122. Moulds: Rare Invasive Moulds

Alyssa and Callum are joined by Dr Neil Stone to talk all things Rare, Invasive, and Mouldy. Specifically Fusarium spp., as well as Scedosporium spp. and Lomentospora prolificans.

Heard of these before? No? Well listen in to find out what they are, and why they matter

Show notes for this episode here: https://idiots.notion.site/122-Moulds-Rare-invasive-moulds-af70fc26e81043669c2bf3ef17c14b6c?pvs=74

Transcript

0:00

Hi everyone. Welcome to the Idiots Podcast. That's infectious disease insights of these specialists. I'm Callum, and that's Alyssa. And we're going to tell you everything you need to know about fungal infection. Soon May the editing, editing come to discontinue Caspo fun gun. One day when the BDG is done, we'll take our leave and go.

Callum: 0:22

Hello Alyssa and Neil. I want to say hi, for all, my co hosts. Hi, hello, hi, for my co hosts. God, that's worse than I thought it would go. Yeah. Alyssa, how are you?

Alyssa: 0:40

Callum. I've had a bit of a tough morning. I really wanted toast for breakfast but the toaster blew. So my pop to the, the hardware store and get a fuse. So I asked the guy behind in the hardware store, where are the fuses? And he pointed over to this like, big tank that was full of water and had all these fuses bobbing around. And he was like, they're in the fusarium. And I was like, this is dodgy. We've got a scelodip here. So, much to my lamentous horror, have cereal.

Callum: 1:13

You know, Actually, before we recorded this episode, I was thinking, how on earth can I make a pun out of Fusarium? And you've done it. I. So we're delighted to be joined today by Dr. Neil Stone who those of you who work in mycology, you'll need no introduction or who are on Twitter X or are you in blue sky now? Neil? I don't know.

Neil: 1:33

I am on Blue Sky, just starting off there,

Callum: 1:37

to the future.

Neil: 1:37

hedging my bets and staying on board.

Callum: 1:41

both worlds. So Dr. Neil Stone is a consultant infectious diseases at the university college London hospitals. and an honorary assistant professor at the London School of Hygiene and Tropical Medicine. He completed a PhD in Cryptococcal Meningitis at St. George's and also has clinical experience in Zambia, Uganda, Malawi and Nigeria. his special interests are in invasive fungal disease and new fungal diagnostics and treatments.

Neil: 2:11

Thank you very much for having me.

Callum: 2:12

Yeah we certainly I've certainly heard you speak at many conferences and communicate very clearly on the need for increased focus and research and fungal disease. So, what Are we talking about today?

Alyssa: 2:26

So in this episode, we're going to focus on molds other than Aspergillus species and mucorales so we're continuing, our Episodes on molds. So we've previously, covered aspergillus and eucrales, and I'm going to talk about some rare, rarer molds that can cause invasive infection in humans. So we're mainly going to be talking about pusarium, scelosporium, and lamentospora prolificans.

Callum: 2:58

So why is this important? Why do we want to talk about these molds that are so rare and I imagine quite a few listeners may never have treated clinically. I've certainly not really got much experience with them. I've maybe thrown that one to you Neil,

Neil: 3:12

I think it is an important topic because yes, they are rare, But you know, I guess most of the people listening and certainly ourselves in this call, we are the infection experts. And those of us who deal with fungal infections, it's already fairly niche. And these are infections which do come up from time to time, and they're important and they're deadly. and really they're going to be looking to us, clinicians are going to be looking to us for advice, because the vast majority of doctors will never have heard of these infections. Those who do won't probably know how to treat them. So they're going to come to us for advice. So I think anyone who's going to be an infection specialist needs to have at least a good handle of at least the general principles, if not necessarily the fine detail of how to manage these infections.

Callum: 3:54

So that's, I guess why they're important. What what are they you, so you said so that they're rare molds. So they're ask ascomycota, if we're thinking about our kingdoms and they're molds, but, what was that horrible pun that I was trying

Neil: 4:09

hyalohyphomycoses and that's just, that's just a very fancy way of seeing clear or transparent moulds essentially. So I guess we just go right back to basics. So when we think about fungal infections, divide them up into yeast, candida being by far the most important, cryptococcus also being important, and then the moulds, which we know, everyone knows from that corner of their bathroom, or crowing on bread if you leave out. But when when we think about mold infections, the overwhelming majority of the time we're thinking about aspergillus infections, whether people know it or not, we're thinking about aspergillus. And then the neutralities, which iisa you've been studying, which are relatively rare, but are probably also relatively well known can be horrible, deadly infections, which affect highly immunosuppressed patients. So these are a infections, which are neither of these really yet, they come under, under molds. So when we think about molds, we can subdivide them into. Essentially clear mold or black pigmented mold known as a dementatious fungi. Actually, you might remember after the COVID outbreak in India, there was an explosion of cases of mucormycosis, and that was called black mold by the press, which was actually a misnomer. When we talk about black mold, we talk about pigmented molds, both under the microscope and when they grow, they're dark or very black. But there are some molds which are not aspergillus. They are not black mold because they're not really pigmented, but they do cause On, on occasion, really serious human disease. And the ones we're gonna focus on today are fusarium infections, uh, and two other species. One is ski spo, ap sper, Lamento, spora ProLiants, which have all got long names, but are ones which, which do come up clinically and the like. Like most fungi, most mos, these are environmental organisms. They're absolutely ubiquitous they're all around us. They're present globally more in some parts of the world than others. And we, we'll come onto that in a little bit. But the present globally and like most fungal infections all their opportunists. So these are things which are absolutely harmless to most of us, hopefully If we have a working immune system Might be breathing it in perhaps when you do your gardening or you're out traveling somewhere or walking around you'll come across these organisms without ever knowing it But of course we have highly immunosuppressed patients they cause invasive and deadly disease and can be fatal So that's why it's important to know about them. The other problem is they tend to be intrinsically very drug resistant and hard to treat. That presents a real clinical challenge. So these are really the key things that we need to be equipped with when we do occasionally come across these infections and we're asked how to treat it, we need to have some idea of what is likely to work and what likely is not in terms of antifungal therapy.

