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- [00:00]
A
This episode is sponsored by Trulearn, a returning sponsor of our show. If you're studying for boards or gearing up for residency exams, Trulearn is probably already on your radar. They create Smart bank question banks for usmle, Comlex and residency exams that are built to help you think clinically, not just memorize facts. Whether you're early and dedicated or deep into residency, Trulearn has recently launched Create youe Own Flashcards, which is a great option if you like, pairing practice questions with active recall. The whole idea is retrieval practice, pulling information out of your brain instead of just cramming, and research shows that this approach leads to better long term retention than just re reading your notes. These flashcards are accessible to all users on the web with an active subscription at no additional cost, so it's another study tool you can easily build into what you're already doing. Right now. You can get $25 off Smart bank subscriptions of 90 days or longer for USMLE, Comlex or residency exams and also get up to 20% off other healthcare exam subscriptions with the promo code RUNTHELIST. That's R U n T H e L I S t. Check out Trulearn and see if it fits your study style.
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B
Welcome back to Run the List, a medical education podcast in internal medicine. As a quick disclaimer, this podcast is made for educational and informational purposes only and should not be understood as medical advice under any circumstances. Before we get to the show, a quick word on the sponsors for today's episode.
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C
Open Evidence is the premier AI powered medical information platform for physicians and medical students. It's like ChatGPT for anyone who practices clinical medicine. Whether you have a clinical question, a question that comes up during your literature review. If you have a question that comes up when you're trying to synthesize a topic you're going to teach, you can just go to openevidence.com, enter your question and it'll synthesize the answer for you while also linking to those actual articles. This an outstanding resource. Welcome back to Run the List. I'm your host Walker Red, and I'm thrilled to be here today with our guest, Matthew Pullin. Dr. Pullin is an Assistant professor in Infectious Diseases at the University of Minnesota. He studies endemic mycoses, cryptococcal meningitis, advanced HIV, and COVID 19. He has a super interesting background in biodefense and bioterrorism and now does work in clinical trials. We got together and were thinking about how we could work to address the little bit of a gap that there is in the common understanding of endemic fungal infections such as blastomycosis. This is a topic that's often only briefly covered in med school and there's groups of ID doctors who are really dedicated to studying these diseases in more detail, helping address that gap in some of our knowledge. So it's important for all clinicians to keep in mind endemic mycosis in mind. And this case presentation, I don't want to build it up too much, but it's one of the more interesting case presentations we've ever done on Run the List and I'm so excited for you to be here today, Matt. Thanks for joining us.
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B
Of course, thank you very much for having me. I love talking about this.
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C
So without any further ado, we're going to go ahead and run the list. Let's imagine you're seeing a 45 year old man in clinic. He has a history of metabolic associated liver disease hypertension and he's initially presented to his dermatologist with several large purple black lesions ranging in size from the size of a dime to a half dollar that have appeared on his trunk flank and thighs over the past month. These lesions aren't necessarily painful or pruritic, but they do seem to be enlarging and new ones continue to show up. Over that same period of time he has developed a sharp pinpoint area of pain in the lateral side of his right ankle. About two months prior to these symptoms developing, he developed a mild self resolving respiratory illness and this occurred while he was spending time at a relative's cabin in rural Pennsylvania where he helped clear rotting pine trees. At the time he was a bit dyspneic and he had a cough that was nonproductive, accompanied by mild fever and chills. He didn't seem to respond much to over the counter cold and flu medications, but these symptoms gradually resolved over the following two weeks and he doesn't currently have any respiratory symptoms. When you see him in clinic and do an exam, his vitals are stable. His well appearing the lesions described on his skin are consistent with what he described on history. His his right ankle is non tender, but he does grimace some when standing and bearing weight on it. His lungs are clear to auscultation. All right, so Matt, honestly if I was seeing this patient, one of my first thoughts would be that I probably need to get the help of an infectious disease doctor. So we want to turn to you and ask what are some of your initial thoughts when you hear about this case presentation.
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B
Yeah. So this is a pretty classic presentation for disseminated blastomycosis. The tricky part about this specific infection is that it can have a really varied presentation. About half of those infected with blastomyces will remain asymptomatic and self resolve. But the most common symptomatic presentation is the classic respiratory syndrome, typically called the pneumonia, that doesn't improve with antibiotics. Beyond the lungs, the most common sites we see involved in disseminated disease are the skin, bones, genitourinary tract, and then the central nervous system.
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C
All right, so given that those symptoms can basically occur anywhere in the body and they're kind of nonspecific, what are some other aspects of the history that you hone in on as an ID doc to help clarify what may be very relevant to the case?
