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Felicia C. Chow, MD, MAS: Hello. I'm Dr Felicia Chow. Welcome to Medscape's InDiscussion series on meningitis. Today we'll be talking with Dr Karen Bloch. Dr Bloch is associate division director for clinical affairs and professor of medicine at Vanderbilt University Medical Center. Welcome to InDiscussion. Karen, it's so wonderful to have you join us today. You probably don't remember this, but we met years ago, I believe, through Carol Glaser and the California Encephalitis Project in collaborations that the two of you had on encephalitis surveillance. More recently, you and I worked together on this study evaluating diagnostics for central nervous system (CNS) histoplasmosis. Of course, practicing here in San Francisco, our group contributed at most a couple of cases and specimens to that study, whereas CNS histoplasmosis is something you see much more frequently — everything being relative — in Tennessee. We're going to start with CNS histoplasmosis, and it's such a treat to be able to pick your brain and learn from your experience and expertise. One question that always comes up in practice is the utility of serum and urine antigen testing and serum antibody testing for CNS histoplasmosis, including, of course, patients with meningitis. In other words, if we have a patient presenting with a chronic meningitis, and histoplasmosis is on the differential diagnosis, I'd love to hear your thoughts on how confident we can be that a patient doesn't have Histoplasma meningitis if their serum or urine testing is negative.
Karen C. Bloch, MD, MPH: Thanks, Felicia. What a great question. I first want to step back and thank you for having me on this podcast. I quote your article on temporal lobe encephalitis all the time. It's a real honor to be here. We are in a histoplasmosis-endemic area, we do see a lot of CNS histoplasmosis, and it is a really important question regarding the diagnostics. We have different tiers. We certainly would want to start with the low-hanging fruit, or the easily obtainable samples. If we had a patient with a subacute or chronic meningitis, sending serum or urine antigen testing is a very appropriate first-line study — keeping in mind that about 30% of patients with CNS histoplasmosis will be negative on these tests. A positive result is very helpful, although it doesn't necessarily confirm CNS involvement. A negative result obviously means it's time to search further and do further diagnostic testing.
Chow: Do you think about that differently in terms of an immunocompromised vs immunocompetent patient as far as the utility of the serum and urine antigen testing or serum antibody testing?
Bloch: I do. That's an important point. The antigen testing for histoplasmosis, whether it's CNS, pulmonary, or disseminated is going to be highest yield in our immunocompromised patient. Conversely, antibody testing is going to be lower yield in that population. We know that CNS histoplasmosis is more common in folks who are immunocompromised, whether it's from HIV, organ transplant, or some of the newer tumor necrosis factor-alpha inhibitor drugs. In that population, the antigen tests have a higher sensitivity, but rarely we can see CNS histoplasmosis in immunocompetent individuals. That's a situation where we may see false-negative extra-CNS testing.
Chow: Great. And then what about a false-positive result in terms of the serum and urine testing? Do you sometimes see cross-reactivity, and is it possible you may have a positive result, but it ends up that a patient in fact doesn't have histoplasmosis? And if that is the case, does that level, in terms of how high the result is, also inform this in any way?
Bloch: That's an important consideration. The specificity of the antigen tests is not perfect, and we do see a lot of fungal cross-reactivity. Particularly in our part of the country, Blastomyces cross-reacts almost 100% with the Histoplasma antigen. Now, you could throw your hands up and say they're both endemic fungi and they're both treated fairly similarly, so why does it matter? But I do think there's an important diagnostic point in trying to isolate which fungus it is. And so, yes, when we see a positive serologic antigen test, if the fungus is not growing, we will often send the complementary study. If it's an initial positive result for Histoplasma antigen, we'll send a Blastomyces antigen study. Based on which one is higher, as well as what the antibody studies show us, we'll often be able to make a determination as to which fungus it is before it ultimately grows in culture.
Chow: Great. So that addresses testing from serum and urine. Now let's turn to the cerebrospinal fluid (CSF), which is often key, of course, to making a diagnosis in cases of meningitis. Of the antibody and antigen testing for histoplasmosis that can be done from CSF, which test in your mind provides the biggest bang for our buck? If there is CSF available, and you have high suspicion for Histoplasma meningitis, do you tend to send every test you can from the CSF, or do you prioritize in terms of what's most important?
