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Felicia C. Chow, MD, MAS: Hello. I'm Dr Felicia Chow. Welcome to Medscape's InDiscussion podcast series on meningitis. Today we're discussing everything you need to know about managing Cryptococcus gattii meningitis in immunocompetent patients with Dr Sharon Chen. Dr Chen is the director of the Centre for Infectious Diseases and Microbiology Laboratory Services, New South Wales Health Pathology at Westmead Hospital in Sydney, Australia. Thank you so much for joining us today all the way from Sydney. I'm so delighted to have you join us to talk about C gattii meningitis. We haven't met before, but I have read so much about your work in C gattii especially in the last couple of years. Where I see patients here in San Francisco, California, we have really seen an uptick in the number of patients presenting with C gattii meningitis. It has blown me away in terms of how different these patients can be compared with patients with HIV or even transplant patients presenting with Cryptococcus neoformans meningitis and also how challenging it has been to take care of some of these patients. I don't want to waste any time because I have so many questions for you. Maybe you could start, Dr Chen, by telling us a little bit about the practice setting in which you work and how frequently patients with C gattii meningitis are seen in your hospital and in your clinics.
Sharon C. Chen, PhD, MBBS: Thank you, Dr Chow. I'm an infectious disease physician and microbiologist, and I work in Westmead Hospital, a busy tertiary referral hospital in Sydney. It has transplant services, intensive care unit (ICU) services including neonatal ICU services, neurosurgery, and the major specialties. We are the referral for a lot of the country centers, as well. In terms of cryptococcosis, we will see maybe five to eight cases a year, of which half will be due to C gattii and the other half due to C neoformans. Although C gattii meningitis is an interest of mine and the interest of many of my colleagues, we do see C neoformans meningitis, as well.
Chow: We're so much more familiar with C neoformans meningitis, at least here in San Francisco where I see it especially in our patients living with HIV. And we also see C neoformans meningitis in patients who are immunocompromised for other reasons. But with the C gattii patients we've seen — and as I said, we're seeing a lot more of them in the recent years — I have been struck by how differently these patients can present and how different their disease course can be. Can you speak a little bit first about the typical patient who is infected with C gattii, which patients present with C gattii meningitis, and then some of the risk factors for C gattii infection?
Chen: Thank you, Dr Chow. The typical patient with C gattii meningitis is not someone living with HIV and probably not someone with an organ transplant, although we do see organ transplant patients infected with C gattii. They're typically apparently immunocompetent, although the definition of immunocompetent is often a subject of discussion. What do we mean by immunocompetent? Do you test all patients for an underlying immune deficiency you do not usually test for such as CD4 lymphopenia, immunoglobulin subclass deficiencies, and so on? In terms of the risk factors for C gattii infection, that's a difficult question to answer because there are few case control studies. There were one or two performed in the outbreak setting when Vancouver Island and Canada had an outbreak because there were many patients, and it was a cluster that was easily identifiable. The two main risk factors in that setting were patients with cancer and patients who smoked. However, in Australia and in many other countries, we see C gattii infection as sporadic cases of infection within an endemic setting. In the absence of a cluster setting, those risk factors are much, much less evident if they're true at all. Apart from the apparently normal hosts, I think it would be fair to say that we have looked at exposure — exposure to a putative environmental source. We've all read about the gum trees in Australia and California and even in Vancouver Island where they do have eucalyptus. There's also other sorts of vegetation that might lend patients to exposure. And then we have the domicile of residence. Are people living in more regional areas or in country areas more susceptible due to exposures? What about agricultural and work factors? There's a tendency of C gattii infection to occur in men. Are they more exposed because of their occupations, working in agriculture and in the country? There's a theory of genetic factors, as well. I know that this hasn't been proven, but we have read that Australian Indigenous populations are more at risk for C gattii than non-Indigenous populations. There have been a couple of human leukocyte antigen studies, but they were by no means conclusive. Identifying the risk factors is a work in progress. To briefly summarize, the mainly apparently immunocompetent patients are more at risk, and there are the theories of exposures to environmental sources, but there are definitely no causal or definitive links to any one source as of yet.