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B
Yeah, so like with a lot of things in infectious disease, you should really think carefully about the exposure history. In this patient's case, he was working with rotting and waterlogged wood in the Ohio River Valley. That's the classic geographic region that we all learn about in med school. When it comes to blasto, the soil spore connection is really key here. Blastomyces is what's called a thermally dimorphic fungus, meaning it exists in two forms. Since the dimorphic, based on the temperature it exists in, it exists as a spore in the cooler soil and vegetation out in the environment, and then phase transitions into the pathogenic budding yeast form in warm environments like the mammalian respiratory tract. Classically, we used to call this the hunter's disease, because hunting dogs would get blastomycosis. Even today, we see this pattern of someone coming in with respiratory symptoms that aren't resolving, and then they say, hey, you know, my dog had similar symptoms a couple weeks before me. A lot of that is because dogs, you know, they're sniffing around in the soil, they're disturbing soil and vegetation, so they likely get a higher burden of disease that they're inhaling, and they disturb those spores and kick them up into the air, which leads to their human being infected as well.
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C
That's so helpful. Just keeping in mind the example of dogs and how they may be able to get it and spread it to their humans really is going to help me remember the soil spore connection. I also know that you've explained to me that the sort of classic geographic distribution we all learned about in med school has been shifting a bit. So could you speak to some of the epidemiologic data and how we sort of understand it these Days.
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B
Yeah. A lot of the epidemiologic studies that are the basis of our medical school training, where we talk about the Ohio and Mississippi River Valleys, those were performed in the 1960s and 1970s, which, you know, understandably, data was a little harder to come by. It was often incomplete, and it likely captured where people were diagnosed rather than where they were exposed. So it kind of biases towards large medical centers even today. More recent studies using Medicare data and multicenter studies have shown that the geographic range of blastomycosis, as well as other endemics like histoplasmosis and coccidioidomycosis, are expanding. Part of that is just revealing what was probably there the whole time. That has a larger geographic distribution, but also the climate's changing. It's getting warmer and more humid everywhere, which is what these fungi love.
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C
So with that context in mind, could you just discuss the clinical presentation in a bit more detail? I know you said that the pulmonary blasto is sort of how it initially starts, but could you speak more to what that's like and what the presentation may be like?
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B
Yeah, absolutely. So by far the most common symptomatic syndrome we see is the classic pulmonary blastomycosis. Kind of like all blastomycosis, this also has a pretty wide range of presentations. It can be anything from a mild subacute subclinical pneumonia all the way up to ARDS, with the ARDS form carrying a nearly 50% mortality rate. So it's a pretty serious disease other than the kind of non specific dyspnea and cough you can often see. Fever, fatigue, hemoptysis, night sweats, weight loss, all of these things that we can see in bacterial pneumonia, tuberculosis, even malignancies, which often leads to the delayed diagnosis that's super common in blast. It just looks like so many different things. Imaging findings similarly are pretty widely variable and often not very helpful. It can be everything from patchy opacities to cavitary lesions to the super unhelpful tree and bud appearance, which, you know. All of this also contributes to the frequent missed or delayed diagnoses in blasto.
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C
Thank you so much for walking us through that. I'm really picking up on a pattern here, which is that this can be a challenging diagnosis, which is why we're covering it today and really highlighting some of the. The subtleties here. So to that end, could you speak to some of the extra pulmonary manifestations of blastomycosis?
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B
About a quarter to 40% of people will develop disseminated disease, most often Disseminating from their initial pulmonary source, since that's the most common way you get infected. The most common site of dissemination by far is the skin. About 40 to 80% of disseminated disease will be cutaneous. The next most common is osteomyelitis, affecting 5 to 25% of disseminated disease patients and then the genitourinary tract at less than 10%. Cutaneous disease usually starts as papulopustular lesions that can progress to warty verrucous plaques. They can develop central ulceration, can become violaceous nodules, or even develop underlying abscesses, blastomyces. Osteomyelitis usually presents as an abscess or sinus tracts or septic arthritis in a seated joint or bone. And then the least common site, the CNS, it's usually in 5 to less than 10% of disseminated disease. More often occurs in people with immunocompromising conditions or other syndromes or conditions that make them more prone to neurologic infection. This can present as a typical meningitis pattern, looking very similar to other fungal or bacterial meningitis diagnoses, or can present as a space occupying lesion or abscess in the cranium or the spine.
