Previous Next

Time Stamps

• 01:46 Pearl 1: What is invasive fungal disease, and who is most at risk for developing invasive fungal disease?
• 10:35 Pearl 2: What are the main classes of fungi?
• 18:16 Pearl 3: Fungal Diagnostics: PCR/B-D Glucan and Galactomannan
• 29:42 Pearl 4: Blood Cultures, Sputum/BAL cultures, Urine cultures
• 34:14 Pearl 5: How is invasive fungal disease treated?

CME-MOC

• Get CME-MOC credit with ACP!

Sponsor: Oakstone CME’s ACP MKSAP Audio Companion

• Use code CORE30: 30% off effective 11/1/25 through 1/31/26! 

Show Notes

Pearl 1: What is invasive fungal disease, and who is most at risk for developing invasive fungal disease?

• Invasive Fungal Disease (IFD) occurs when fungi invade areas that should be sterile 
  • Bloodstream infections, abscesses in visceral organs (brain, liver, kidney, and spleen)
• The right host is important. 3 major buckets of hosts: 
  • 1)Who:  Patients with suppressed immune systems, especially hematopoietic stem cell transplants, solid organ transplants on immunosuppression, patients on high dose steroids. Mechanism: Immune suppression! 
  • 2) Who: Patients undergoing high risk abdominal surgery. Mechanism: direct spillage
  • 3) Who: Critically ill patients in the ICU. Mechanism: Lines are a conduit for fungal growth 
  • Immunocompetent individuals can also develop IFD. Highest risk is those with structural lung disease.

Pearl 2: What are the main classes of fungi?

• Yeasts
  • Obligate unicellular growth
  • The most clinically relevant yeasts are (most) candida and cryptococcus.
    • Invasive candidiasis is the most common IFD in non-neutropenic, critically ill adult patients in the ICU, and can have a mortality rate as high as 40% in those presenting with septic shock
    • Cryptococcus is typically inhaled and can cause lung infections, but the most feared complication is meningoencephalitis
• Molds
  • Obligate multicellular organisms 
  •  The most clinically relevant molds are Aspergillus and Mucor
    • Aspergillus spores are prevalent in the air, and those with anatomic issues in the lungs preventing secretion clearance (like bronchiectasis) or compromised immune systems are at risk. 
    • Mucormycosis is particularly seen in individuals with advanced diabetes. Inhalation of Mucor spores in this setting can lead to invasive rhino-cerebral mucormycosis, that can invade sinuses, bone, and the CNS, often requiring surgical resection
    • Fusarium is a hyaline mold that causes disseminated disease in profound and prolonged neutropenia in hematologic malignancy patients. Skin manifestations resemble ecthyma gangrenosum, positive blood cultures occur in 50% of cases, and it often spreads to the lungs hematogenously with an appearance similar to septic emboli.
• Dimorphics
  • Mold in the environment, yeast in the host. “Mold in the cold, yeast in the beast”
  • Key examples are the “endemic mycoses”: Histoplasmosis, Coccidioidomycosis, and Blastomycosis.
  • Endemic fungi are no longer strictly confined to their old historical borders
  •  Clinical Pearl: CDC now recommends testing for dimorphic fungi in patients with pneumonia who have failed one round of antibiotics. 

Pearl 3: Fungal Diagnostics: PCR/B-D Glucan and Galactomannan

• • Beta D Glucan 
    • “Pan-fungal marker” detects a cell wall component found in most fungi 
      • Notable exceptions:  Cryptococcus, Blastomyces, and Mucorales
    • Sensitive but Non-Specific: Useful for detecting invasive candidiasis and other fungal infections, but cannot localize or specify the fungus.
    • False Positives Are Common: Can result from IVIG, certain antibiotics (e.g., Bactrim, cefepime), albumin, and dialysis (especially with older cellulose membranes).
    • High values (>500) are more suggestive of true infection; mild elevations may be false positives, especially in dialysis patients.
  • Galactomannan Antigen
    • Detects cell wall components of Aspergillus, Histoplasma, and Fusarium
    • Higher Specificity, Lower Sensitivity: Particularly for Aspergillus; may be negative even in true infections.
    • Susceptible to False Positives: Notably from antibiotics like Zosyn and Unasyn, among others.
    • Cutoffs Vary by Sample: Positive if >0.5 in serum; >1.0 in BAL fluid is more consistent with true infection.
    • Avoid sending galactomannan for patients without risk factors! 
  • Other Tests
    • Fungus-specific antigen tests 
      • Ag test for specific fungi like blastomyces, histoplasma, coccidioides, and cryptococcus
      • A few notable cons: cross reactivity between the different endemic infections, and sensitivity is dependent on the timing of the disease course 
    • PCR tests
      • Available for Candida (T2Candida) and Aspergillus (Septifast)
      • A few notable cons: no standard methods yet and lack of validation of these PCR assay, these tests are often send-outs only and have a longer turnaround time or barriers to ordering

Pearl 4: Cultures

• Blood Cultures
  • Sensitivity averages around 50% for invasive candidiasis. A negative result does not rule out infection, especially in high-risk ICU patients.
  • Repeat Testing: Multiple sets increase yield, but if 3 sets are negative, further cultures are often not beneficial.
  • Candida in blood is never a contaminant and typically warrants an ID consult and antifungal therapy.
  • Candida forms strong biofilms on central lines, which may limit shedding into the bloodstream and cause intermittent negatives.
• Urine Cultures
  • Candida in the urine usually does not indicate invasive disease, particularly in asymptomatic patients.
  •  Unless the patient has textbook UTI symptoms or a recent renal transplant, antifungal therapy is generally not indicated.
• Sputum and BAL
  • Candida is Typically a Colonizer: Growth of Candida from BAL is very common and almost never indicates invasive lung disease.
  • Cutoff for Galactomannan in BAL: A cutoff >1.0 in BAL fluid is more consistent with true Aspergillus infection; values between 0.5–1.0 may be false positives.
• “What and Where” Principle: As with all fungal diagnostics, it’s crucial to ask both “what organism?” and “from where?” to determine clinical significance.

Pearl 5: How is invasive fungal disease treated?

