Thank you, Talia, for that wonderful overview of the epidemiology of fungal infections in the ICU. I'm going to focus on one particular subpopulation, and that population is the solid organ transplant patient, and the patient who is at risk for fungal pneumonia, so I have no disclosures. The learning objectives here are we're going to review the common causes of fungal pulmonary infections. I'll try to walk you through a decent diagnostic approach, and then John will follow up with some treatment approaches. Here's my outline. I'll introduce a case. I'll show you a diagnostic approach. I'll introduce you to the fungal pathogens you need to know when you're concerned for a fungal pneumonia in a solid organ transplant patient. John will talk about treatment, and then I'll return to the case. So I love this expression from our military colleagues, the bottom line up front, so you know where our talk is going. Making the diagnosis of fungal pneumonia in a solid organ transplant recipient is rarely straightforward. There's not going to be a eureka moment, unfortunately, today where we introduce to you the equivalent of a troponin test for diagnosing fungal pneumonia in a patient. CT imaging and laboratory tests can be very helpful in terms of guiding you towards a diagnosis but are rarely definitive, and clinical judgment and experience are really paramount to making a diagnosis in a patient with solid organ transplant. So the case I'm going to present is one of a six-year-old man, renal transplant recipient. He presents with very nonspecific shortness of breath-like symptoms. He hasn't improved since starting on his azithromycin. He, as the board exam likes to say, enjoys gardening, but in his case, he also traveled to a motocross race in Southern California. So the first thing that oftentimes we encounter is the CT exam, and what we find in this case is both nodular and ground glass disease throughout the lungs. So when seeing a patient like this, I think it's reasonable to start by playing the odds. So what are the fungal pneumonias, and when you see a CT like that, you should be thinking that this patient could have a fungal pneumonia. What organisms should you be thinking of? And as Talia has already mentioned, aspergillus should really come to the top of your mind in terms of a fungal infection that might be present here. You should know your host factors, but realize, knowing your host factors... This is a dramatic pause, I guess. Here we go. Realize, though, that even this is limited. So this is a classic diagram from Jay Fishman's work, and what you should take from this is simply that at any point post-transplant, a patient is at risk for a fungal infection, and that's related to the intensity of chemotherapy, it's related to antimicrobial prophylaxis when it starts, when it stops. You should know your environmental risk factors, both for the patient in front of you, but also for your board exam. So when you see bird or bat guano in the question stem, you should be thinking histo or crypto. When you see decomposing plant material, soil construction, you should be thinking aspergillus, histo, or cryptococcus. You should also be very well aware of where these organisms are found. So for those of you out of town and on behalf of coxiomycosis, welcome to Ground Zero for coxiomycosis. CT findings that should trigger your mind to think, could this be a fungal infection? Upper lobe disease, nodules, and then these various signs that I'll walk you through. So the halo sign is the classic sign that we think of with a fungal infection with ground glass surrounding a nodule. When patients like this are neutropenic and their neutropenia recovers, you can often find this air crescent sign that I'm showing you with an arrow. And then finally, there's something called the reverse halo or bird's nest sign, where the ground glass is actually at the center of that lesion and the consolidation surrounds it. And this is most concerning for mucormycosis. Other CT findings, if you want to play the word association game, if you see nodules, you should be thinking histoplasmosis. If you see diffuse bilateral ground glass, or if you see pneumatic seals, you should be thinking pneumocystis. And then cavitary lesions should make you think of fungal endocarditis. So this is how our ID colleagues classify fungi into three groups. You have yeast, molds, and then you have the dimorphic fungi, which, depending on where they're growing, so in the environment, they are molds. But when they encounter a warmer environment, i.e. the host, they convert to a yeast. So very quickly going through the fungi you should know and be aware of in the single organ or the solid organ transplant patient. So aspergillus, as we've already mentioned, should come to the top of your mind. Realize though that when you turn to update eight or something like this to consider aspergillus, realize there are five clinical syndromes. But what we're concerned with is the invasive pulmonary aspergillosis, not the colonization, not the ABPA. So the microbiology to know is, in one word, it's ubiquitous. The epidemiology to know is the mortality rate is high and it is the most common fungal pneumonia amongst patients with solid organ transplant. And then the risk factor that you really jump out at you is neutropenia. So how do you go about diagnosing this? So again, I'm going to walk you through the same series of steps with each of these organisms. The clinical picture is going to be nonspecific. You're suspecting a pneumonia. You're almost certainly then going to rush to your risk factor. So in this case is the patient neutropenic. You're going to have a CT almost invariably to look at. And unfortunately, even though I just talked to you about this halo sign, it's incredibly or not incredibly, but it's very rare in patients of who have had organ transplants. The cytology sensitivity is not very good, the specificity a little bit better. Culture in almost all of these cases is not very helpful because the patient in front of you needs treatment now and the culture results aren't going to arrive for weeks. The fungal marker that we lean upon for aspergillosis is the aspergillosis galactamannan. And the take-home message here is if you have the opportunity to test BAL