Chow: The point you made about the apparently immunocompetent host is a really good. I like it when people use the term previously healthy because that's descriptive, at least regarding them not having any identified immunocompromising condition up until the point they present with C gattii meningitis. Just to make this clear, medical students love to talk about C neoformans infection and exposure to pigeons, for example. With C gattii then, from what you're saying, that isn't something we should really be looking for or thinking about. Is that fair?
Chen: We always ask in our history taking about exposure to gum trees or various other vegetation. We always ask about exposure to pigeons even before you know the meningitis is due to C neoformans. But the link, even with molecular typing, I would think is not definitive. To put the finger on the gum tree or on the pigeon is probably premature even at this stage.
Chow: Okay. And what about in terms of how these patients present with C gattii meningitis? Is headache the big thing we should be looking for, or do these patients present differently than our typical C neoformans meningitis patients?
Chen: Headache is a common presentation, and it would be hard to diagnose anyone with meningitis if they didn't come to your clinic or to the hospital complaining of headache warranting a lumbar puncture. There has been a number of studies, including from the United States, Canada, Australia, and Asia, comparing C gattii and C neoformans. Central nervous system (CNS) infection and meningitis and headache seems to be more common in patients presenting with C gattii meningitis. Having said that, headache is a very common presenting feature in both species of infection. What we've noticed — and I think it's the same in the United States and Canadian studies — is that patients with C gattii CNS infection are more likely to have brain disease. So cryptococcomas and mass lesions, if they have them, often tend to be large. In the Australian series, about 30%-40% had mass lesions in the brain. Hydrocephalus is also apparently more common in C gattii disease. I will qualify this by saying you need to know what the patterns of disease are in your country, in your region, and even in your institutions. What is more common in Sydney might be different in Western Australia. You can't always assume patients will be presenting with a blueprint of what you might think is C gattii infection. We're talking about meningitis today, but cryptococcosis also affects the lungs, so we should not forget to look there. With C gattii disease, you often find more mass lesion–type abnormalities. You can get nodules, of course, in C neoformans disease, but they tend to be smaller and maybe more frequent, but less coalescent and less large. The most dramatic patient I saw who eventually had meningitis as well presented with a Pancoast-type syndrome. When you asked him to raise his arms above his head, it was like the case in a medical student's exam — he went blue and, thankfully, there were people around to make sure he didn't come to any demise. So it's not just about CNS infection — look elsewhere.
Chow: It's really helpful to hear about some of these differences. For example, you might expect to find a brain cryptococcoma on brain imaging with C gattii patients, as you mentioned, whereas in our HIV patients with C neoformans, it's not that uncommon to see a totally normal brain MRI, for example. I also wanted to ask you about cerebrospinal fluid (CSF) diagnostics and the CSF profile in patients with C gattii meningitis. Is it pretty comparable to what you would expect in someone with C neoformans meningitis? We generally think about, for example, the cryptococcal antigen testing from both serum and CSF as being quite sensitive for C neoformans infection, including meningitis. Is that the same for C gattii meningitis, and is it usually a cryptococcal antigen and CSF culture you're using to make the diagnosis?
Chen: Yes, and I would agree with everything you said. It's not hard to diagnose C gattii meningitis. The serum cryptococcal antigen test is sensitive, so we should start there. But on the CSF test, the parameters are the same. You get your lower glucose, your higher protein, and your positive antigen titer, and you frequently grow C gattii from the CSF — at least that has been our experience. I know there are a number of kits now that can be used to diagnose cryptococcal antigen in CSF. There's the lateral flow assay kit, and then there is the latex agglutination kit. They are comparable in sensitivity, and you can pick C gattii meningitis as easily as you could pick C neoformans. We're not talking about veterinary disease today, but you could also diagnose veterinary C gattii meningitis by the usual complement of tests. It's not a difficult disease to diagnose, and you do not need fancy molecular tests. Of course there are polymerase chain reaction–based tests now, but by and large, it's still culture based and antigen based.
