115. The Yeasts: PCP/Pneumocytis jirovecii

Listen to this Pretty Comprehensive Pod on PCP. 
Alyssa and Callum cover:

• Epidemiology
• Taxonomy (PCP vs PJP?)
• Diagnosis 
• Treatment

Note this pod episode also includes some Positively Jolly Puns on PJP

Notes for this episode here: https://idiots.notion.site/115-Yeasts-Pneumocystis-jirovecii-ac05a01902b8457688b40c07020f2c2c

Chapters

• 0:00 BSMM PCP
• 20:09 edited to here 19/11
• 27:33 edited to here 6/7
• 32:53 Edited to hre 14/7
• 37:02 edited to here

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 come to discontinue the Tazo sun one day when the S piece done, we'll take our leave and go.

Alyssa: 0:22

Hi Callum, how are you? Oh

Callum: 0:25

I'm okay. I was doing well. And then something happened and it's not so good

Alyssa: 0:29

What's happened?

Callum: 0:30

I had to shave because there was a patient required airborne precaution. That's where my FFP free And then I was growing back my facial hair. In particular, I was growing back my new moustache, or, for Australian listeners, my mole. So I had a new mole, but then I got a cyst on my lip. So I've got a new mole cyst. Yes.

Alyssa: 0:57

That's terrible.

Callum: 1:00

Shout out to Australia, though.

Alyssa: 1:02

It's funny because today we're going to be continuing our Humble series talking about yeasts. do you have a favourite yeast?

Callum: 1:11

Someone the other day asked me my favourite bacteria, and I was really it's tricky, isn't it? I have a yeast name that I know. actually I have to say, and this is not this episode, so don't hate me, but Cryptococcus gatii, I just love the fact that we talked about before, presumably, about the eucalyptus trees and like that whole story to me is like infectious diseases, where it's you're talking to a patient like, oh, you went to Papua New Guinea, did you stand under any eucalyptus trees? And they're like, what are you asking this for? Never relevant, but one day I'll ask that question. And I think that's maybe my favorite Uset for a very silly reason. Do you have a favorite

Alyssa: 1:51

been thinking about this, and I think pneumocystis probably is my favourite yeast. I think it's just quite cool.

Callum: 1:59

Yeah, when I first started learning about this that I was still like, is it a yeast, is it not a yeast? Then is it is definitely something that we see a lot of. In an infection and other specialties as well. So it's pretty common, globally, and,, yeah, can be pretty difficult to treat. So definitely something worth talking about. It's, the first question is it a yeast?

Alyssa: 2:20

Used to be, people used to think it was a protozoa, and then it was only when they started studying the RNA for taxonomy tests that they realised that it was a protozoa. it was found to be a fungus. So it's an atypical yeast., And I find it interesting because it's atypical, so it's different to all the other yeasts. Humans are its only host, so you can't get it from animals or the environment or whatever. It's opportunistic in immunocompromised people, but like you were saying, we see it quite commonly in the group that are immunocompromised. compromised and susceptible to pneumocystis is quite broad, in rheumatology patients or solid organ transplant patients or quite broad patients with HIV. and the other cool thing, it can't be cultured at all. No one's ever managed to culture it in vitro. So it's really hard to study, and understand, its pathogenicity and, look at anti. antifungals and yeah, to research it. That's why I find it interesting.

Callum: 3:32

It's fascinating. Actually, maybe you'll convince me to change my favorite yeast. Maybe our listeners as well. so pneumocystis or PCP, what does that stand for? What are we meant to be calling this? You said pneumocystis gyroveci. What, what's going on?

Alyssa: 3:50

Yes, it's really confusing that the nomenclature and I don't think we've ever recovered from this change. So essentially, the yeast used to be called pneumocystis carinii, but then it was found later that pneumocystis from humans is quite different to the pneumocystis that's found in other animals. So the name Girovecchiae, Pneumocystis girovecchiae, was given to the species that's pathogenic in humans, whereas the name Pneumocystis cariniae continues to be used for, species found in other animals. So the term PCP can still be used, but that's specifically to refer to Pneumocystis pneumoniae, but the pathogen is not PC. PC. PC. P. J. So you could also call it P. J. P. Pneumocystis Gerebecii Pneumumbulae.

Callum: 4:48

I am again, taxonomy changes, confusion, ultimately, when we're communicating, all we need to do is that both people speaking understand. So locally, we've decided to just keep calling it PCP because that's in people's nomenclature and they understand what they mean. And, Changing to PJP, you can do it if you want, but, if you just say pneumocystis or the C standing for cystus now, pneumonia, it's so straightforward. And as you said, before we started recording this, I was like, why did the animals get the, keep the name? Why can't we keep it? Why can't we keep it? It would have solved so much problems, but yeah. So I think we'll probably just call it PCP in this episode, to keep it straightforward, use the term that you want to use. So what makes it atypical? Is there something different in, say, the cell membrane?