Callum: 6:49

There's a overview, so I guess we'll focus first on the Fusarium species. So I think that the main two to my understanding is you've got Fusarium solani. Which is Latin for sunny, and then Fusarium oxysporum, which is like sporing in the air, I think is that's about right,

Neil: 7:09

Yeah. So fusarium, there, there are hundreds of species of fusarium and I guess, if, if you're only going to know of two both for clinical or purposes it's, solan is really the most common that we see clinically, spo being the second most common. Solan is about 70% of clinical isolate's forget. And so yeah, these are, these are a mold that they,, they're out in the environment. They're not all pathogenic. So just a couple of o factoids that I always quite enjoy. So those of you who are, cricket fans and cricket followers. So, I wasn't really, I was raised in Scotland and wasn't exposed much to cricket, but those of you out there who are big cricket fans, there was a test match, an ashes test in 1972, at Headingley in Leeds, where the pitch was completely ruined by fusarium infection. And it was known as the fusarium test match. And so that was, it's either harmless or it can be an agricultural pathogens But it's also, it's used in, it's used in industry. Um, you might be aware of the meat substitute food quorn, for example, that is fusarium. That's fusarium, denitaximab. So that's obviously completely harmless and it's quite a popular meat substitute. So, I guess, Just to reiterate that these are everywhere in an environment, usually harmless, can be plant pathogens, but occasionally human pathogens.

Callum: 8:18

Any further little factoids, alyssa?

Alyssa: 8:20

I always with pusarium, I always think bananas. So, Fusarium oxysporin is, a major banana plant pathogen. They have knocked out huge harvests of crops. And so they're called it's called Fusarium wilt or Panama disease. I would say under the microscope the macroconidia, the banana shaped, curved macroconidia. Fusarium think bananas.

Callum: 8:46

I think that's a good exam tip because certainly for my part two, that was what I was revising a lot of was, a picture of a fungus or mold or, on a microscope to try and, just guide you. yeah, I, I was really fascinated by that corn fact. Complete tangent here, if you eat a lot of corn, could you then get a false positive on some of your fungal diagnostics?

Neil: 9:09

I was actually asked that question by someone when I put I think I put that factoid out in social media somewhere because I thought it was quite interesting and some people came back to me and said oh i'm a bit immunosuppressed should I not eat corn then and i'm surprised the manufacturers went on to me because I might have been tacking the share price back but I think actually you know by the time you come to eat it is completely dead. And there's no way it's going to do anything once you eat it, digest it, and it's not not a danger.

Callum: 9:38

Could you get a B2D Glucan with, if you,

Neil: 9:42

is a fascinating question. Shall we do a little trial of that? Wouldn't expect much of it to be circulating in bloodstream by the time you digest it. And it's a very non pathogenic species, so just in case the manufacturers of quorn are listening to this and are about to phone their lawyers, we think it's safe to eat and it is not a danger to anyone.

Callum: 10:01

I love it, I eat it all the time so,, yeah, come back on target,

Neil: 10:06

Yeah, I guess coming back to it, so I guess we could, yeah, so Liz has already mentioned it, so exactly, so it's a lab diagnosis, so we've it. Yeah, it's. So these are infections which happen in patients who are incredibly immunosuppressed. And I think we're probably familiar by now with what we mean by that. This is your patients who are neutropenic for a long time. I don't see these infections very often, but when we do, we're not talking about solid tumor where you're at chemotherapy and you're neutropenic for three days. We're talking about patients with hematological malignancy and neutropenic for weeks and months. But not only that, they've got refractory disease where they're neutropenic for a really prolonged period of time. Those are the patients that get trouble with these. So it's a real marker of really severe and extreme immunosuppression, I would say. These are not diseases that healthy people get, at least invasive form. And we'll come back to diagnosis because Alyssa made a really good point about bananas. key thing, I guess, in clinical practice, Fusarium is one of the very few molds that you might see growing in the blood culture. We almost never see molds growing in a blood culture. Aspergillus won't grow in a blood culture, and of course, that's by far the most common mold that we worry about. Fusarium can, in anything up to 60 70 percent of disseminated cases, you'll get a positive blood culture. So, If one of your lab staff calls you saying, I think there might be a mold and there's some hyphae in the blood culture, instead of dismissing being a bit off their game that day and that it can't possibly be true, just think for a moment whether actually, is this the sort of patient that might be at risk for Fusarium

Callum: 11:29

this, Neil saying there that, we're, These are the severe immune compromised people and it's in the environment. So what clinical syndromes are we seeing? How is it getting into the host? And, what sort of severity are we looking at? Is this, I presume pretty severe because it's invasive fungal disease.

