Dr. Gary Procop, CEO of the American Board of pathology and professor of pathology at the Cleveland Clinic, Lerner School of Medicine discusses the importance of early detection and diagnosis in order to prevent fungal invasion leading to poor outcomes, particularly in immunocompromised patients. He emphasizes the importance of thinking fungus early, shares his passion for mentoring and talks about key updates in the recently released 7th Edition of Larone’s Medically Important Fungi.
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Ashley's Biggest Takeaways
- Many invasive fungal infections are angiotrophic, meaning they actually grow toward, and into, blood vessels.
- Once the fungus has penetrated the blood vessel, the blood essentially clots, causing tissue downstream from the blood clot to die (infarction).
- When tissues that have been excised are viewed under the microscope, hyphal elements can be seen streaming toward or invading through the wall of the blood vessels. Once the clot forms, those hyphal elements can be seen in the center of the blood vessel where only blood should be.
- Antifungals cannot be delivered to areas where the blood supply has stopped. Therefore, treatment requires a combined surgical and medical approach, and the process is very invasive.
- Early detection can prevent these bad outcomes by allowing antifungal treatment to be administered before angioinvasion occurs.
Featured Quotes:
Diagnostics – Think Fungus EarlyThe variety of different types of diseases that these organisms cause, in some ways, they're a little bit underrepresented. You know, we have important molecular diagnostic tests for transplant-associated viruses CMV (cytomegalovirus), BK (Human polymavirus 1), EBV (Epstein-Barr virus). But we still have transplant patients that are succumbing to invasive fungal infections. And the types of tests that we have are really limited—often limited to culture, antigen detection tests, those types of things, and some histopathology. You know, we really haven't yet exploited the power of molecular diagnostics in a routine way for mycoses.
One of the issues is that these organisms are underrepresented, or less frequently encountered. The other issue is there's such a great variety of different types of fungi that can cause infections in these patients that you can't build one single assay, or it surely has proven difficult to do so. But with the advent of next generation sequencing—you know, kind of broad range PCR—there's hope on the horizon for advanced diagnostics for early detection. And the real key is early detection of fungal infections in immunocompromised patients.
From a purely pathophysiologic standpoint, once an organism gets into an area where it shouldn't be, that would be the earliest phase of infection. Of course, it's always number one to do our best to maintain host defenses, which of course, is not always possible. And after invasion [we want to] understand how we can treat these organisms most effectively.
The problem with our responses to injury or infection is they're often nonspecific. So, we have swelling and redness and fever. And so those things are common to bacterial infections, fungal infections, a variety of different types of injury. So, they're really quite nonspecific. Somebody's getting a fever, it could be anything.
You bring up an important point, often fungi are not the number one cause [of disease]. So, folks are going after the number one cause with regards to treatment. And it's kind of quite far down the line when the patient isn't responding to treatment that the light bulb goes off—well, maybe it's not a bacterial infection, after all; it could be fungal. And now it's 2 weeks into antibacterial therapy, and the fungus has been invading that whole time.
That’s why we need advanced diagnostic tests that can actually tell us, so it's not just guessing. And who knows, it may not be a test that detects the fungus itself, it may be a human immunologic profile—an RNA profile or something like that—that actually gives us the right answer.
There are, fortunately, a lot of smart people working in these spaces. So, I'm just waiting for that breakthrough where we'll have a diagnostic test that will help signal early fungal infection. Because we do have some very effective antifungal drugs, and, again, we [want to] get those antifungal drugs on board, prior to the organism being deeply invasive.
Mycology and histopathology really work hand in hand. And you know, this is honestly sometimes a difficult concept, it doesn't seem like it should be. But to get across to some of our surgeons, when removing potentially infected tissues, you need to make sure that part of it goes to the mycology laboratory, and that it doesn't all get put into formalin and sent the pathology.
I really think this is a national quality metric that could be pushed forward. Talk to any microbiologist, and you'll get a rise out of them when you talk about how many times does the tissue all get dumped into formalin. Somebody finds a microorganism in the tissue, and now we have nothing growing in microbiology. So, really a quality issue.