Alyssa: 5:42

There is? Oh, yeah. It has cholesterol instead of agosterol in its cell membrane. And that is why we don't use antifungals to treat it. So lots of commonly used antifungals target the agosterol cell membrane of fungi. so things like. Azoles and amphotericin just aren't effective in treating pneumocystis because it doesn't have a gastro in the cell membrane. So that's why we end up using antibiotics to treat pneumocystis.

Callum: 6:17

Human cell membranes have cholesterol. I guess that makes it more, similar to humans. I guess that might affect our treatment options. And as you say, a lot of our antifungals. Are targeting that it will come on to that into our antifungal episodes. But yeah, really, interesting. I actually, I always forget that I think antifungals are something that I struggle with. and as you said before, we can't culture this in vitro. So I guess studying it is quite tricky. But we know that it has two, forms during its life cycle. So initially there's a trophic form, which is, I think trophic just means like body, isn't it? so it's metabolically active. And that's when. You find it within the lungs of infected hosts. It lacks a cell wall, so it's got the cell membrane, and it's doing its thing. And then the other form is the cystic form. So this is a dormant, thick walled structure, so it allows the organism to survive outside the host. The cystic form has beta D glucan in the cell wall, which is another thing that's important when we're targeting these organisms. Is there, does that have any sort of therapeutic implications?

Alyssa: 7:26

so during an infection, both of these life forms are present in a host, so both the trophic form and the cystic form. and it's the cystic form that has BCD glucan in its cell wall, and that's useful for two reasons really. One is that, BCD glucan, and we'll come on to this in the diagnostics bit, is that BCD glucan is used as a diagnostic test. so it's frequently, strongly positive in cases of PCP. And then there is some, thought that perhaps echinocandins could be used, as an adjunct in therapy, because they target the B2C glucan. You couldn't use an echinocandin to fully treat the infection, because it wouldn't be active against the trophic form. But I think there's an RCT going on at the moment in South Africa, which is looking at if there's any benefit in using the kind of candens as an adjunct in therapy. Maybe I can dig that paper out and put that link in somewhere.

Callum: 8:30

Yeah, that'd be great to see and obviously once we get the outcomes, maybe you'll be listening to this episode in a couple of years time and you'll be like of course you use the kind of candles to treat people. What were they talking about? but as always things will advance hopefully. so that's the sort of taxonomy and I guess part of the, biology. Where in the environment is it found?

Alyssa: 8:48

so I don't think it is actually isolated from the environment. It's more that this, it's the cystic form that is transmissible. It colonizes upper respiratory tract of humans and people go through this cycle of, clearance and recolonization. And it's maintained by being passed between people. And then, like you said, it's only when it's, when you're immunocompromised that it then starts to cause Yeah,

Callum: 9:20

I've had a couple of times is about infection control of patients who have PCP pneumonia. And I've always thought, you're going to get exposed to it anyway. People will probably be colonized quite regularly. So it doesn't really make any sense to need to do respiratory precautions. Do you think that is the case? Or if someone's got it, then obviously they're going to have a higher burden of it and potentially more infectious and we should be isolating these patients.

Alyssa: 9:44

And I think, yeah, so we should, I do think we should be isolating these patients. There have been, outbreaks on, I think it was like a hematology waiting room where, a patient had, PCP and then transmitted it to several of the other immunocompromised patients. So there is, rationale for isolating patients. And like you said, if somebody's got active infection, they're going to have a higher fungal burden, they're going to have respiratory symptoms that are going to, probably be able to transmit it more effectively. so it's one of the few, yeasts that, or fungi that you need to think about from an infection control perspective. And then I think just generally, after COVID, if somebody comes in. And they've got a cold. There's definitely a move where we are that actually should we all be wearing a mask if we've got, a bit of a cold because we're going to be spreading whatever virus or pathogen that's causing it. And I think there's good logic to that, in that we don't always know what's causing our runny nose.

Callum: 10:52

So what about the clinical side of things? what does this cause, in these patients that are at risk? What's the disease?