Alyssa: 11:45

the main way that people become infected, with Fusarium, as with most, mold infections, is either by inhalation of, conidia, which are in the air, or by direct inoculation of cuts and injuries, or such as burns. And then with regard to clinical features, Fusarium most commonly affects skin deep soft tissue, lungs, or sinuses, as far as I'm aware. And frequently disseminates haematogenously, so, as we've said, can be picked up in blood cultures, in up to 60, 70 percent of cases. I think this is it because, some of these species are able to sporulate in vivo in the tissue and in the blood, which is known as adventitious sporulation. I think one interesting feature of fusariosis is that often people have a skin rash. So we saw this in a case in Exeter where, it was a patient with hematological malignancy. on very intense chemotherapy, very prolonged neutropenia, not responding to antibiotics. And then she came in with this, perpuret rash all over her, extensor area. and subsequently we did pick up Fusarium in her. So Neil, have you seen these sorts of skin rashes and how to treat them?

Neil: 13:10

absolutely. And again, where I work at university college also, we've got really big hematology units. One of the biggest in Europe. We don't see this very often, even with that big cohorts. but when we do see it, yeah, so the cardinal signs really often like a lot of these things, it's a refractory patients usually have high spike in fever. They're usually pretty sick and someone who's already very immunosuppressed. it's this skin rash, these skin lesions. It's almost like black necrotic, almost like eschar, it can be very disseminated. So really when I see someone, like that, who I think is at risk who's febrile, with these skin lesions, one of the things I do think about is Fusarium, and it is, as in always, sometimes it turns out to be a pseudomonal ecythema or staphylococcus infection, but you've got to think about Fusarium because that is how it presents, and that these skin lesions are a kind of cardinal sign, and what we think is probably happening is. It's disseminated in the bloodstream. We've mentioned you might get a positive blood culture because it's got this property where it's able to reproduce actually in the blood sample and in the bloodstream and then you get these deposits of disseminated infection causing skin lesions. So really that's the classic presentation of disseminated Fusariosis in this kind of patient.

Callum: 14:17

And I guess when you're seeing this, I think the quoted mortality in the literature is, 50 to 70 percent

Neil: 14:23

Yeah, absolutely. I mean, it's a very, it's a grim disease, and that is very, very true. Now, of course, that, that is because The vast majority of these patients already have refractory haemophilogical malignancy. So there are probes is usually very poor from that. Add into that and we'll come on to this later. It's often very drug resistant, so treating it is very difficult. So those all contribute to mortality, but yes, it's a very serious infection and very grim and for patients to have any chance of survival, we need to be recognized and picked up and diagnosed and treated as early as possible. I think just whilst we're on the clinical presentation, so you mentioned this. So this is hematogenous spread, probably from the lungs. There is also the inoculation type injury, and I think just to bring in an almost completely different type of Fusarium disease that we see quite a lot is Fusarium eye disease, Fusarium keratitis. So one of my other roles, I work with Moorfields Eye Hospital, it's one of the big eye hospitals in London, and we quite often get consults for patients who are not immunocompromised at all, but they've had an inoculation injury into their eye, and they've got Fusarium, and that can cause a nasty keratitis. So that's of course completely different. And that causes really severe eye disease and eye loss, but not the disseminated haematogenous spread. So I think really important for our listeners to think about these two really important, highly distinct clinical presentation that we see

Alyssa: 15:42

And then also, Fusarium, can cause more superficial infections such as nail infections. And also it's an agent in Mycetoma, which we're going to talk about in a subsequent episode.

Callum: 15:55

So you mentioned obviously picking up this early and I guess maybe we could move on to talk about lab diagnostics. This is, with lots of fungal disease, the diagnostics is a sort of tricky bit It and you can chip in and correct me if I get something wrong. we've got quite a lot of detail in there, in our prep notes that Alyssa's put together. So thanks for doing that and link to a couple of references. The University of Adelaide website has got so much information on these organisms. It's great. If you're looking for a bit more detail. But essentially like with most fungal. Diagnostics, your main things you're thinking about are your sort of di direct microscopy whether that's direct samples or in histopathology culture. And then looking at the microscopic and microscopic features from the culture. Things like biomarkers, so like a fungal antigens and then molecular techniques. So thinking about things like reference lab, PCR tests and maldi to.

