal disease. So people with progressive disseminated histo present with shock. That's usually a primary involvement of the adrenal gland. So there's a hemorrhagic injury to the adrenal glands that could cause adrenal injury. It's a multi-organ failure. It could present with septic shock or glompatia ARDS. Diagnosis is key. Rapid diagnosis is key, because the later the diagnosis is, the more progressive the disease becomes, and then you have more organs, and the mortality is higher. These are some manifestations. You can have a GI illness, you can have oral ulcers, you can have colon lesions. This colonic lesion here could be easily mistaken for Crohn's disease. I'm sure you remember the paper in the New England Journal, No Stone Unturned, I think the title of the paper was somebody who had a lesion in the colon, they biopsied, they saw granuloma, they thought it was Crohn's, they gave him anti-TNF therapy, it turned out to be histo. Of course, it disseminated and the patient died. You could have CNS disease, you could have spinal disease, and you can have skin lesions as well. But these are the adrenal involvement. You can diagnose this, actually, by a smear of a peripheral smear. First case of this that I've ever seen, I was a resident in Indianapolis, it was a circulating neutrophil that was loaded with yeast, like this one here. But that's not a common manifestation, that's 20, 15% of cases. If you do a bone marrow biopsy, the yield is extremely high, but who's going to do a bone marrow biopsy on somebody with ARDS? We have simpler ways, much less invasive ways. This is a summary, a multi-center study that we did, looking at AIDS patients, other immunocompromised patients, or non-immunocompromised patients. Again, the same outline, antigen, pathology, culture, and serology. You can see histo-antigen was highly sensitive, mostly in AIDS and other immunocompromising conditions, a little less in non-immunocompromised patients, and the title tend to be higher in AIDS patients than immunocompromised patients. Pathology, three quarters are positive, if you want to do this. Two quarters can be positive, and three quarters, but then it takes time. Again, serology is useful in those who are not immunocompromised. Look at the example of solid organ transplant recipients. Only 20% of those who had confirmed disseminated histo, tested positive in the histo-serology, simply because we give them medications to suppress production of antibodies. We give them microphenolate as a type, because we don't want them to make antibodies. Well, here you go, they don't make antibodies. So the histo-serology will not be that useful in these patients. This is the newer test that is still under development. This is a study we did on samples that were stored of progressive disseminated histo patients from Indiana, Kentucky, and Vanderbilt. And this is, we're all familiar with this. All of us had this test on the LFA, right, lateral flow assays. We did it for COVID, and it was used for pregnancy testing and many other testing. It's a point of care test. So here we looked at these samples, and you could see from negative in A to mild to a little more positive to highly positive in D on those little STIRP examples. So it's visual. It's not quantitative, but it's very useful in diagnosing rapidly a progressive disease or severe disease. So those with moderate to severe disease, the yield is very high. Those who have a relatively high antigen level, yield is high. Those who are mild disease, the yield is not very high. But it could be a point of care test in areas that have no access to antigen, but they have severe disease. So it could be a rapid diagnostic test. This needs to be validated further. There are actually ongoing studies in Latin America looking at this technology for diagnosing histo. What about that case we talked about had positive galactomanin, right? So this is a series we published now in 2007, many years ago. We looked at patients who had histo and then patients who had aspergillus, and we tested them with the other antigen. And you can see 23 of 48 patients with histo had positive aspergillus galactomanin. And those who had high levels of antigen, 71% had positive galactomanin assay. So the lesson from this, if you have histo, you're likely to test positive for the galactomanin. What about the other way around? So we had a number of patients who had aspergillus. So 20 serum and 18 BLs from patients with confirmed aspergillus. None of them tested positive for histo. So histo patients could test positive for aspergillus antigen. Those patients will not test positive for the histo antigen. So test, obviously, treatment implications, you know, Echinocanin are often used in combination therapy for aspergillus, but those don't work for any of the endemics. Avori is a first-line therapy for aspergillus, but it's not for histo for sure. It's not even a third-line agent. So it's important to recognize this. Here's the other test that we used in that patient, beta-D-glucan. So here in this series, we looked at 23 patients who had the histo, and 20 out of 23, so 87% of them had positive galactomannan. So again, the same story. If you have histo, you could test positive for galactomannan. And this is important because histo and pneumocystis, clinically, believe me, they look the same. In Indiana, a pneumocystis is histo until proven otherwise. This is how similar they are. So these are two real cases, AIDS patients, same presentation. The one on the left had a positive galactomannan, negative histo antigen, and was confirmed case of pneumocystis and treated with trimethoprim sulfa. The one on the right had disseminated histo with positive beta-D-glucan, positive histo antigen, and the treatment is amphotericin. So it's important to recognize this confusing scenario. So just to summarize these antigens, and there's so many of them, and I just put more diseases than I'm supposed to, but you have highlighted histoplasmosis here in the bottom, bottom third, and test positive for aspergillus, test aspergillus galactomannan, test positive for beta-D-glucan, for histo and blasto antigen, because they're essentially the same test, and it could test positive also in the coxie antigen test. And you can see for aspergillus galactomannan, for example, test positive for aspergillosis and all the endemics, beta-D-glucan, essentially all of them except for crypto, et cetera. So I'll go back to that patient we had, had aspergillus galactomannan 4.6, beta-D-glucan of 468, both highly positive. The histo antigen was highly positive in the urinary serum, and based on that, he was started on amphotericin, cytopathology showed intracellular yeast that was consistent with histo, and then eventually his culture grew. Four weeks later, histocapsulitis. So if we waited for that four weeks later, I think he would be long dead. And this patient received ITRA, cleared his antigen on therapy, and did well.

endemic fungal infections

histoplasmosis

coccidioidomycosis

blastomycosis

changing maps

diagnostic methods

treatment options

antifungal medications

early diagnosis