Chow: Once you have made the diagnosis and you're caring for a patient and thinking about how to treat them, what about the impressive inflammatory response we've seen in a lot of our patients with C gattii meningitis with very high intracranial pressures? Some patients even require a decompressive craniectomy and a shunt of some kind. That's something I feel is uncommon in patients with C neoformans meningitis or, for example, a patient with HIV. I'm curious to hear a little bit more about this and whether that inflammatory response in some of these patients is a result of them often being apparently immunocompetent or if it is more related to the species of Cryptococcus itself.
Chen: That's a really interesting question. My feeling is that it's the host response rather than the species because we do see a lot of these complications in apparently normal hosts with C neoformans infection and in non-HIV infected but otherwise immunocompromised hosts with C neoformans infection. Like a systemic lupus erythematosus patient with bad C neoformans disease, you often encounter hydrocephalus, raised intracranial pressure, and so forth more often than in an HIV patient. I think it's the host response rather than the species because we do see the impressive inflammatory response with C gattii, but we also see it with C neoformans.
Chow: Has it also been your experience that these patients with C gattii meningitis tend to need a shunt much more commonly than your typical patient with C neoformans meningitis?
Chen: If you compared them to an HIV patient, yes. But if you compared them to all C neoformans patients — and normal hosts get C neoformans, as well — if you take 100 normal hosts, 50 will have C neoformans and 50 will have C gattii, at least in our local setting. So it is an interesting question. I don't think we would see more need to shunt a C gattii patient in a normal host than the C neoformans patient without HIV infection. But the last few we've shunted have all been C neoformans infections in non-HIV infected individuals.
Chow: Very interesting. It really does get to the fact that it is more likely the host as opposed to the pathogen.
Chow: Okay. Let's now talk about the general approach to treatment, starting with induction therapy for patients with C gattii meningitis. Are there differences in terms of your approach to induction therapy, the agents you use, and the duration of induction therapy in a patient with C gattii vs C neoformans meningitis?
Chen: Yes and no. There are no differences in the choice of antifungal therapy. You can read all the Infectious Diseases Society of America (IDSA) guidelines, the European Confederation of Medical Mycology guidelines, and even the Australian guidelines. We would all agree that for CNS infection, you would use a combination of a lipid amphotericin formulation plus 5-flucytosine, so you can offer the patient the best chance of clearing the CSF. We would do the same for a patient with C gattii meningitis. The difference is the duration of the induction therapy. For your typical HIV patients, it is a 2-week course, and if you read all the studies coming out of Africa now, you might use a single dose, a high dose, and maybe opt for a shorter duration. But we have found that if you lumbar puncture your typical C gattii meningitis patient at 2 weeks, you find that about a quarter of them still have a positive CSF test result. By that, I mean growth of C gattii from culture, meaning that you still have active disease. Therefore, we do not typically recommend a 2-week duration for induction therapy but at least 4-6 weeks. I know the IDSA guidelines recommend 4 weeks. In Australia, we tend to treat for 6 weeks because longitudinal retrospective studies show that you need the 6-week mark to clear the CSF of C gattii. If you want to catch all C gattii, it depends on how dogmatic you want to be, and therefore it is 6 weeks for us. We also know that by following all the CSF parameters — and again this is retrospective study — it's about 6 weeks until the glucose level is back to normal and the white blood cell count reduces. I know we aren't supposed to rely on falling titers to monitor therapy, but we really like to see it going in the right direction rather than the wrong direction. We go for the 6-week mark, and I know this has been debated in many circles, but our experience tells us that this offers our patients the best chance. One of my teachers talks about induction, consolidation, and maintenance therapy for HIV patients but induction, consolidation, maintenance, and eradication for patients with C gattii meningitis because you actually can cure the patient — unlike your HIV patient who is offered the best chance. In that case, they are doing well with highly active antiretroviral therapy. But cure is a slightly different concept in an HIV patient than in a patient with C gattii disease or a normal host.