Neil: 16:47

I can talk about the diagnostics in general. So we've mentioned obviously that the easy way to diagnose it as a positive blood culture, in, more than half of cases. You'll see. the hyphae in the blood culture, and it'll grow quite easily later on. Negar plate, if you can identify it locally in your lab, that's great. But usually it's something you send off to the reference laboratory. And also sensitivities are important. We'll come on to that later. The other thing which will usually be positive are B to D glucan most of the time, and often galactomannan as well. So fungal biomarkers, as they're known, cause an awful lot of confusion firstly, they're limited by sensitivity and specificity, but also what should and shouldn't give you positive tests. The Fusarium, Will give you a positive B2B mutation, like many of the pathogenic fungi, But it's one of the few clinically important fungal infections that we see, at least in the UK, which might give you a positive Galactomannan, which is not Aspergillus. So I think that's an important point to remember. You might get a positive Galactomannan. Which, as I've mentioned in our practice, 99% of the time we use that to look for aspergillus, but it's one of those Moulds which might give you a positive galman and the other ones being endemic like histoplasma, which we don't really see in the UK very often at all. so galman and can be used for marker. Certainly btd glucan The other thing to say is that you've got skin lesions. Often they are actually packed with fungi. So if you do get a biopsy. A, you'll see them under the microscope and you may even be able to culture it if you get a PCR. So, That's also another way of diagnosing it if your blood culture is negative.

Alyssa: 18:21

Oh, that's really, yeah, that's really useful know because, I guess it's much less invasive. sample than getting a deep tissue biopsy or a BAL.

Neil: 18:31

Absolutely. Yeah.

Alyssa: 18:33

And they're quite characteristic in the lab, aren't they? So I know when we've isolated the minoxidil before, we've been able to get a good idea that this is Fusarium and we've actually sent photos of the culture plate and of the lactam phenol cotton bootstain to Bristol to get some guidance, but they, grow quite readily on standard, Saburo's, Dexpro's agar, and they often have quite fluffy cottony colonies. So more of a gray white for your, solan and then more of an apricot color for sporin. And then the microscopic features again, are quite characteristics. You get lots of, small oval curved microdia, and then these really characteristic crescent or banana shaped map pre nidia. that have scepter, so usually about three to five, scepter. And I've put some pictures of those in the show notes, if anyone's wants to see those.

Callum: 19:28

I was thinking they look like, Canadian canoes almost.

Neil: 19:30

Sickles, everyone, sickles, bananas, canoes, but they're very characteristic, aren't they? And it's a classic for exam questions where they'll show you a picture And it's pretty much pattern recognition that if you've seen it a few times, you do get to recognize it.

Callum: 19:44

So I guess that's the, that's all we want to say for the diagnostics. Is it worth, because when you mentioned the blood culture earlier on, you said, someone phoned you overnight and they've got a hyphae, but my understanding is it can often appear, it looks like a yeast

Neil: 19:57

Yeah, it often do, that's the thing, I think Alyssa mentioned something called adventitious sporulation, so it's the ability of these conidia, or these spores, to break off, and they themselves have got the ability to reproduce in the bloodstream, so you might just see those in the blood culture, actually. So it might be that you might be called by the BMS with something which just looks very odd, possibly it's like a yeast. but it's going to look unusual and not something you would see often in the blood I know, hopefully by the next morning it's probably going to have grown But just something to be aware of in terms of a patient at high risk and there's something odd in the blood culture which looks fungal, do think about Fusarium when you come to your treatment consideration, which is probably what we're going to move on to talk about next.

Callum: 20:38

Yeah. I often think about the phrase that someone taught me clinically, which was the eyes cannot see what the brain does not know. Then sometimes in microbiology, it's less the eyes and more the ears. You can't, getting that story and you've never heard of fusarium, then you might not think to worry about it.

Neil: 20:54

Yeah.

Callum: 20:54

guess it's, the, just even just having awareness, that's something to think about in that clinical context is the first step. And then you can always look it up and find out more information. so you mentioned there about, about treatment, Neil you, you've both got clinical experience treating this. What's the treatment is I presume it's gonna be challenging because it's invasive fungal disease.

Neil: 21:14

yeah it's probably a good direct to, you know, guidelines resources. If you people want to look things up, which is always a good idea. And one of the, one of the papers we've referenced in our notes, which I think is a crucial document is the global guideline for treatment of rare molds, which was published in 2019? It was just before COVID hit around then. It's a really amazing paper actually, because guideline itself is 12 pages and it's really concise and really to the point and it's got tables about what you should treat with which I think is really useful clinically. Because we all know you've been on call and you're looking up a paper and you don't want to read a thesis. You want a table and an algorithm. What do you do now? And it's got that. Incredibly, the supplementary material is 236 pages long, and it reads like a text, but it's got intense detail about these rarer molds, like Fusarium, and some of the other ones we'll speak about later. So that's really good for reading up in great detail. That's the supplementary material, but the 12 page guideline is actually really useful. So I would encourage everyone to get a copy of that. Both the short version for clinical use and the long version for reading in real detail and perhaps for, exam revision or people who really want to get to the nitty gritty of it. that's a really, really useful resource. Albeit based on limited evidence because these are Just a little bit back to epidemiology, for example, Physioreosis, as I mentioned, we don't see it very often. If you work in Brazil or Argentina, for example, you see loads of it all the time, presumably just because there's a lot more of it in the environment in that part of the world, perhaps due to climate. But that is, Brazilian haematologists, when they deal with neutropenic patients, it's one of their big concerns, Physioreosis, whereas those of us working in the UK, we will see it times a year, maybe, if that. But yeah, coming back to that guideline, it's really useful to have both for clinical practice in the main document and detailed reference.

Callum: 23:03

So that's the global guidelines for diagnosis and management of rare mold infections by ECMM, ISHAM and ASM.