Bloch: That's a dilemma we deal with all the time. We sometimes call CSF liquid gold because we have so many tests we want to run on it, and often the volume is fairly limited. One thing you didn't mention, and I'm glad you didn't, is how much you reserve for culture. Culture is probably the least sensitive diagnostic test for CNS histoplasmosis, although it is obviously the most specific, and the yield is much higher when you have a higher volume. If you had an unlimited amount of CSF, sending 10 cc for CSF culture would be ideal. Often that's not possible. I do think CSF fungal culture is an important ancillary test, and obviously the results will be delayed. For more rapid diagnostics, it's a little bit of a toss-up. The data show that CSF antigen testing is somewhere around 70%-80% positive in individuals who have CNS histoplasmosis. But an important corollary is one you made earlier, and that is that there is a differential in immunocompromised and immunocompetent patients. So, that 77% is going to be higher in immunocompromised patients and that probability of detection is going to be lower in immunocompetent patients. I'd incorporate some of the host characteristics in my considerations. If I only had enough for one test, the antigen test is one I find very reliable and useful — again, noting that it's imperfect. For an immunocompetent patient, I might veer a little bit more toward that antibody testing, knowing that it's a higher yield in that population. Ideally, if I had enough CSF, I would send both tests. What the studies have really shown is that if you do synergistic testing, you're going to have the highest yield.
Chow: Great. So to wrap up diagnostics for CNS histoplasmosis, tell me a little bit about your thoughts on beta-D-glucan testing from CSF as part of your workup of patients with chronic meningitis in general and specifically when you have a high suspicion for CNS histoplasmosis. I really like using beta-D-glucan testing from CSF. It's not specific per se for a particular fungal infection, but unlike beta-D-glucan from blood — where I've seen a ton of false positives — in the CSF when it's elevated, it definitely raises some alarm bells for me in terms of a possible fungal infection. I'd love to hear more about your thoughts on the CSF beta-D-glucan test.
Bloch: I'm going to answer your question backwards because when I'm thinking histoplasmosis, I don't think it is a particularly helpful test. The sensitivity is only about 50%. When it's positive, it might push you toward that, but it's such a nonspecific test, as you mentioned, so I don't know that I could differentiate histoplasmosis from some other fungal organisms that might cause a positive result like Aspergillus, Candida, etc. That being said, if you asked me my approach to chronic or subacute meningitis, I love it. I'm with you. I use it routinely for immunocompromised patients where Aspergillus is an important concern. I found one or two unexpected cases of Candida in folks that are not the classic population for that. I do think it's an important test when you have a nondifferentiated patient with chronic meningitis. If my suspicion was high for histoplasmosis, I might go right to the more specific tests of the antigen and antibody.
Chow: While we're on the topic of diagnostics in subacute and chronic meningitis, what about next-generation sequencing? Is that something you all are using a lot? What are your thoughts on using it in those patients who are our mystery cases where we don't know what's going on, but they have some sort of a more subacute or chronic meningitis picture?
Bloch: That is an amazing modality and a tool we are probably going to be using more and more. We have used it at our institution. I had a patient test positive not so long ago and it was completely out of left field. It was leptospirosis, which has been reported as a pathogen found in chronic meningitis, and next-generation sequencing is a great way to detect it. You're always weighing the cost-effectiveness of testing. If you have a high clinical suspicion, some of these other tests are probably going to give you the answer. But next-generation sequencing has an important role in folks who are presenting where the first level of diagnostics yield negative results. We're seeing histoplasmosis outside of some of the classic endemic regions. In a part of the country where histoplasmosis isn't all that common and maybe it's not as high on the differential but you have a patient with chronic meningitis who appears infectious, next-generation sequencing is a wonderful modality to get a diagnosis.