• Azoles
  • Mechanism: Inhibit ergosterol synthesis (a vital component of fungal cell membranes).
  • Examples: Fluconazole, Voriconazole, Posaconazole, Itraconazole, Ketoconazole, Econazole, Isavuconazole
  • Key Points: 
    • Fluconazole and ketoconazole primarily cover yeasts (Candida, Cryptococcus).
    • Newer azoles (e.g., voriconazole, posaconazole) also cover molds.
      • Voriconazole, Posaconazole, Isavuconazole all generally cover Aspergillus
      • Posaconazole and Isavuconazole generally cover Mucor as well (but Voriconazole does not)
    • Voriconazole is first-line for probable Aspergillus (per IDSA guidelines).
  • Drug Interactions: Major interactions with calcineurin inhibitors (e.g., tacrolimus), QT-prolonging agents (e.g., methadone), and CYP3A4 substrates (anticonvulsants, DOACs, statins, and many psych meds)
    • Carefully check a patient’s medication list before starting an azole! 
  • Side Effects: GI discomfort, elevated LFTs 
    • For Voriconazole specifically:  photosensitivity, visual hallucinations, bone pain, hepatitis.
    • Counsel patients to use sun protection during therapy
• Echinocandins
  • Mechanism: Inhibit β-glucan synthesis, impairing fungal cell wall integrity
  • Examples: Micafungin, Caspofungin, Anidulafungin
  • Key Points: 
    • Excellent activity against Candida spp. → First-line for candidemia, especially in ICU or immunocompromised patients.
    • Limited efficacy against molds
• Polyenes
  • Mechanism: Bind to ergosterol and disrupt fungal cell membrane integrity.
  • Examples: Amphotericin B, Nystatin
  • Key Points:
    • Amphotericin B: First-line for severe fungal infections like cryptococcal meningitis and mucormycosis.
      • Toxicity: nephrotoxicity and infusion reactions.
    • Ambisome (the liposomal form) is strongly preferred at most institutions unless in a resource-limited setting due to less toxicity 
    • Nystatin: Used topically or orally (swish & spit) for localized fungal infections (e.g., oral thrush).
• Remember: Local ecology matters! Be aware of local resistance patterns and ask ID to help guide treatment.

Transcript

Dr. Andrej Spec: And we say, well, it’s not there. We invest in diagnosing it. And then we say it’s rare, but because we say it’s rare, we don’t look for it, therefore we miss it. So we say it’s rare and it’s a positive feedback loop and it’s just bad PR. Fungus is common. Fungus is everywhere. Fungus is causing an incredible burden of disease. We just don’t see it.  

Dr. Shreya Trivedi: That’s Dr. Andrej Spec, a transplant infectious disease physician and the director of the Invasive Mycoses Clinic at Washington University. Welcome to the Core IM 5 Pearls Podcast.  I’m Dr. Shreya Trivedi, and I’m joined by…

Dr. Sam Schuetz: I’m Sam Schuetz, a resident physician at Beth Israel Deaconess Medical Center and today we are talking all things invasive fungal disease. 

Dr. Shreya Trivedi: Let’s get started with the pearls that we’ll be covering in this episode. Be sure to test yourself by pausing after each of the 5 questions. Remember, the more you test yourself, the deeper your learning gains. 

Dr. Sam Schuetz: Pearl 1: What is invasive fungal disease, and who is most at risk for developing invasive fungal disease?

Dr. Shreya Trivedi: Pearl 2: What are the main classes of fungi?

Dr. Sam Schuetz: Pearl 3: Fungal diagnostics: What are our options for testing for invasive fungal disease and how good are these tests?

Dr. Shreya Trivedi: Pearl 4: How should we think about blood cultures and urine cultures when testing for fungal disease? 

 Dr. Sam Schuetz: Pearl 5:  What is the treatment of invasive fungal disease?

Pearl 1: What is invasive fungal disease? And who is a t risk for developing an invasive fungal disease?

Dr. Shreya Trivedi: Sam, when you had pitched the episode on invasive fungal disease, I thought to myself that invasive fungal, that’s kind of a vague term. And maybe first and foremost, we should all be on the same page by what we mean by invasive fungal disease. 

Dr. Sam Schuetz: I had the pleasure of sitting down with Dr. Michael Mansour, an infectious disease physician at MGH who simplified things so beautifully.    

Dr. Michael Mansour:  The word invasive to me means that it’s crossed outside to inside. For example, we have Candida normally on our skin, in our mouth, in our gut. Those are outside. The minute you cross over into a bloodstream, deep tissue, I term you now invasive, you’ve now invaded into areas that should be sterile and free of fungi. 

Dr. Michael Mansour: That could be an abscess, it could be a bloodstream infection. Sometimes you’ll see dissemination through the bloodstream and then multiple abscesses in different visceral organs. So invasive, again, is an umbrella term. It can be, unfortunately, incredibly severe. It can be all just local invasion or it could be really disseminated invasion with abscesses everywhere, brain, liver, kidney, spleen.

Dr. Sam Schuetz: Wow. Fungus is truly all among us. 

Dr. Shreya Trivedi: Thank you for that poetic reference. I am genuinely so excited to learn about this. Our patients are sicker more than ever, and we are seeing more and more invasive fungal disease. So this is quite pressing. 

Dr. Sam Schuetz: Yeah, and it’s in part because we have so many treatments for cancer and for autoimmune disease, so that the “at-risk” population keeps growing. Dr Spec even went as far to say, “If you haven’t seen fungus yet, it does not mean it has not seen you” which is just…so ominous! and made me wonder if i’d missed it in my differential in the past.

Dr. Shreya Trivedi: Yeah. Why don’t we solidify when we should be having invasive fungal disease on our differential? And that really comes down to knowing who is at the highest risk.

Dr. Michael Mansour: There’s three big groups there. One is that team that caring for patients receiving chemotherapy, and their bone marrow is just slowly getting ablated as part of their treatment, and their white count is going down to zero. That person is literally at risk in the hospital for translocation of Candida from their normal reservoirs. There’s Candida on the skin and in the gut, and so you worry that with disruption of the GI tract, with no immunity, you’ll have Candida move from inside the gut lumen to, let’s say, the bloodstream. 

Dr. Sam Schuetz: So yes, chemotherapy is a big risk, but the main teaching is  basically any treatment that eliminates key aspects of our immune system puts people at risk. So think of the patient who has had a transplant, or they are taking certain T-cell or B-cell immunosuppressants, and, of course, steroids.

Dr. Shreya Trivedi: The classic teaching on steroids that I learned from the 5 Pearls episode on it was that it’s going to be someone who has been on steroids for more than two to three weeks, on equivalent dose of 20 milligrams of prednisone or more, that’s going to be at highest risk.