Neil: 23:11

That's the one and it was published in Lance ID by a grouping of world experts.

Callum: 23:17

Oh, I know what I'm doing after this podcast episode.

Neil: 23:19

You're going to read all 236 pages of the supplement.

Callum: 23:23

That's where we can.

Neil: 23:25

But coming, so yeah, so then I guess, so that's a good guy. But coming on to I'll talk in general terms and then maybe I'll pass it over to you, Alyssa, about how you would choose it. The big message I always want to get across to people you can't infer sensitivities just from the name Fusarium. It varies species to species, and even within species isolate to isolate. So thinking about first principles in we learn early on in micro, that sometimes the name of the organism helps you and sometimes it doesn't. So a gram negative in the whether it's called an E. coli or a Klebsiella, often doesn't really matter because you're much more interested in the sensitivities. Whereas if you know it's a Pseudomonas, then you know, for example, Comoxglab is definitely not going to work. So that's where the name of the organism is instantly really helpful. Fusarium is a tricky one, because let's take Fusarium solani, for example. Isolate to isolate can have completely different sensitivities. It's so important to send our susceptibility testing. It's absolutely critical. And that should be done at a reference laboratory, because mold we have a a bunch of different tests that we can go through to determine which symptoms are difficult. But we don't know what it's going to be susceptible to until we get that testing. So normally, we have to hedge our bets in a sick patient until we get that back. So just knowing that it's Fusarium solani, you cannot say, oh, this is going to be sensitive to Voring because it's a Fusarium solani. And of course, that has to come into your thinking when you're choosing your empirical therapy before you've got the results back. And maybe, Alyssa, you want to talk about what you might choose to start off with in

Alyssa: 24:50

I think one of the, one of the key things in with a lot of these mold infections because they're in immunocompromised patients, possible, reversive immunosuppression is key to helping them clear, clear the infection, but obviously that's not always possible. And I think one of, as Neil said, one of the challenges is that the susceptibilities are unpredictable. And often you can have pretty pan resistant or, only intermediately susceptible to some of the antifungal agents. So often therapy involves a combination, of agents. The guidelines that we refer to recommend first line for a connoisseur with therapeutic drug monitoring to, to check levels are adequate. Thanks guys. Or for a connoisseur in combination with, liposomal amphotericin B. So I guess with that, would that be what you would start empirically whilst you were waiting for those susceptibilities to come back in, in these patients?

Neil: 25:50

Yeah, I must say, because of the fact these patients are usually so sick and we can't guess the susceptibilities, I often do start with combination therapy, high dose. Like some amphotericin B plus for e carnisol, because, we know that we get azole resistant isolates and for B resistant isolates, and literally you can have two, as I mentioned, two Solanase, which have completely different profiles. The patients are desperately sick. So it's one of the rarer occasions where I go in with dual therapy. Generally, We get asked a lot about dual therapy. So there's very little, Data in general that treating severe fungal infections with two agents is better than one with the exception of cryptococcus So we know that amphotericin plus flucidocytosine is better than monotherapy Most of the other invasive fungal infections. We don't have any convincing evidence that two is better than one But given the fact this is rare, so we don't have good trial data. It's all retrospective case series level given the fact There's an incredibly sick and given the fact that we don't know what it's going to be susceptible to You If they can take it in terms of duct cysts, they'll often go on with dual therapy, which can be tailored and That's just the clinical reality of it. Antifungal stewardship goes out the window in these cases, but there's a time and a place for that. And these rare cases where it's life threatening, it's probably not the time to scrounge on the antifungals. So often going with dual therapy and then tailor it to get results.

Callum: 27:13

And you mentioned getting this susceptibility data, Neil. So what what options are there, Alyssa, in terms of, do ECMA give us guidelines from the antimicrobial susceptibility testing.

Alyssa: 27:23

Yeah, so, as with as with most molds, is performed by broth mite dilution. So this is something, like Neil said, that we're going to be sending to the reference lab to be done. But really challengingly, there are no clinical breakpoints. So the MICs are often interpreted using breakpoints for acid fillers. did recently, published a tentative amphotericin B off of, eight milligrams per, so high mics, to amphotericin B I think typical susceptibility patterns. As Neil said, it varies a lot. typically these organisms, the Fluconazole and Econazole resistant, so these aren't gonna have any moles activity. They're intrinsically resistant to a echinocandins. Your kin Camden are arrive straight away, resistant to flu, cytidine as well, and many the intermediate or resistant terin. B. and susceptible, intermediate or resistant to boricomazole and posaconazole. So your main options are going to be amputerasin B, and posaconazole, can be used as a salvage therapy. We did have a case in, in Exeter, um, with Fusarium, a spinal Fusariasis. with Fusarium solani, where, it was resistant to everything except intermediate to boriconazole. And we did actually use a combination of boriconazole and flucitazine. Because of somatic datal evidence of logistic effect. We actually had a good treatment outcome with that. So, Sometimes it looks like this. Perhaps it looks worse Than the patient responds. I don't know.

Callum: 29:16

that coincide with a reduction in their immune suppression as well? Do you remember? So

Alyssa: 29:21

so they didn't go into further cycles of chemotherapy.