fluid, that is your best approach where you get the best sensitivity. Still not great, but better than in serum and with very good specificity. Be aware though of the false positives. It can be found in food. So patients with mucositis can actually be positive for galactamannan. Galactam antibiotics, this used to be a greater problem in terms of being a false positive. This has somewhat been corrected. And then it cross-reacts with mucormycosis in some cases. The beta-D-glucan is nice, but it's not terribly sensitive or specific, unfortunately. Moving on to cryptococcus, the second most common. In terms of microbiology, words that should jump out at you are exposure to pigeon or avian droppings. In terms of epidemiology, this is a high-yield point. When you find a patient with organ transplant who you diagnose with crypto, you need to realize they almost certainly have disseminated histo, and these patients deserve a lumbar puncture as the organism is trophic for the CNS system. Risk factors, steroids, biologic. So again, you're going to get a nonspecific clinical picture. You're going to be thinking, did this patient get biologics, for example? If I see nodules, again, it's already going to bubble up in your mind. Maybe this is crypto. Know that the serum cryptococcal antigen amongst solid organ transplant patients is pretty good with a sensitivity of 83% in one study. But it may be negative in patients who have low burden of disease, for example, with a single nodule. Moving on to histoplasma, which is one of the endemics. And from this map, so first of all, it's aerosolized. So you should be thinking farming, demolition of buildings, exposure, chicken coops, caves. Once again, this first map that the CDC shows basically is almost unhelpful in the sense it's half the country. But another way of looking at it is the second map they provide, which is where they've actually done studies looking for where the bug, the environment is most supportive of histo. And so a map like this can actually sort of shift your view in terms of where to find histo. And it should also be mentioned along those lines that with climate change, we can expect these endemic organisms to change in terms of their location. So again, they're going to present with symptoms of pneumonia. You're going to be thinking about environmental exposures if you live in one of these parts of the country. The CT can be very varied, but know that the antigen testing, again, high yield point is best in BAL fluid, and that interestingly, it concentrates in the urine so that urine is actually better than serum. MUCOR, the nomenclature here is in flux, okay? Sometimes your lab will report zygomyces, think MUCOR, for example. The epidemiology can be very tricky. It's fairly rare, again, in solid organ transplant patients, and it can be tricky to diagnose because oftentimes these patients have associated bacterial pneumonias. Realize though, if you miss it, the mortality rate is high. The risk factors include neutropenia, renal failure, interestingly, iron overload and deferoxamine therapy, and steroids. The symptoms, nonspecific, the risk factors are just as I've mentioned. If you see a reverse halo sign, that's highly suggestive. Know that this disease can extend across tissue planes and invade the chest wall or the pericardium. On histopathology, you're going to see broad, ribbon-like hyphae, and interestingly, beta-D-glucan in this case will be negative. In terms of COX-E, microbiology is fascinating. It's an aerobe, so it lives just beneath the surface. It can't live too deep, and in wet, excuse me, in dry, windy seasons, it becomes airborne. The epidemiology is really, really narrow here with almost all the cases reported to the CDC in this time period being from Arizona or California, so risk factors, geography, either here or travel to this area. And also be aware that severe disease is seen in African Americans, Filipinos, and Pacific Islanders for reasons that aren't fully explained. Terms of the diagnosis, again, clinical, they're going to look like they have pneumonia. The major risk factor here is geography. The CT can be very nonspecific and diverse. In terms of BAL, once in a while, you'll get lucky and see these spherules that I'm showing you. In terms of the serologic testing, this is when you definitely want to phone your ID expert and realize that the backbone of testing is going to be IgG and IgM testing. And unfortunately, though, the IgM, where we think of acute disease, there are a number of false positives, just like any other IgM test, think Lyme disease. There are other tests, immunodiffusion and complement fixation. These are largely confirmatory tests. And if you do have a patient with COX-E, again, you need to warn your lab because culturing of this organism is a potential risk to laboratory personnel. Moving on to pneumocystis. When this occurs in a patient, it's either a case of reactivation or direct infections. Interestingly, it cannot be cultured, despite our colleagues' efforts the last 30 years to try to culture it. And really, the key risk factor here is, are they off of their prophylaxis for PCP? So what I was taught in fellowship was that pneumocystis looks very different in the non-HIV patient. It hits them more like a ton of bricks, has a much shorter clinical course. Again, the risk factor, no prophylaxis. The CT, classically, ground glass, bilaterally, you can see these metaseals. There's a variety of cytopathology tests that you can use, as I've listed here. And then finally, blasto, which is really a niche organism. The microbiology is interesting. It can either be spread by inhalation or inoculation directly through the skin. On the boards, you're looking for broad-based budding yeast. The epidemiology, again, shows half the country, but most of the cases focus around the Great Lakes and Louisiana. Risk factors include construction and camping. They will sometimes have skin lesions and bony lesions to go along with their pneumonia. Risk factors are outdoor exposure. Again, the cytopathology, broad-based budding, you do have an antigen test, but know that it will cross-react with histoplasmosis.

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Aspergillus

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