You know, I tell you, when you can reach the diagnosis that everybody's been grasping at, that just kind of makes you feel like, that's why I'm doing this. That's probably the most rewarding, when you can you can feel like, even though you may not have ever met that patient at the bedside, that patient is getting better because either you, with your microscope, or your team and the laboratory, etc. were able to make the diagnosis when no one else could.
Antifungal Resistance
Antifungal resistance is very different from antibacterial resistance. I mean, these really are apples and oranges. The reason is that we have eukaryotic organisms with fungi, and we have prokaryotic organisms with bacteria. Prokaryotic organisms are pretty promiscuous in the exchange of genetic material, and there are many different ways that they exchange it. It's just not the same for eukaryotes.
So, that being said, the genome of fungi is much more stable. And we will often say, if you can get to the identification, you've got some good information about the likelihood of responses to certain drugs. In my mind, anyway, identification becomes priority to antifungal susceptibility testing.
That doesn't hold true for all organisms; we know there are some that you can't predict their profiles, like Fusarium, etc.
The CLSI antifungal susceptibility subcommittee has been working on and publishes what's called epidemiologic cut off values, or ECV’s. And essentially what they've done is they've gotten these less-common fungi—usually ones that we won't have enough in clinical trials to get breakpoints for—and they test them in numerous laboratories. And they look at what is the normal distribution of these fungi with respect to MIC’s (minimal inhibitory concentrations) against different antifungals.
And so, from that, you can kind of see how are these fungi probably going to act. And from that, as well as clinical trials, that group has also worked on lists of fungi that have intrinsic resistance. So, for example, you always know that Candida krusei is intrinsically resistant to fluconazole. So, I think knowing what the intrinsic resistance profile is, is very important. And then, if you have an identification, that can be used to help guide therapy.
Larone’s Medically Important Fungi: A Guide to Identification
I have known Dr. Larone for many, many years, and we've given presentations together, and she is just an amazing lady. We've used that book, and I've seen how the medical laboratory scientists at the bench have used it. You can tell when a book is good when it's falling apart, right? People are using it so much. That's that kind of book that this is.
First of all, it was just an honor to be able to try to contribute to it. Look at these coauthors I was asked to be with! It's as if I was a rhythm guitar player, and they asked me if I wanted to sit in with The Beatles. So, the other authors are just superstars. Just really an honor to be with them.
I will say, we really worked hard on updating this book, and I really hope the users will be pleased. I really tried to update the histopathology section with regards to descriptions of fungi in tissue, etc.
Fungal nomenclature changes quickly. I think we took a very reasonable, middle-of-the-road approach to that. That's well described in the book, and it will really be in sync with other documents that are out are coming out. We really tried to make sure that even if the name has changed, the important information is conveyed appropriately to the clinician, so they know what's going on.
Mentoring
I had a very good mycology professor in undergrad. And I think that's probably an important point to underscore: we've studied individuals that go into pathology—because a lot of people that finish medical school, don't go into pathology—and most of [those that do] can connect the dots back to a mentor. So, I think having somebody really important early in life that demonstrates how interesting a certain field of microbiology could be, that probably is what got me interested in medical mycology.
Be active in seeking out a mentor. You know, folks are busy. We're all too busy. And established individuals, I think probably if they're in academics, that's why they're there. And they would love to be a mentor. Sometimes they don't really know your interest, etc. So, no matter what your interest is, scope out the faculty, find somebody that you think would be great to work with and introduce yourself to them. Take an active role in finding a mentor.
And, of course, to all of our established people, be a mentor. If somebody asks you, you know, say yes, and help them along. It's all about paying it forward.
The other thing I've told my residents this year is that you’ve really got to follow your heart. Do what you love, and 20 years from now, and you'll still be doing it.
Links for the Episode:
- Expand your clinical mycology knowledge with the recently released Written by a new team of authors, Lars F. Westblade, Eileen M. Burd, Shawn R. Lockhart and Gary W. Procop, this updated edition continues the legacy of excellence established by founding author, Davise H. Larone.
Since its first edition, this seminal text has been treasured by clinicians and medical laboratory scientists worldwide. The 7th edition carries forward the longstanding tradition of providing high-quality content to educate and support the identification of more than 150 of the most encountered fungi in clinical mycology laboratories.
Get your copy today with $1 flat rate shipping within the U.S. or ASM members enjoy 20% off at checkout using the member promo code.
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