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C
All right, so we have to keep in mind the skin, the bones, the genetic urinary tract and the cns. That's a lot to think about. And as we have gone through this case, we've already gotten a lot of relevant history. You have described all the different aspects of the presentation. And so once this is in our differential and we're trying to think about how to diagnose it, what are some of the tests we should be looking to perform to sort of quench the diagnosis?
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B
So there are a few tests available to us. A lot of it kind of depends on where the disease is and what you have access to. In cases where you have skin disease, like in this patient, or bone disease, the old adage of tissue is the issue applies. If you can biopsy something, biopsy it. You know, sometimes that can lead you to a quick diagnosis just by a preliminary pathology exam that shows budding yeast. Biopsy is not always possible. And, you know, getting tissue for fungal culture can often be slow. Cultures of fungus can take up to five weeks. So often it's just that preliminary pathology look that's really helpful. In pulmonary cases, often we don't have anything to biopsy. And that's where antigen testing is really key. Antigen testing can be done on blood, on urine, those two are by far the most common sources we use, but it can also be performed on CSF as well as BAL fluid. The turnaround time is fairly quick, even though it's a send out test. And one important thing to note is that there's broad cross reactivity between the blastomyces antigen and histoplasma teleromyces and pericoxidioides antigen. So if there's a risk that they could have one of those infections, you should also order specific tests for those as well, just to kind of ferret out which one is the actual infection here. There are some newer tests being developed, most of them PCR or next generation sequencing based. They're not really on the market yet. So, you know, keep your eye out for those. But right now the focus is antigen testing and tissue biopsy.
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C
Perfect. So in this patient's case, dermatology actually performed a punch biopsy of one of the thigh lesions and that shed broad based budding yeast ongomory methenamine silver staining. And so once we have the diagnosis, how do you approach treatment? I know it's really dependent on disease severity, so could you walk us through that?
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B
Sure. Treatment really depends on severity of the disease. The main break point is amphoteric or no amphotericin. For mild to moderate pulmonary disease, we typically don't use induction therapy with amphotericin. Instead we go right to an oral azole, typically treating for six to 12 months. The azole of choice for blasto, just because it's the most well studied and as far as we know, most effective, is itraconazole for mild to moderate disseminated disease, but without CNS involvement. We take a similar approach using an oral azole right up front, usually treating for about 12 months, so a little bit longer than pulmonary disease. If patients have severe disease, which is typically based on clinical judgment, they may warrant induction therapy with amphotericin. So for severe pulmonary disease, severe disseminated disease, or any of those forms with CNS involvement, or if they're immunocompromised and have any form of blastomycosis, then we would start out with one to two weeks of liposomal amphotericin as induction therapy. You can even extend it if you're not seeing signs of clinical improvement right off the bat. Once you finish that induction, then you step down to oral therapy, which again is oral itraconazole. In immunocompromised patients, you may want to continue lifelong suppression. If it's anticipated they will continue to be immunosuppressed and potentially continually exposed to blastomyces. Itraconazole, like all azoles, does have pitfalls and drawbacks. It has plenty of drug drug interactions. Patients can often report GI side effects and rash and absorption of the drug can be pretty variable. If someone isn't tolerating intraconazole, we'll often switch to an alternative azole like posiconazole or voriconazole. But data is pretty limited and we often have to select the specific agent based on where in the body we're trying to treat. So in those cases, definitely get get ID involved. That's what we live for. Love it.
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C
I always love to hear that. And thank you so much for stepping through all the aspects of how to diagnose and treat blastomycosis before we wrap up. As always, we just want to get the top three pearls that our listeners can take away from this discussion today. And then I also know that you just wanted to include a quick reference to direct our listeners to one of the study websites that you have in case they have any of these cases themselves.
- [15:40]
B
Yeah, I would say that the three big takeaways are that bustomycosis can mimic a wide variety of other conditions. So your workup just isn't quite making sense with your working diagnosis and they have a compatible exposure history. Think blastomycosis. The second point would be considering tissue in your diagnostics combined with antigen testing. And the third point would be that itraconazole is the most well studied oral therapy and should be preceded by induction therapy with liposomal and flotericin in severe cases, CNS disease or any infection in an immunocompromised patient. And then, yeah, if you have any patients with blastomycosis or histoplasmosis or coccidioidomycosis, please send them our way. The website is fungalstudy.org we're doing a large nationwide online study looking at patient reported outcomes and treatment responses. All they have to do is answer online surveys and we'd love to hear from people out there that are being treated for these infections.
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C
Well, thanks so much for joining us again, Matt, and thanks to our listeners for tuning in. We'll catch you next time.
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B
Thank you.