Chow: This leads to a follow-up question, which is that if you're thinking about maintenance and then eradication, what are you thinking about the duration of that period of treatment? After induction therapy, patients are presumably on an azole therapy, and they've been on it for a period of time. In someone with HIV, you're waiting for their immune system to reconstitute for a period of time and then you feel comfortable stopping their fluconazole or whatever therapy they may be on, but obviously this isn't applicable for many patients with C gattii meningitis. How do you approach this in terms of when you feel comfortable stopping their maintenance treatment?
Chen: If the initial imaging results were normal, we would still perform follow-up imaging at 3 months and 6 months to look for new lesions or immune reconstitution inflammatory syndrome (IRIS) — and I know that opened up another can of worms. If the imaging results were abnormal in the first place, we would definitely use follow-up imaging, particularly at the 6-month mark. This is where new lesions or progression of disease would take place — hopefully that's not too common — and then it would help inform how long you go for your maintenance therapy. Our retrospective studies have shown that by 12 months of maintenance therapy, you still have a substantial portion of patients who could be labeled as having partial response according to your Mycosis Study Group Education and Research Consortium criteria. To get a complete response, you really have to go up to the 18-month mark, and many infectious disease physicians who look after patients with C gattii infections would hopefully support the notion that 12 months of therapy is probably not a long enough duration in the majority of patients with C gattii meningitis.
Chow: Can you tell us a little bit more about what you mean by complete response and what you're looking for?
Chen: A complete response is more than a 90% reduction in the imaging abnormalities. If you have a large cryptococcoma, you would like to see it shrink to almost nothing. Your CSF parameters have to be normal. You must not grow Cryptococcus from any site that previously grew Cryptococcus. And there must not be any new lesions.
Chow: Great. We're getting to the end of our time, unfortunately. I want to wrap up by asking one last question that hearkens back to what we were talking about earlier in terms of the robust inflammatory response we often see with these patients. And you mentioned just now this idea of IRIS. This is something we've seen frequently as far as a paradoxical immune reaction for these patients. Thinking about steroids for these patients is something we've had to do. I would love to get your parting thoughts on how you make the decision in terms of host-directed therapy like steroids and the duration of steroid therapy in treating these patients.
Chen: We do not routinely use steroids, but I know the thinking might be changing because there is one large study center at the National Institutes of Health. I think Johns Hopkins is looking into this. We do not use steroids routinely. We use them if there are mass lesions — very large ones — and particularly if there are mass effects. We use them in anybody with a mass effect or midline shift. In anybody with a mass lesion with moderate mass effect, the answer is probably yes. It's all about cerebral edema and large cerebral cryptococcomas. We don't have the same approach for lungs because we don't have the same experience or weighed evidence in how it works in lung lesions. But obviously, if a lesion is around the trachea and it's compressing some vital structure, we would use steroids. The last indication for which we would use steroids is in the event, IRIS, where you have new lesions. The patient has responded well and you can't grow the Cryptococcus, but new lesions are popping up either in the brain or sometimes in the lymph nodes. Then, yes, you would use a steroid to shrink the lesions and taper the steroid as quickly as you can.
Chow: Have you found that particular for that last category of patient, sometimes they require a longer duration of treatment, and when you try to taper it, things get worse? If so, then you have to bump the steroid back up and start your taper all over again.
Chen: Yes, we would monitor them very closely as to how they respond to high-dose steroid therapy.
Chow: All right. Thank you so much. We've had Dr Sharon Chen today discussing C gattii meningitis. 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: The Other Cryptococcus: Managing C gattii Meningitis - Medscape - Aug 10, 2023.