Dr. Sam Schuetz: Yeah. And what I took away from that episode is the importance of chart reviewing to look for how many short courses of steroids a patient has been taking. Is this someone who comes in multiple times over the past several months and gets five days of steroids for COPD exacerbations?

Dr. Shreya Trivedi: Yeah. Many people can miss that. Frequent short bursts of steroids does increase your risk of adrenal insufficiency as well as invasive fungal disease. 

Dr. Shreya Trivedi: Great points on a more global view on what’s been going  to their immune system. On to the  second major group at risk is those who have undergone surgery. 

Dr. Michael Mansour: The other big groups of patients are those who are undergoing abdominal or gastrointestinal surgery. So again, you’re just disrupting that Candida reservoir, the gut. Someone’s going to manipulate your bowel, and you’re going through resections and re anastomoses. So those individuals are at risk, one for just mechanical spillage into the abdominal cavity. They’re at risk for abscesses that can end up being Candida, or direct inoculation into the bloodstream.

Dr. Shreya Trivedi: And the third being patients in the ICU, especially the ones with central lines, PICC lines, tubes for drains, with lines for TPN for nutrition.   

Dr. Michael Mansour: That really stems from the skin being a reservoir for Candida. And then what we do in the ICU is we start putting in very large caliber lines, plastic lines that go from skin with a direct conduit to the bloodstream and Candida certainly can crawl down and adhere to that plastic material, grow on that Plastic and then disseminate deep into that person.

Dr. Sam Schuetz:  So picturing candida crawling up lines, it makes sense Invasive candidiasis is the most common invasive fungal disease in non-neutropenic, critically ill adult patients in the ICU. But what’s even crazier to me is that the mortality rate can be as high as 50% in patients presenting to the ICU with septic shock from Candida.

Dr. Michael Mansour: Candida forms one of the best biofilms of all microbes. It sticks to plastic really well. It grows, it secretes lots of extracellular molecules that makes a little community, and that’s biofilm, and those are very hard to get rid of, literally impossible, without taking that line out and replacing it with a new one, I say, nearly impossible to treat through. All guidelines say if you have candidemia, there really is no salvage of a line. It has to come out. And without it coming out, more studies show that your mortality is higher.

Dr. Sam Schuetz: So that’s the ICU but I remember on the general medicine wards, there was a patient who kept fevering despite broad spectrum antibiotics.  

Dr. Shreya Trivedi: And let me guess, someone threw out fungal disease on differential.

Dr. Sam Schuetz: Of course, but the patient really didn’t fit into those categories Dr Mansour laid out. So I pressed our discussants, if immunocompetent individuals can develop invasive fungal disease.

Dr. Michael Mansour:  I can meet patients who, by all measures, have a normal BMI, they have no diabetes, they’re not on steroids, they have a normal immune response, and yet they have an invasive Aspergillus in their lung, and those tend to be anatomic issues. It’s someone who has a history of bronchiectasis from a previous infection, they’ve been left with airway structures that are not as open. Pulmonary toilet is not as good. I lump all of those individuals as anatomic sort of dysfunctions or problems. It’s just a lack of clearance when it comes to secretions, and in those secretions, you can get overgrowth of many things, including fungi like Aspergillus, but also mycobacteria like Mac. 

Dr. Shreya Trivedi: Oh, surprise plot twist. There is actually a fourth category, and it’s patients who have some type of structural abnormality.

Dr. Sam Schuetz: Yes, but the anatomic issue is really mostly in pulmonary patients.

Dr. Shreya Trivedi: Okay, so patients are less likely to get invasive fungal disease due to a urinary tract abnormality.

Dr. Sam Schuetz: Exactly. Before we close out on this pearl, I sat down with Dr. Audrey Han Ngoc Le Mahajan, a transplant infectious disease doc at BIDMC, to talk through the rap that fungal disease sometimes gets for being indolent.

Dr. Audrey Mahajan: Generally, it often does present with fevers with no other clear, localized signs of infection. Those can occur a little bit later. And so it’s indolent. For example, a neutropenic patient who has invasive pulmonary aspergillosis might not have respiratory symptoms at all, but when they present with fevers and you scan their chest, there are diffuse nodularity lesions that make you worry about an invasive fungal infection. A lot of that has to do with the host substrate that generally gets these infections, in that their cell lines are so depleted that they don’t have the typical inflammatory symptoms you would expect in a normal person.

Dr. Shreya Trivedi: I am loving all these explanations. There’s so many good things clicking here, and maybe a good time to recap who is at the highest risk for invasive fungal disease. This is going to be really important, because in Pearl 3, we’re going to talk about fungal studies, and it’s all about sending in the right host. So we’re going to be thinking about people who have, in their one-liner, some kind of suppressed immune system — think chemotherapy, organ transplant. Maybe they’re on some meds that end with -mab or -nib, and they have some history of prolonged steroids or, as Sam pointed out, multiple bursts of short courses of steroids.

Dr. Sam Schuetz: Also, the people with recent major abdominal surgery, where there can be mechanical spillage of Candida, or critically ill patients in the ICU, where Candida can form sticky biofilms in the lines they have. And the fourth surprise risk factor is pulmonary anatomic abnormality that really prevents these patients from clearing secretions as effectively.

Pearl 2: What are the main classes of fungi?

Dr. Shreya Trivedi: All right, so before we get into interpreting different labs and then treatment, we need to have a good foundation on the different types of fungi, which I’ll be honest, has never really stuck for me. 

Dr. Sam Schuetz: Same. Our experts helped us break things down in a very non-intimidating way, and we focused on just the most clinically relevant species under this fungus umbrella.

Dr. Michael Mansour: From a medical mycology perspective, I like to silo three major buckets. The first bucket are the yeasts. These are obligate, unicellular, growth. Examples include some of the Candida — not all the Candida — Candida glabrata is one of those. Cryptococcus, Cryptococcus neoformans, Cryptococcus gattii. Those are obligate yeast. No matter where you grow them, how you grow them, for the most part, they’re growing as single cells. They bud off each other, and then they’ll make a daughter cell, the parent cell — but they’re individual cells.

Dr. Shreya Trivedi: Okay, so a takeaway here is that the two major yeasts, clinically are most Candida, but not all, and Cryptococcus.