Chow: Let's talk about treatment for CNS histoplasmosis. The Infectious Diseases Society of America guidelines for histoplasmosis are from 2007, and in those guidelines they recommend AmBisome (amphotericin B) followed by itraconazole. Obviously those guidelines are quite dated, and a number of newer azoles are now available. Is itraconazole still your go-to azole for the treatment of CNS histoplasmosis? What has your experience been in terms of treating CNS histoplasmosis with some of the newer azoles available like posaconazole or isavuconazole?
Bloch: Medical years are like dog years. The year 2007 is like ancient history at this point. I agree that those guidelines are a bit dated. The initial upfront treatment with liposomal amphotericin is a key component in therapy, and there have been good studies that have shown that individuals who are treated with an azole to begin with vs step-down therapy to an azole do much worse. I agree with the guidance of initial 4-6 weeks of liposomal amphotericin testing. Then it becomes a real conundrum because you're right, the data we have support use of itraconazole, but we also know from pharmacokinetic studies that itraconazole doesn't get into the CNS very well. That's a bit of a challenge. I typically will start with itraconazole. It is a difficult drug in terms of metabolism, so I like to follow these patients very, very closely and make sure they're getting a therapeutic level. The one way I know therapy will fail is if they're not getting adequate levels to cross into the CNS. Alternatives for azole therapy are a little less studied, and it's a little less clear what the alternative should be. Fluconazole is a drug that gets into the CNS very well but is very inactive against histoplasmosis, so I probably would not use that. Some of the newer azoles you mentioned are really appealing. Posaconazole gets into the CNS quite well, and isavuconazole also has good pharmacokinetic properties. I struggle a little bit with this. I'll usually start off with itraconazole, but if patients aren't able to get a therapeutic level because they're on an acid or if they're not tolerating it or if they have strong lower-extremity edema, I'll pretty quickly switch over. I typically would go to posaconazole, but if there's a corrected QT interval (QTc) prolongation issue, there are enough case reports for isavuconazole that I would feel comfortable giving it. This is an area that really needs study and one that hopefully we'll have more defined answers on soon.
Chow: It sounds like a lot of the same challenges we faced with Coccidioides meningitis, which of course is what we see a lot more of here on the West Coast. What about the duration of therapy, Karen? The guidelines suggest about a year of therapy. In your experience, has that been adequate for CNS histoplasmosis? How do you gauge the response to treatment, and when are you comfortable stopping treatment?
Bloch: A year of treatment is a very reasonable approach for patients who are doing well clinically. If they had elevated urine or serum antigens, I use those as markers and trend those. If those have come down to either undetectable or at a nice plateau under 2 ng/mL and the patient is immunocompetent, I'll usually feel comfortable stopping, with the caveat that I want them to be adherent with follow-up. This is a population I worry about a lot. I like these folks to come back for regular follow-up for at least a year and often for 2-3 years to make sure they're continuing to thrive off treatment. The immunocompromised population is tough because the guidelines are a little bit ambiguous. Actually, they talk about indefinite treatment, which at the time they were written, might have been a reasonable approach. But now that we have highly active treatment for antiretroviral treatment for HIV, and we are able to de-escalate transplant patients a little quicker, I'm not sure how realistic lifetime treatment is. The other thing the guidelines say that I struggle with is doing a lumbar puncture at the end of the year and seeing if there are still abnormalities. Honestly, in the few cases where I've done this, I have not found it to be terribly helpful or informative. I like going by the clinical thinking about the host immune status and then trending serum or urine Histoplasma antigens.
Chow: It's really interesting to hear that it sounds like repeat CSF evaluations is not your usual practice and that you go with those other markers you mentioned. Well, we could easily spend the whole podcast on CNS histoplasmosis, but we have many other topics to cover. I want to shift gears and go through some more rapid-fire questions, starting with one of my favorite questions for infectious diseases physicians: What are the top five infections that should run through our mind in a patient who's presenting with rash and meningitis? As a neurologist, I'm pretty terrible with rashes. I have a limited vocabulary for how to describe rashes and to know what to look for. And yet, when I teach our trainees about approaches to meningitis, I always talk about the importance of searching for diagnostic clues outside of the nervous system. The skin, of course, is a big one. Karen, what pearls do you have in terms of rash and meningitis?