Callum: 29:26

I guess we've spoken there about Fusarium. Anything else that people want to say before we move on there? I think that's pretty comprehensive.

Neil: 29:33

think we've got the key issues. Yeah, I think, yeah, the key message there is, yeah, avoid kind of candidates. Caspo, Energelon are not the drugs to use.

Alyssa: 29:40

Yeah. Yeah,

Callum: 29:41

Yeah. which

Neil: 29:42

key.

Callum: 29:42

now using empirically for,

Neil: 29:44

Yeah.

Callum: 29:44

candidemia. So I guess,

Neil: 29:46

Yeah.

Callum: 29:46

about that, if you've got that, severe immune compromised patient, you get a blood culture back, it's a bit of a funny yeast, Maybe think about using an alternative like amphotericin. So what about scelosporium, I guess there's some similarities between these rare molds, but there's a lot of differences as well. So I guess there are ubiquitous environmental molds. And there's some naming trickiness, do you want to take that, Alyssa? And we'll try to narrow down what we're talking about, and then we'll say why it's important.

Alyssa: 30:18

Yeah. So I think yeah, so as you said, ubiquitous environment models are found like soil, water, manure. Yeah. Um, And the main species that cause disease in humans are Scetosporium apiospermum and Scetosporium boidei. But then sometimes they're also referred to as, I'm not sure if I'm saying this right, Pseudalicheria. confusing. Pseudalicheria apiosperma Pseudalicheria boidei. And I think that refers to the sexual state of the fungus. So spor is for the asexual and amorphic state, and s sharia refers to the sexual or polymorphic state. So sometimes you might hear those terms used interchangeably.

Neil: 31:09

Yeah, I think that's right. I think people don't need to get too tied in knots about all of that because it's all about what is that, what stage of the life cycle of the particular mold is that when it's recovered from the human being and it can vary, but essentially, they're the same thing, fall intensive project.

Callum: 31:24

So now we know what we're talking about. So it's good. So I guess similarly. to fusarium is acquired by inhalation of skin trauma. What sort of patients are we worried about this? And

Neil: 31:36

exactly the same as with the Fusarium and most of these molds. So it's an opportunistic, it's patients who are highly immunosuppressed. So really all the same risk factors. Occasionally there have been episodes where patients have had drowning events. Or near drowning. So in rivers and lakes, particularly freshwater, and it had massive inhalation, of some of these molds, and they've been, have become very unwell for a long time. And they've got infection that way. So you don't need to be immunosuppressed. in that particular scenario, but most of the time in our clinical practice, it's going to be Immunosuppressed patients as an opportunistic pathogen.

Callum: 32:11

and, my understanding is that in the near drowning patients, the organism is quite neurotrophic, if you've got a pulmonary disease and then they start developing some signs of CNS infection that's another sort of thing to trigger thinking about scoliosporium.

Neil: 32:24

Absolutely, and that's only been described, so we're not talking about massive numbers here But it's well described in case series that is a phenomenon which does occur So again in that very particular clinical scenario, it's something to think about when you start to see brain lesions, for example

Callum: 32:39

So, so this is rarer than fusarium, which was already rare.

Neil: 32:44

To some extent, so it depends where you work again. So as we mentioned, so for someone like the Fusariosis in say Brazil or Argentina, which is relatively common, whereas rare for us, where it's the Ascidosporium infections. Again, they're global, but there are certain parts of the world where they're seen more often. so there's another species that we'll talk about called Lamentospora, which is very similar. That's very much more common in Australia, for example, or anecdote that I might tell you about my experience with that in Australia. Yes, They're rarer, but parts of the world, they are less rare, because there is an epithelial variance, because as with all environmental molds, it just depends on how much there is an environment

Alyssa: 33:25

I think where I've mainly seen, um, is like in patients with chronic lung disease Is it just a colonizer? Does it cause exacerbation of their chronic lung disease and deterioration in their lung function and lung infection? I don't know,

Neil: 33:42

That's another important clinical scenario where we do see this, absolutely, so in patients with chronic lung disease. who we know get colonized with all sorts of organisms, including aspergillus, for example. So that's a classic example. When we get aspergillus from an airway, from a sputum sample, it doesn't mean they've gone into aspergillosis. It may be colonizing. The same goes for schizosporium, lung disease, cystic fibrosis, for example. We do see it sometimes colonizing airways. And again, it's a clinical decision, whether you think it's actually causing disease or not, or whether it's a passenger. So yeah, I'm glad you raised that, because that's yet another kind of different point. clinical scenario as opposed to the invasive, life threatening vaccine for the immunosporous

Callum: 34:21

So we've been suspecting this, we've found a, we've found a mold or we've got this near drowning patient, so you're in the lab. So I guess, it's similar to other hyalohyphomycosis. It's indistinguishable microscopy and histopathology. So it looks very much like aspergillus, which is our most common. But the identification normally is done by culture, so looking by colony morphology, microscopic features and sending off to the reference lab for molecular. The Adelaide website has got some really great pictures, which we've not put in the show notes of the way that it grows and how you see it on the lacto phenol blue. so I'd certainly recommend having a look at that. And, again, I imagine If I was going to write an exam question about this, I probably would go for something quite recognizable as a clinical syndrome and put the picture in as a clue because, it is rare, but something to think about. Yeah any other sort of particulars about the lab diagnostics that we should mention here? It's quite similar, isn't it? And