Dr. Sam Schuetz:  And just to give Cryptococcus some love, since we talked a lot about Candida in Pearl One — Cryptococcus is usually inhaled and wreaks havoc in the lung, but the most feared complication is meningoencephalitis. I’m always testing for it when I’m getting an LP.

Dr. Michael Mansour: Then we’ll swing all the way over to the far bucket on the right, and those are molds. Those are obligate multicellular organisms. They always grow together, bonded together.

Dr. Shreya Trivedi: What are the most common molds? Aspergillus and Mucormycosis are the most common molds that we see, in terms of invasive mold disease.

Dr. Michael Mansour: There’s a lot of Aspergillus spores in the air, and we all, in an estimated way, are breathing in, on average, about 100 spores per day. But, of course, with normal immunity in our lungs, we would clear those spores and eliminate them. It’s when you have anatomic issues or you have a compromised immune system that those spores now have a chance to really take root, germinate, make mold, and then cause problems.

Dr. Michael Mansour: Many cases of individuals renovating their home,  they’ll tell me, in the last month, we took down a wall, we were expanding the bedroom, we’re adding this to the kitchen and they don’t even have to say they encountered mold. But the act of breaking down that structure, or excavating to build out a basement, and they’re unearthing the backyard, or they’re gardening, or they’re redoing the lawn, or they’re out there working hard in the backyard, or clearing brush out, they’re sitting in the environment. They’re growing in dark, kind of moist spaces. That spore density in the air at that moment is so high, you get exposed to those, and if you don’t have a normal immune response, that’s a perfect setup for having an invasive mold infection.

Dr. Sam Schuetz: Oh, man, I am soaking all of that up. And next time I’m worried about possible mold like Aspergillus, I’ll be asking about any recent home renovations. Do you work a lot with gardening or in the backyard, or any other exposures to moist environments?

Dr. Shreya Trivedi: So far, we have, on one end of the spectrum, we have yeast,  that’s going to be Candida, Cryptococcus. And then on the other end, we have mold — Aspergillus, Mucor. I was trying to think of some way to remember this. It’s like yeast is CC (Candida, Crypto) and then mold is AM (Aspergillus, Mucor). I don’t know if that helps, but somehow it makes something a little bit more sticky. But we covered those two ends. So, what’s in that middle bucket under the fungal umbrella?

Dr. Michael Mansour: The middles are the dimorphics. And they’re dimorphics because they morph their shape. They’ll phase change between molds and yeast. So they sit in the middle. And for the most part, if you grow them at room temperature, in a resource-poor setting, there’s not a lot of nutrients, there’s not a lot of water and moisture. They may grow as molds, and that’s what they’ll grow in the soil. Outside, their spores are released, just like Aspergillus, spores are released, and we inhale them. And once we inhale them, they actually can sense higher protein, temperature, moisture, and it’ll turn on different genes and cause them to then germinate, not as mold, but as yeast. And then they’ll grow as single-cell yeast in us.

Dr. Shreya Trivedi: Oh man, these dimorphic fungi, shape shifters here! All 3 of our reviewers had a handy rhyme, “mold in the cold, and yeast in the heat” to help make it stick.

Dr. Sam Schuetz: Or some preferred “mold in the cold, yeast in the beast” which I actually prefer, little twisted.  So who are these dimorphics? These fungi include our “endemic mycoses” that we all took Step Questions on — Histoplasma, coccidioides, and blastomyces.  

Dr. Shreya Trivedi: I remember these questions too well, and I think it was always about figuring out what region of the country was on the question stem as a clue. And I don’t know, is that really true anymore, with climate change? 

Dr. Audrey Mahajan: Another issue that I think we’re seeing with a lot of endemic infections is that they’re no longer respecting their geographic borders anymore. So, like histoplasmosis kind of being in that Texas, Ohio, Mississippi River Valley areas is no longer the case. I test for histoplasmosis very often for patients who are basically from anywhere on the East Coast. Endemic fungi are no longer just where they’re supposed to be, and it then is leading to us having to think about it more often in patients we wouldn’t necessarily do so. And then it also leads to misdiagnosis, because you don’t expect it.

Dr. Sam Schuetz:  On the topic of misdiagnosis,  I was surprised to learn from our experts that the CDC is now recommending us to test for dimorphic fungi in patients with pneumonia who have failed just one round of antibiotics.

Dr. Shreya Trivedi: Wait, what, really? That’s like a ton of patients, right? Because many patients come in with pneumonia after not getting better from one round of antibiotics, and it definitely has not been on my radar to send off a histo antigen, blasto antigen, and a coccidioides. 

Dr. Sam Schuetz: Technically, you don’t need to send all of these. The CDC still recommends that you test based on the travel history or where the patient is living, if they’re in one of these endemic areas. But we know that these areas are growing.  

Dr. Shreya Trivedi: Okay. Don’t go sending off everything on everyone unless they’ve traveled to all the regions of America or elsewhere. All right Sam, this has been good so far. Let us recap all things on the different fungi.

Dr. Sam Schuetz: Yes, so to recap this pearl on the different types of fungi, and remember, we’re using fungi as the umbrella term. There are yeasts, which are Candida and Cryptococcus. There are molds, with Aspergillus and Mucor. And then, in the middle of those two ends, are the dimorphic fungi, which can shape shift between the two buckets. And these are the endemic mycoses.

Dr. Shreya Trivedi: And we just want to call out the paradox here. On one hand, our discussants are telling us we have to be so judicious about the fungal markers we send and make sure it’s on the right host.

Dr. Sam Schuetz: Yeah. And at the same time, we also want to broaden our differential of who the right host is, because our patients are sicker and more complex, and on top of that our environment is changing. So on one hand we want to keep our eyes as wide open as possible for fungi and still be thoughtful on who you send fungal studies on.

Pearl 3: Fungal Diagnostics: PCR/B-D Glucan and Galactomannan 

Dr. Shreya Trivedi: Okay, now say we do have the right host. We have a good pre-test probability for fungal disease. What tests are we sending off? Are we sending off Beta-D-Glucan Galactomannan on everyone, throw in some crypto antigens and some other things?

Dr. Sam Schuetz: Before we go sending tests, let’s start by understanding the basics of the fungal cell wall. This actually helps me remember the fungal tests and the targets of the antifungals. The cell wall consists of an outer layer of proteins, followed by a middle layer of beta-glucan.

Dr. Michael Mansour: The most part, we see a positive galactomannan in probably you should think, oh, there’s Aspergillus somewhere. 