Bloch: I also find that a fun topic, and it's a little bit of infectious diseases bingo right there. Let me think about that. At the very top of my list would be meningococcal meningitis. That's the one you never want to miss. And obviously, when I hear the words meningitis and rash, that comes to the forefront. The rash in that case is often purpuric, so it looks like terrible bruising, although it can have a petechial component as well. Something I like to teach the trainees here is the rash may not be present initially, or it can be subtle and it may be difficult to recognize in somebody with a darker complexion. So, really doing a careful evaluation and reevaluating is important, but the combination sure brings that to mind. A second thing, which also is an infectious diseases emergency, although maybe a little bit less urgent, are rickettsial diseases. In our part of the country, the one that we see the most of and that causes the most severe disease is Rocky Mountain spotted fever. That is a petechial rash and, again, the rash may not be present at the time of presentation, so keeping a high level of suspicion, even in the absence of a rash, is important. And then we get to some that maybe are less emergent but where I think the rash is a really good clue to the diagnosis. We don't see chicken pox very often in kids, but in adults, varicella-zoster virus remains an important cause of meningitis, and you can see varicella-zoster virus CNS infections with shingles zoster. You can see it without any skin manifestations, and you can see the skin manifestations arise after the CNS disease, so it can be a little tricky. When I see vesicular lesions, particularly in a dermatomal distribution, it would make me consider the diagnosis of varicella. Another disease we don't see too much in the adult world but that pediatricians are very attuned to is enterovirus meningitis, and often you'll see lesions in the mouth. Herpangina, or hand-foot-and-mouth disease, would be another manifestation of this. I'm struggling with number five, but I'm going to put my money on West Nile virus because I think it's underrecognized that you can see a rash. Rash occurs in about 50% of cases with West Nile fever and a smaller proportion of cases with CNS disease. A rash might be an important clue and during the right time of year, something that might trigger testing for West Nile virus.
Chow: I love that you mentioned West Nile. That one, like you said, is a little bit under the radar in terms of rashes and CNS infections. It's great to hear you include that in your top five. You also mentioned Rocky Mountain spotted fever, which is a nice segue to our next question on tick-borne infections. Often when we think about tick-borne infections that can cause meningitis and other CNS infections, Lyme disease is top of mind, but there are in fact a number of other tick-borne infections in the United States that can cause meningitis. Though again, they're not necessarily always on our radar. Which of the tick-borne infections would you say you think about in the United States that can cause an acute meningitis or meningoencephalitis? Are there any clues that make you think more about some of the maybe lesser-known tick-borne infections in someone presenting with acute meningitis?
Bloch: An emerging tick-borne disease that is highly associated with encephalitis is Powassan virus disease. This is an infection that was not on my radar at all until maybe about 5-10 years ago. There's a number of reasons why there's been a shift. There had been cases previously in Canada and in some of the Great Lakes states, but it's really moved into Lyme-endemic areas. The reason is that the virus has spread by the Ixodes tick, which is the same tick that causes Lyme disease. Powassan virus disease is probably underreported and underidentified, so it's a little bit of an iceberg disease. We're probably seeing the most severe cases, but in most of the cases that are reported, the patients do have meningoencephalitis. It's an important consideration during summer months and particularly along the Eastern seaboard north of the District of Columbia and around the Great Lakes states. Anywhere you could see Lyme disease, you could see Powassan virus disease. The other tick-borne diseases that can cause CNS disease — and I'm a little influenced by my geography — here in Tennessee and in a number of states around the United States is Rocky Mountain spotted fever. That is an important one to consider. Again, summertime is when you might see this disease. Rash is an important corollary but may come on late in the disease course. An important clue in my mind is looking at the blood counts. You'll often see thrombocytopenia, and you'll see elevated liver function test results. Those often trigger me to think about Rocky Mountain spotted fever. A final one is ehrlichiosis, and that can happen throughout the southeast and south central United States. It's spread by different tick — the lone star tick. We sometimes call it spotless Rocky Mountain spotted fever because the clinical manifestations are very, very similar. About 20% of patients will have CNS manifestations. In addition to low platelet counts and high liver function test results, you can sometimes see leukopenia. That can be a bit of a clue.