Alyssa: 35:21

you know, about, whether cases of invasive sclerosporiasis have, positive BtD glucan or glactamannan, like Fusarium? I

Neil: 35:30

poorly described actually, but the answer is yes, can do. Again, these are models which can give you a positive beta D glucan and occasionally a GlaxoVan, and I think less so in terms of GlaxoVan and Fusarium, but certainly beta D glucan, they do have beta D glucan, Definitely one to think about. So yeah, that can be a useful marker and so that might be actually the first indication that you have some sort of invasive fungal infection, even if you might not, it might not be instantly apparent that it's schizosporiosis. So yeah, they're useful to start with that. But again, yeah, it's really about culturing it. And, given the rarity and given the expertise needed, these are really isolates which we will be sending off both for identification and susceptibility testing.

Callum: 36:09

then finally, similarly with the antimicrobial susceptibility, we don't have clinical breakpoints, we don't have e coughs so often interpretations done as per those for aspergillus or using the UCAST where there are no breakpoints guidance. Sometimes CLSI and I think my understanding is generally it's either I, so increased dose susceptible to amphotericin or resistant. Interesting. So this one, Echinocandens might be a treatment option, whereas they weren't for Fusarium.

Neil: 36:37

I would generally avoid them. So there have been case reports of it being used synergistically because of the synergistic effect, although in vitro usually it will come out as being resistant to that. There have been salvage attempts where it has been thrown in. But really with sketosporine apiospermum, which is probably the most common sketosporine that we'll see, common in amongst the rare group, but relatively more common, voriconazole is usually the treatment of choice. It's usually got the lowest MICs, and voriconazole, the consensus is that you have a, if you have a sketosporine apiospermum infection, voriconazole is what you would start with. And again, yeah, all kinds of combinations have been thrown in as salvage, but it's really voriconazole is absolutely the mainstay of therapy. Thank you.'cause pretty consistently it's got the lowest mi posaconazole as well may be useful. I of Econazole variable that needs to be tested. And again, don't have, very robust break points at all, but it's really voriconazole. I think that's the that if you have one of these infections that your go-to drug,

Callum: 37:38

and clinical experience

Neil: 37:40

we've got a current case ongoing at the moment. we have A current case of scelosporium apiosperum, which is disseminated in this cause that liver lesions and lung lesions is proving difficult to treat. And actually, we're using one of the newer therapies, which I'll probably come into talk more when we talk about our next mold, which is Lamentospora prolificans, because it becomes relevant for that. that's a lorathin, But we're using it for that because voricomazole wasn't really doing the job. So, Certainly because of the limitations of treatment options for some of these, we're looking at some of the new therapies such as Olorifen,

Callum: 38:15

Yeah, we'll come back to talk about novel antifungals, okay. So yeah, you're hinting at the next organism. The Lomentospora prolificans, which I have to say prior to now that I think I knew about Fusarium, I'd heard about Scadosporium, I couldn't remember much about it. I've never heard of this. So do you want to talk us through what this is? I

Neil: 38:36

Yeah that's probably because it scatosporium. When I started training, it was called scatosporium prolificans. So, It's had a name change to Lamentospora, which is Not uncommon in the world of fungal infections, the taxonomists love to change names. Lamentospora prolificans, formerly known Scythosporum prolificans. that, that is something which, is global, but it's seen much more commonly, particularly in Australia, and they have a big problem with it there, again, it's an environmental mold and much as the other infections we've been talking about, it's the same story of being an opportunist

Callum: 39:11

think it is more common in Australia? Just because of the vegetation that's there? I presume it's in the environment or is it the climate? It's very dry

Neil: 39:19

Yeah, it seems to be very dry. It seems it's also relatively common in dry desert parts of Spain and the Midwestern United States. So it's probably related to, to climate and environment. It is found globally. You don't have to have traveled to those parts of the world. But it's certainly relatively more common in Australia and that's where I first came across it actually. And I, this might be a time to tell my anecdote. I was actually a, what was then an SHO, so IMT level equivalent in Australia in 2006 now. So I went to Sydney for a year and I was on a haematology ward. And we had a patient, very memorable case, very tragic case, a young woman who was diagnosed with acute leukaemia in pregnancy, believe it or not, and within 24 hours she had the pregnancy induced and she had a PICC line and getting chemotherapy. She was from Indonesia originally as it happened, but anyway, she did very well initially with her chemotherapy But then at some point developed cerebral entropenia and we grew this organism in the blood culture So again, this is another one which you might grow in the blood culture and in those days It was called scidisporium prolificans and I was completely new to this I've never heard of it But the glum faces of the microbiologist at the time told the tale that they were very actually distressed by this Result because the outlook was so poor and the patient at the time wasn't that sick But the treatment options were incredibly limited because these mold infections are problematic anyway, but Lamentis spora is particularly difficult because it's often pan resistant to all of the antifungal is incredibly hard to treat. So they were very, very gloomy about this and very sadly that proved to be the case and she eventually died from this infection. So I think that had quite a big impact on me and might have been an early indication that I might end up getting involved in this field. But there were a lot of lessons there for me that this is something that in that part of the world was important. She was exactly the type of risk patient with acute myeloid leukemia, and it turned out to be essentially untreatable because it was pan resistant. And regardless of what she was given, it didn't work and she sadly died. So really, I think a good case to just sum up the terrible problems we have with this albeit rare, but very horrible infection.