Dr. Shreya Trivedi: If beta-glucan is in the cell wall of fungi, that’s probably like the broadest test we have in terms of fungal stuff. It’s basically like a pan-fungal marker.

Dr. Sam Schuetz: Exactly. But beta-D-glucan is not a perfect test.

Dr. Audrey Mahajan: Beta-D-glucan is inherent within most fungal cell walls. It is not present, however, in high amounts in three specific fungi: Blastomyces, Mucorales, and Cryptococcus.  

Dr. Shreya Trivedi: It was too good to be true. Beta-D-glucan won’t help us in Blasto, Mucorales, and Crypto, and I’m guessing that’s because things like Blasto and Crypto just have a different cell wall that doesn’t have as much beta-glucan. 

Dr. Sam Schuetz: Yep. And then on the flip side, there are a LOT of causes of false positives for Beta-D-glucan.

Dr. Audrey Mahajan: So, you do, again, have to be careful, because if somebody had invasive candidiasis, a glucan would be positive, but it could also be positive in somebody with just thrush, for example. And so, that’s why it’s sensitive for quite a few different fungal entities.

Dr. Sam Schuetz: And you have to ask yourself, did my patient get IVIG or albumin in the last couple of weeks? Did my patient get certain antibiotics, especially IV beta-lactams? Did my patient recently have dialysis?

Dr. Shreya Trivedi: Dialysis? Really? Like half my patients usually are on dialysis. Does this mean we should just be avoiding sending beta-D-glucan in end-stage renal disease patients?

Dr. Sam Schuetz: That is the consensus. It’s the dialysis membranes that have cellulose that change the beta-D-glucan levels. But, of course, the caveat is that there are newer dialysis membranes that won’t cause this problem.

Dr. Shreya Trivedi: Okay, so it sounds like the general thought is avoid sending BDG in ESRD, or interpret with caution, unless you’re sure you’re at a place that has modern, synthetic membranes for dialysis, fancy, smashy places, or just ask your nephrologist if that’s the case.

Dr. Sam Schuetz: The other thing that was good learning is that when the beta-D-glucan does come back positive, it’s not a binary positive or negative. In fact, our ID friends actually look at the number, and especially when it comes back very high.

Dr. Audrey Mahajan: Like, false positives can only account for so much. Like, somebody getting dialysis, their dialysate membrane is only going to make their beta-D-glucan positive to a small degree, not be greater than 500. So, you have to wonder why certain patients have really elevated fungal markers.

Dr. Shreya Trivedi: That’s good to know. I’m not sure if I’ve ever peeked at the beta-D-glucan level, so that’s something I’m definitely going to start to look at more. All right, I feel like we covered really good ground on beta-D-glucan. I’ve finally understood that test. Sam, walk us through galactomannan.

Dr. Sam Schuetz: Galactomannan measures a carbohydrate component of the fungal cell wall that’s found in Aspergillus, Histoplasma, and Fusarium species.  

Dr. Shreya Trivedi: I hadn’t appreciated for the longest that galactomannan was so specific for just a few fungi — Histo, Fusarium, and I guess the popular one being Aspergillus.

Dr. Audrey Mahajan: The bigger issue is that it’s not very sensitive in general, so it can be negative in individuals who do have invasive pulmonary aspergillosis. But the sensitivity for the galactomannan can be extremely low in some circumstances. So, the galactomannan is more specific than the beta-D-glucan, but the issue with it that we deal with is that it can be falsely positive in certain scenarios, and the literature has shown that it can be positive after receipt of certain antimicrobials. So, that would be Zosyn or Unasyn. Many antimicrobials have been implicated as being reasons for false positives.

Dr. Sam Schuetz: Our tests for fungal disease come with their confounding limitations. And just like beta-D-glucan, the amount of positivity for galactomannan matters, and so does where the sample you’re running a galactomannan on came from.

Dr. Audrey Mahajan: The Aspergillus galactomannan assay usually has a cutoff value of 0.5, and when it’s anywhere above that, it reads off as positive. When we test it within the serum, 0.5 is the cutoff that we generally use to say that this is a positive test for Aspergillus, and you should think about it as a patient having possible aspergillosis. But the cutoff when you send it from a BAL sample, for example, I would consider using a higher cutoff, and therefore ranges between 0.5 to 1 are more susceptible to being a false positive. And I would consider something above 1 to be more consistent with true Aspergillus infection.

Dr. Audrey Mahajan: I feel like the data is pretty strong that beta-D-glucans and Aspergillus galactomannans that are sent from sera in the right host, in hematologic malignancy patients, have pretty good diagnostic accuracy. Ballpark sensitivity in patients with hematologic malignancy is still within the 70 to 80. It’s still not incredibly high, but it’s reasonable. Specificity is higher, and it depends also on where you’re obtaining the galactomannan from, so whether it’s serum or bronchoalveolar lavage galactomannan, and then if you’re using a higher cutoff.

Dr. Audrey Mahajan: I like to think of these fungal markers as more of a continuous result, instead of looking at it as a beta-D-glucan is detected or not. Similarly, with galactomannan, there are cut off points for which you say somebody does have a positive galactomannan or not, but I do look at the numeric value in those tests.       

Dr. Sam Schuetz: Pay attention to where your sample came from. For BAL fluid, you need a higher cutoff — think above 1. And for serum, think above 0.5.

Dr. Shreya Trivedi: I think this reminds me of the fact that a lot of us have fallen into a rabbit hole chasing a positive galactomannan that ends up being nothing. And I think, it’s reps and spaced repetition about being so judicious on who we send off the galactomannan on, who is really at risk for histoplasmosis and, more commonly, Aspergillus? 

Dr. Michael Mansour: Who’s that patient? That patient really needs to have the risk factors for invasive Aspergillus, and that person is someone with anatomic dysfunction. This is your advanced COPD patient, advanced bronchiectasis. Another cohort are those with neutropenia or neutrophil dysfunction. Anybody on the BMT service, anybody undergoing induction therapy with leukemia, admitted with leukemia, all of those patients are at high risk for invasive Aspergillus by virtue of lack of neutrophils. By losing neutrophils and coming in with leukemia is a loss of neutrophils. Your neutrophils have been replaced by tumor. And then, solid organ transplant patients, especially lung transplant patients, are at incredibly high risk for invasive Aspergillus. Sometimes that Aspergillus is found growing on the anastomosis between the large airways being anastomosed to the donor lungs. And I think when we don’t have that, we end up spending a lot of money and a lot of effort running galactomannans, and they make zero impact. It ends up costing the hospital and the healthcare system a lot, and we make no impact whatsoever.