Chow: What about infections in the differential diagnosis that are tick-borne for patients with more of a subacute to chronic meningitis picture? Does that include some of the infections you just mentioned or are those more for acute meningitis?
Bloch: Typically those are more for acute meningitis. For subacute meningitis, you mentioned Lyme disease, and that could be a whole topic in and of itself, but that's one that might cause a more indolent or subacute presentation.
Chow: Great. In our final minutes, Karen, I want to end with your thoughts on free-living amoeba in the brain, including Naegleria, Balamuthia, and Acanthamoeba. These cause infections that are in general, not very common yet. We hear about cases in the news infrequently. In fact, here at the University of California San Francisco (UCSF), we've had several cases in the past couple of years that feels like a mini-epidemic. Can you tell us a little bit about your experience with free-living amoeba in the brain and when you think about free-living amoeba in terms of your differential diagnosis in someone presenting with a meningitis or with a meningoencephalitis?
Bloch: In my mind, I divide it up into two different categories. In somebody presenting very acutely with CSF studies that suggest bacterial meningitis, particularly during the summer months, and particularly in southern states or states bordering warmer regions, that's when I might think about Naegleria. The syndrome caused by Naegleria is a primary amoebic meningitis or meningoencephalitis, and that's the one that gets all the press with a brain-eating amoeba and these very fulminant and horrible cases. I think that's a very different spectrum from other free-living amoeba such as Acanthamoeba or Balamuthia that cause a much more indolent disease, often with mass lesions of the brain. When I think about those, I think of them as tuberculosis mimickers with the addition of often having, again, a defined CNS space-occupying lesion. They are slower in onset and patients have hypoglycorrhachia and a high protein level — really mimicking tuberculosis to me.
Chow: The cases we've had here at UCSF have been from Balamuthia and have all been in presumably immunocompetent hosts. Is that the usual? Is it typically immunocompetent hosts in whom you see Balamuthia infections, and how does it compare and contrast with Acanthamoeba infections?
Bloch: Most Acanthamoeba infections occur in an immunocompromised host, so that is a defined relationship. Balamuthia infections are a bit different. I think it's a 50-50 split if I remember right, but it certainly can occur in immunocompetent individuals. Both of these are widespread in the environment, so there is a relationship between outdoor work — particularly work that involves exposure to soil and aerosolization of dust — and the development of Balamuthia. Some of the immunocompetent individuals, again, may have been working in an environment where they were exposed through work or through recreation to that free-living amoeba.
Chow: If we have a suspicion for a free-living amoeba brain infection, what do you recommend in terms of how to approach it from a diagnostic perspective?
Bloch: It is tremendously difficult to diagnose and it's really important to make the diagnosis early. A free-living amoeba brain infection is almost universally fatal, especially without very intensive multidrug treatment. This is where I turn to the experts, and there are just incredible resources at the Centers for Disease Control and Prevention (CDC). If I have a patient in whom I might suspect the diagnosis, I go to the CDC website and call their medical officer. They're so helpful in terms of arranging transfer specimens and doing advanced testing that isn't available in commercial labs. In my mind, this is the one situation where bypassing traditional testing through commercial or university-based labs and going right to the CDC might be important.
Chow: Fantastic. Thanks so much, Karen. It's been such a pleasure to have you on today. We've had Dr Bloch discussing diagnostic and treatment pearls for Histoplasma meningitis and key diagnoses to consider in patients presenting with rashes and meningitis, including some of the emergent diagnoses of meningococcal meningitis and Rocky Mountain spotted fever. We have also discussed tick-borne infections that can cause CNS diseases such as Powassan virus disease and ehrlichiosis, and Dr Bloch gave us her thoughts on free-living amoeba that can affect the brain. Thanks so much for joining us. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on meningitis. This is Dr Felicia Chow for InDiscussion.
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Cite this: Brain on Rapid Fire: Viruses, Mycoses, Amoeba, and More - Medscape - Sep 12, 2023.