Alyssa: 41:31

Yeah, no, that's a tragic case and I think, something that I keep coming back to when talking about mould infections is that, yes, they are rare, but they're associated with such high mortality,, that, they, do deserve a lot more, discussion than I think maybe they're given. So that's really interesting. So another another mold agent that can be detected in blood cultures when it's in disseminated infection, and also pan resistant to all antifungals. So when I was reading the global guidelines about how to treat these infections, essentially, no drug appears to be effective. There was some reports of successful treatment voriconazole terbinafine, so you could give that a stab, surgical debridement of the infected tissue to try and, limit the infection and reduce the bioburden. And then recovery of the immunosuppression are key. Neil, earlier you touched on a novel antifungal agent, that might offer some hope for treatment of pneumothorax polyphagans.

Neil: 42:35

Yeah, which is really key because as we've mentioned, we don't really have treatment options. Yes, boric horizontal terpenephine is the most commonly used combination in Lamentis. spora infection because of some anecdotes that it's worked. Although individually, they don't seem effective. They might be synergistic. But yeah, we were looking to new drugs because none of the drugs we have are particularly effective. And olorofilm I mentioned before, which I've used a couple of times you and a case of skelosporin apusperumum, but certainly there's a lot of interest in this drug for Lamentis spora prolificans because at least in vitro, it looks to have very good activity. And that's really a major breakthrough because it's really, First drug that looks to be on the horizon, which will actually treat these infections. So again, particularly in somewhere like Australia, where they see relatively more of these cases in their hemato oncology neutropenic population, there's a lot of interest in this drug. It's a, it's interesting. It's an interesting drug. It's a completely novel mechanism of action. It's known as a dihydroerotamide, which is an erotamide anti inflammatory. So it's got, it basically blocks one of the fungal enzyme which are present in a lot of the molds. And it's completely, as I mentioned, unique can be given orally or IV. I should mention at this point, our listeners, that it is only in phase two and now phase three trials. It's not licensed and clinical use routinely yet. It's going to be a late stage clinical trial and is available on compassionate use basis and a named patient basis. Thank you. So if you come across a patient like this, particularly with Lamentis spora, for example, or one of the other rare moles not responding to standard therapy, it's something to think about, but you'd have to go through a process of getting it through compassionate release. So just to make people aware, it's not licensed yet. It's in late phase clinical trials, but it's very promising. And certainly phase two, there was a big phase two study which came out looking at its use in patients for, if there were no other treatment options. And there was some really encouraging results. And I think the future is a little bit more bright than it has been Absolutely,

Alyssa: 44:29

and I think there have been some case reports of these cases where it's been used, the compassionate use that have reported successful treatment. So I guess that offers a glimmer of hope on the horizon.

Neil: 44:42

and much needed.

Callum: 44:43

So, Again, thanks so much for coming on, Neil, just to to summarize all the, stuff that I've learned. And certainly, I guess we've talked about three different genera of fungi fusarium, scelosporium, and lamentus. Lamentospora talked a little bit about, we've talked about the significance of these rare mold infections, predominantly in immune compromised with some more niche presentations for some of them the diagnostics and then the treatment, which is limited and in the show notes you'll find we've referenced to a couple of guidelines. Okay. And then for educational purposes, the University of Adelaide website is a really useful resource as well. Anything else that we should be pointing people towards if they want to read up on more? That's probably enough, isn't it? 236 pages is a lot to, to deal with. Thanks again from both of us and from James as well, who I know is a big fan. For coming on the show, Neil, and hopefully we'll be able to have you back at some point in the future and any sort of closing statements that either of you would like to make.

Neil: 45:49

Firstly, thank you for having me on. Again, it's always a pleasure and it's always a pleasure to talk about my favorite topic, which is fungi. It is a topic which is getting more awareness now because it's only becoming more common because we keep talking about this group of immunosuppressed patients. And because of the wonderful advances in treatment of things like leukemia, people are living longer than ever before, but it does mean that there are more vulnerable patients than ever before who are going to get these infections. So it's only going to increase. And it's just something which I want people to be aware of. To know how to start dealing with these difficult infections and to know where to look for

46:24

this Mycology series has been supported by the British Society for Medical Mycology. The BSMM aim to bring together clinicians and academic researchers in the field of medical mycology. For more information, you can find the link to their website in our show notes on notion. Please consider joining up to become a member. Thank you for listening to The Idiots Podcast, the UK's premier Infectious Disease podcast. Questions, comments, suggestions. Why don't you send them into Idiots podcasting@gmail.com. Have a five star review in your pocket at Calm, and I would love to have it. Please drop it in your podcast player of choice. We tweet at idiot under pod, and if you want to donate to support the show, there's a link to do so in the description. But until next time, I'm Jane. I'm Callum. See you now. Now that the episode's done, we hope you learn and had lots of fun. So go forth and treat people with some of what you now know.