Dr. Shreya Trivedi: Okay. Now that it’s loud and clear, I just want to add, on top of finding the right host, something else that might raise your pretest probability is if there is some concern on imaging. For example, like a deep-seated infection, that would definitely warrant some further investigation. Now that we went over common fungal markers, Sam, can you walk us through what else we have in our arsenal.

Dr. Sam Schuetz: Of course. There are a few other specific fungal antigen tests. You’ll have to actually type out the antigen test for specific fungi like Blasto, Histo, Cocci, and Cryptococcus. There is some antigen test cross-reactivity between the different endemic infections, so I definitely appreciate infectious disease specialist input on these things.

Dr. Shreya Trivedi: Okay, good. Sounds like we have some antigens. What about PCR? PCR is usually pretty good in most things, so is it also helpful in invasive fungal disease?

Dr. Sam Schuetz: There are some PCRs that can help us detect Candida and different ones for Aspergillus, but it’s not like their sensitivity and specificities are foolproof. One meta-analysis we found for Aspergillus PCR showed a sensitivity of 85% and a specificity of 76%. On top of the mediocre test characteristics, there aren’t standardized methods of validation of these PCR assays yet.

Dr. Shreya Trivedi: Ah, bummer! Okay, so we’ve covered a lot of good ground. Let’s summarize some of the salient points. Beta-D-glucan is our broad fungal marker, but heads up, it’s not going to catch blastomycosis, mucorales, and Cryptococcus, because their cell walls are just built differently. On the flip side, we have to watch out for false positives, right? Asking, is the patient on IVIG, albumin, certain antibiotics like Bactrim or Cefepime, or are they on dialysis with that old-school cellulose membrane? That can definitely lead the beta-D-glucan to be a bit misleading. The pro tip here is that the actual numbers can be helpful. A slightly positive could be nothing, but if it’s over, like 500, then fungal disease might definitely be brewing.

Dr. Sam Schuetz: Now, about galactomannan. This one is more specific for Aspergillus, Histoplasma, and Fusarium, but honestly, it’s not super sensitive, and tons of antibiotics can cause false positives, especially those frontline sepsis drugs like Pip-Tazo. And please don’t go ordering galactomannan on everyone! Save it for the patients who actually have risk factors — severe COPD, neutropenia, blood cancers, or transplants.

Dr. Shreya Trivedi: For specific fungi, there are antigen tests, like Blasto, Histo, Cocci, and Crypto have them, but they can cross-react with each other. There is PCR that exists, but isn’t that great in terms of sensitivity and specificity, and then there’s also limits in terms of validation and standardization.  

Dr. Sam Schuetz: And just to say it out loud, if your pre-test probability is high for fungal disease and you are looking in the right host, do not stop the workup just because the test is negative!

Pearl 4: Blood cultures  

Dr. Shreya Trivedi: So, we talked a lot about lab testing. Let’s switch over to the other tab in the EMR and go to the micro section.

Dr. Michael Mansour: If I meet someone in the ICU, ongoing fevers, ongoing pressure requirements, unable to wean off, there’s no obvious source. We’ve imaged, there’s nothing really obvious to explain that. Thinking about Candida should definitely be on that differential. What can you send? Here’s the problem, our diagnostics for fungi are poor. For Candida, a blood culture has a 50% sensitivity. There are lots of studies. Some go down to 10% sensitivity, some will say 80% but the average, and what we teach, is 50%. So, you’re missing a lot of Candida.

Dr. Shreya Trivedi: 50% sensitivity? That’s like flipping a coin on blood cultures catching Candida!  

Dr. Sam Schuetz:  So, remember, Candida is really sticky, and it makes biofilms, and sometimes the blood cultures won’t catch it. Think about Candida in a patient who is still sick and fevering, despite many days of antibiotics and blood cultures are negative.

Dr. Michael Mansour: One trick people like to do is then repeat blood cultures, and so then at least you’re increasing your chance of catching a candidemia. If you have three sets of blood cultures, in my practice and in my opinion, and none of them are positive, I think you’ve exhausted your blood.

Dr. Sam Schuetz: I really appreciate that rule of thumb to increase our yield on catching Candida. And if you do catch Candida in the blood, that is a hard stop.

Dr. Audrey Mahajan: I don’t generally think of a positive Candida culture, a positive growth of Candida from any culture, as being immediately a knee-jerk reason for starting antifungal, unless it’s from the blood. In that case, call ID, you have a problem, and I would never consider that to be a contaminant.

Dr. Shreya Trivedi: Okay, no hand waving that from early yeast growth in the blood is some contaminant. Let’s shift to urine cultures. I think we’ve all been there, an altered patient, some bump in the white count, low grade fever, and then the culture comes back, few yeasts in the urine. And then the question here is, do we go towards treatment or trash that result?

Dr. Audrey Mahajan: I would think about treating positive Candida in urine if somebody has recently been transplanted or has undergone a recent kidney transplant. Otherwise, there are not many times that I would say that somebody should get fluconazole, even for Candida growth in the urine, unless it was truly symptomatic to them. Usually, that’s a colonizer.

Dr. Shreya Trivedi: What about those respiratory samples? We’ve all kind of faced  that moment staring at some “yeast” on a sputum culture or BAL report.

Dr. Audrey Mahajan: Candida growth in the lungs is very common, we’re often presented with scenarios where a patient had a BAL for whatever reason, and there’s Candida on one or two specimens. Candida doesn’t generally cause invasive pulmonary fungal infection, and so there are almost no scenarios where I would treat a positive Candida culture from the lung.

Dr. Shreya Trivedi: Now, throwback to Pearl 2. Yeast is going to be Candida and Crypto (CC) and that is different from mold like Aspergillus, which likes to really make a home in the lungs..

 Dr. Sam Schuetz: The next time I’m hovering over the micro tab of my immunocompromised, fevering patient, I’ll be asking not just what organism, but from where, because context is a big deal in the fungal world.

Dr. Shreya Trivedi: Let’s recap some of the more granular takeaways for patients with a fever with no source, but maybe some lines as a risk factor. I’m going to keep Candida on my radar, but won’t rule it out if blood cultures come back negative. Maybe I’ll send off multiple sets to increase my sensitivity, and if the blood culture does come back positive for fungi, that definitely warrants attention and ID consult.

Dr. Sam Schuetz: And those “few yeast” reports in urine? Unless it’s someone with a kidney transplant or my patient has textbook UTI symptoms – I’m leaving it alone! 

Dr. Shreya Trivedi: Yes. As for those BAL results showing Candida? I’m practically never treating that now – it’s almost always colonization, not invasion. 

Pearl 5: How is invasive fungal disease treated?

Dr. Shreya Trivedi: I am so excited to dive into all things fungal treatment, I learned it so many times, it never stuck for me. And thank you to our discussants, as well as Sam, for finally having something stick.

Dr. Sam Schuetz: Yes, so to understand the treatment, we have to do some spaced repetition to our three big fungal families- the yeasts, molds, and dimorphics. It will also be helpful to remember the fungal cell wall so we can picture our antifungals at work. The cell wall consists of an outer layer of proteins, followed by a middle layer of beta glucan, and the innermost layer is a polysaccharide and ergosterol membrane. 

Dr. Shreya Trivedi: Great. So, with that background, I am ready to re-tackle (restructure) the antifungals that we have in our arsenal.

Dr. Michael Mansour: Big buckets of antifungals that we have readily available are the azoles. Everything that ends with azole, the ketoconazole, the fluconazole, voriconazole, all these azoles block the production of ergosterol. In our cells, we keep our membranes fluid with cholesterol. Fungal cells use ergosterol. That’s a cousin of cholesterol, it’s a related molecule, and they rely on that. All azoles do is block production of ergosterol. You poison that machinery, you don’t make it.

Dr Shreya Trivedi: Azoles essentially starve the fungi of their cholesterol cousin. Okay, now onto the second bucket of our fungal defenders. 

Dr. Michael Mansour: The second big bucket are all the polyenes, like Amphotericin and Nystatin, oral Nystatin swish and spit. Those integrate into the membrane. They bind to ergosterol. They don’t inhibit its production. They bind to it, and they can disrupt the membrane that way.

Dr. Shreya Trivedi: Great. So, rather than blocking production, polyenes like Amphotericin and Nystatin kind of punch holes into the fungal membrane. Then, last but not least, what is our third weapon on hand? 

Dr. Michael Mansour: And then, the third bucket are echinocandins. Examples of echinocandins are micafungin, caspofungin, and echinocandins inhibit a specific enzyme called beta glucan synthase. You don’t make beta glucan. And many fungi rely on that inner layer of beta glucan for structural support and protection. So, without that layer, that’s how you deliver killing there.

 Dr. Shreya Trivedi: Micafungin and caspofungin are essentially destroying the structural support that has beta glucan. But Sam, which drug works best for which fungus?  

Dr. Sam Schuetz: Before we get into it, let’s preface this by saying we’ll talk about what agents are generally the first line, but of course, trust and know your own hospital’s local ecology and your local microbiology data.

Dr. Michael Mansour: But in general, when it comes to azoles, you have your old version of azoles we dial back to, like the ketoconazole and the fluconazole. Those were some of the early azoles. Those only covered yeast. That was it. It was just yeast.

Dr. Shreya Trivedi: Okay. First, some spaced repetition, because, my gosh, anything micro related needs it. What are the types of fungi under the yeast umbrella?

Dr. Sam Schuetz: The classic yeast duo is Candida and Cryptococcus that fluconazole was built to fight!

Dr. Michael Mansour: And then you have the echinocandins. The echinocandins, their big unfortunate gap is mold. It’s a second line agent at best for mold activity. An echinocandin, that’s your workhorse yeast. It’s Candida, it’s some of the dimorphics, but the minute you step into the mold territory, echinocandins sort of fail. They’re second line agents.

Dr. Shreya Trivedi: Echinocandins like micafungin and caspofungin are going to be our go-to for candidemia, especially suspected azole-resistant candidemia, and that is why ID often recommends for patients who say have port of entry:  someone on chemotherapy, abdominal surgery, central lines in the  ICU and they get candidemia, micafungin or caspofungin.

Dr. Sam Schuetz: Great, so to recap where we are at so far: early azoles like ketoconazole and fluconazole are good for the yeast umbrella. Within that, if we are trying to fight some invasive Candida, especially candidemia, we will reach for the echinocandins, like micafungin and caspofungin, because they are broader, especially when someone is very sick. Of course, later when sensitivities return, we may be able to step down to azole therapy for the candidemia.  

Dr. Shreya Trivedi: We talked a lot about early azoles. And I’ve seen a lot of my patients where ID recommended voriconazole or posaconazole. I’ve even had a bunch of patients go home on once-a-day econazole.

Dr. Michael Mansour:  And then you get into the itraconazole, and now later the voriconazole, posaconazole, and isavuconazole. Then you add to the yeast coverage mold, so you’re getting much broader spectrum coverage with the later azoles. And if you’re now confident that you have a probable Aspergillus infection, current IDSA guidelines say that the agent of choice is an azole. An azole is the agent of choice, and that agent is voriconazole.

Dr. Sam Schuetz: So, the later azoles are great broad spectrum agents. And what makes the later azoles like voriconazole more broad is that they help us cover mold in addition to yeast.

Dr. Shreya Trivedi: Voriconazole may be our Aspergillus superhero, but every superhero has kryptonite. What side effects should you warn your patients about before they walk out the door with that prescription?

Dr. Michael Mansour: One, the photosensitivity, if this is summertime, can be pretty intense. I’ve had patients who have started voriconazole and then walked from their car through a parking lot to a grocery store, and a little bit of sun exposure has caused sunburns. It’s really intense. It’s sort of the same counseling we give patients if they’re on doxycycline. You really need to counsel, long sleeves or sunscreen while you’re on voriconazole, especially in the summer months.

Dr. Michael Mansour: Other things are you may get some visual hallucinations. You may see some different types of dreams, and all those kinds, resolve on their own. Other things are bone pain, which are longer term things. Bone pain because of high fluoride content is something that’s a large issue.

Dr. Michael Mansour: Things that lab work will hopefully catch before you see onset of symptoms — hepatitis, you can see some kidney dysfunctions and other things. If someone needs to be on long term voriconazole, we’re screening with blood work. 

Dr. Sam Schuetz: Sunburns, hallucinations, bone pain — voriconazole packs a real punch! Our pharmacy reviewers taught me that the weird dreams and visual effects from voriconazole can be related to serum levels that are too high. Fortunately, this can be fixed with dose adjustment.

Dr. Shreya Trivedi: Nice. I am glad that’s the case. Posaconazole has its own challenges, liver issues, GI upset, but I think the bigger headaches are just the day-to-day things.

Dr. Michael Mansour: I would say nowadays, the QT drug, drug interactions, and then insurance coverage, like, who’s going to pay for this, for these drugs, are the three things we sort of juggle.

Dr. Shreya Trivedi: And of those, the drug interaction minefield. What are some major drug-drug interactions we should be anticipating before the pharmacy calls us?

Dr. Michael Mansour: Things I worry about, seeing transplant patients, are the calcineurin inhibitors like tacrolimus. You can absolutely skyrocket tacrolimus levels starting an azole, and then someone says, oh, okay, we’re done. Aspergillus is treated, now we’re going to stop the posaconazole. They unfortunately end up being at risk for a rejection episode, because now the tacrolimus level just bottoms out, and we haven’t resumed their normal dose from before the azole. You have to be incredibly careful with anti-seizure medications, pain medications, and things like opioids. Methadone, for example, is a QT prolonger.

Dr. Sam Schuetz:  And last but definitely not least, the nuclear option of antifungals. The one we all respect and fear in equal measure: the polyenes, particularly amphotericin.

Dr. Andrej Spec: It’s hard to get a good antifungal that doesn’t also happen to be a good anti-human. Amphotericin is kind of the old one, the polyene. It is still the best antifungal we’ve ever made. Nothing kills fungus as well as Amphotericin does. The problem with it is that it’s also a pretty good anti-human. Amphotericin is IV. It is toxic. It is difficult to manage in terms of kidney and infusion reactions, but it does work really well, and it tends to be my go-to drug for most serious cases. 

Dr. Sam Schuetz: “Ampho-terrible” earned its nickname honestly, but it remains our go-to for the most serious infections like cryptococcal meningitis and mucormycosis. Fortunately, nowadays we have the liposomal form of Amphotericin, called Ambisome, which is much less toxic than the original formulation.

Dr. Shreya Trivedi: Yes and yes. And with that, let’s wrap this up with a quick cheat sheet you can keep in your white coat pocket or, at this age, Patagonia pocket. So, our antifungal arsenal is a trinity: azoles, echinocandins, and polyenes. Newer azoles like voriconazole or posaconazole tackle tough molds like Aspergillus. Older azoles like fluconazole crush Crypto and Candida, especially superficial Candida and Candida we know is sensitive to azoles.

Dr. Sam Schuetz: But who is the true Candida workhorse, also known as the empiric big guns that treat candidemia and deep-seated infections? We reach for echinocandins like micafungin and caspofungin. And Amphotericin? The fungal nuclear option, effective against almost everything but at a possible significant cost to the host.

Dr. Shreya Trivedi: I loved learning what to tell our patients if they go home on voriconazole. I’m counseling patients to wear long sleeves to avoid sunburns, and to let us know if they experience visual hallucinations or bone pain so we can assess if a dose adjustment is needed.

Dr. Sam Schuetz: And then, last but not least, I still remember Dr. Mansour’s zinger of the best treatment for fighting fungi.

Dr. Michael Mansour: So, we’ve talked about all our different buckets of antifungal drugs, but really, the best agent of all, better than Amphotericin, is your own natural innate immune response.

Dr. Shreya Trivedi: That is all for today. Thank you so much for listening. If you have ever gotten any value from the podcast, please share this with at least one other colleague who might also get something out of the episode.

Dr. Sam Schuetz: Thank you to our reviewers, Drs. Matthew Lee and Todd McCarty, and Pharmacist Kendall Bell. Thank you to Amy Mu for the accompanying graphics. This episode was made as a part of the Digital Education Track at BIDMC.

Dr. Shreya Trivedi: Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

Dr. Andrej Spec: Really, a lot of it has to be on us as physicians to remember that fungi exist. And it’s unfortunately all too common that fungi end up being the hindsight — they end up being the diagnosis we stumble into, rather than the diagnosis we thought of ahead of time and made

References

• Bassetti M, Giacobbe DR, Agvald-Ohman C, et al. Invasive Fungal Diseases in Adult Patients in Intensive Care Unit (FUNDICU): 2024 consensus definitions from ESGCIP, EFISG, ESICM, ECMM, MSGERC, ISAC, and ISHAM. Intensive Care Med. 2024;50(4):502-515.
• Douglas LJ. Candida biofilms and their role in infection. Trends Microbiol. 2003;11(1):30-36.
• Salmanton-García J, Cornely OA, Stemler J, et al. Attributable mortality of candidemia – Results from the ECMM Candida III multinational European Observational Cohort Study. J Infect. 2024;89(3):106229. 
• Kousha M, Tadi R, Soubani AO. Pulmonary aspergillosis: a clinical review. Eur Respir Rev. 2011;20(121):156-174.
• Ashraf N, Kubat RC, Poplin V, et al. Re-drawing the Maps for Endemic Mycoses. Mycopathologia. 2020;185(5):843-865.
• Center for Disease Control. Surveillance for Coccidioidomycosis, Histoplasmosis, and Blastomycosis — United States, 2019.
• Prattes J, Schneditz D, Prüller F, et al. 1,3-ß-d-Glucan testing is highly specific in patients undergoing dialysis treatment. J Infect. 2017;74(1):72-80.
• Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-e50.
• Herrera LN, Khodadadi R, Leal S, Kulkarni P, Pappas P, McCarty T. Clinical Utility of Routine Use of Fungal Blood Cultures. Am J Med. 2023;136(6):514-517.
• Alves J, Alonso-Tarrés C, Rello J. How to Identify Invasive Candidemia in ICU-A Narrative Review. Antibiotics (Basel). 2022;11(12):1804. Published 2022 Dec 12.
• Mercier T, Castagnola E, Marr KA, Wheat LJ, Verweij PE, Maertens JA. Defining Galactomannan Positivity in the Updated EORTC/MSGERC Consensus Definitions of Invasive Fungal Diseases. Clin Infect Dis. 2021;72(Suppl 2):S89-S94.
• IDSA. Clinical Practice Guideline for the Diagnosis and Management of Aspergillosis: 2016 Update by IDSA.