Alyssa: 11:04

It's transiently colonized as upper respiratory tract of adults and children and it's thought that we're exposed from a very young age. And generally it doesn't cause any symptoms or it might cause, minimal symptoms like runny nose, particularly in children, but it causes, disease in patients with T cell deficiencies. So this is quite a broad, group of patients. There's lots of different risk factors for getting, Pneumocystis, disease. So I think the most widely thought about one is, HIV infection. It's got a really strong association with Pneumocystis. But actually in, in the UK, where we don't have such a high incidence of HIV, we're seeing that the majority of cases are occurring in our non HIV population. So they've got risk factors such as solid organ transplant, underlying cancer or hematological malignancy. I think prolonged cortico steroid use is a really important one. and then use of other immunosuppressive drugs like, chemotherapies for treating cancer, or drugs that are used to prevent transplant projection.

Callum: 12:23

And, obviously some of those are quite common in terms of prolonged corticosteroid use, is there like a cutoff? dosing that you might consider, because some people will be on maintenance, adrenal insufficiency, five milligrams, six milligrams of PrEP a day. When do we start worrying about this?

Alyssa: 12:41

So my understanding is that when corticosteroids used for, as replacement in adrenal insufficiency, that isn't immunosuppressing in the same way as when it's used. As a high dose for therapeutic reasons. and I think there's probably some thought that it's even higher risk if the corticosteroids used as part of a multi drug treatment. So in addition to, an immunosuppressant for transplant rejection, for example. so it's hard to pin down exactly what dose and duration your patient's going to be at risk. But I think the general thought is that if they're at, if they're on more than 20 migs, of prednisolone a day for more than two to four weeks, then you need to be thinking, are they going to be at risk of PMP and do they need to be on prophylaxis?

Callum: 13:35

It is interesting that we have quite a broad brush, I'm sure immunologists have a more nuanced view on it, but certainly my practice, often it's like, they're immune suppressed, they're not immune suppressed. As you say, there's going to be a spectrum of, the patients that just had a solid organ transplant on their own, MMF and tachylimus and prednisolone and maybe something else. Down to that low dose, borderline. steroid use. I don't know. Maybe there's some sort of immunosuppression score or something I don't think my impression, you don't have to be that, compromised to be at risk of it as opposed to some of the more, unusual opportunistic infections patients with CD4 counts of less than 50 in the HIV terms. I usually have quite a high index of suspicion for this, even if they're slightly immune suppressed and they have a clinical picture that matches. Coming on to it. What are there clinical pictures?

Alyssa: 14:26

So I think that there are three main clinical forms. The first one is asymptomatic or very poor, asymptomatic upper respiratory tract infection. a bit of a runny nose or just no symptoms at all? the main one is, PCP, so pneumo, pneumocystis, vei, pneumonia. so that is the main, that's the most important clinical syndrome that we see with this pathogen. And then you can very rarely get extraculmonary disease. and I think that's mainly in, patients with advanced HIV.

Callum: 15:01

And just what sites do we see extra pulmonary disease

Alyssa: 15:04

The most common organs involved are lymph nodes, spleen, liver and bone marrow, but essentially it can affect. Any site, but it is extremely rare.

Callum: 15:15

Yeah, it's, it's pretty small print and, we've put a longer list and a reference in the show notes talking about it, but, won't dwell on that any further. I guess PCP when we see it, the presentation varies. So when you see these patients come in, it's usually pretty insidious, they've got this sort of slow onset, shortness of breath, particularly on exercising, there's a non productive cough generally, with their exercise tolerance going, days to weeks, maybe even months. And sometimes there's a history of fever as well. Not always, I would say.

Alyssa: 15:46

Yeah, and I think that's what you've described there is particularly true for patients with HIV, and that's who we've classically thought of as the adverse group for PCP. But actually the clinical presentation for non HIV patients is quite different. So it can be much more acute and aggressive with much more rapid, deterioration as opposed to the more insidious, insidious onset that you see in HIV patients. So they can get, quite acute onset of fever, shortness of breath, nonproductive cough, and often have quite severe hypoxia.

Callum: 16:27

Definitely. And, that sort of hypoxia in the HIV patients that I've seen with this, often they have, normal oxygen saturations when stationary. And, sometimes we do, I think less so now, but, we used to often do, a, Exercise like a walking desaturation test. So you would get like your sats probe and mine are always on the trolleys. You're like walking awkwardly next to the patient, reeling this trolley. The wheels don't work very well. And they're walking on the corridor of the sats probe on and you see their sats drop quite dramatically when they start mobilizing when they were normal at rest. Yeah, I think once you've seen it a couple of times, it does have quite a classic, pattern. But yeah, as you say, not the same pattern in the non HIV, patient. And so having that high index of suspicion and then when you examine, so I guess auscultation it's, fine crackles, I would say,

Alyssa: 17:21

Yeah, I think so. Fairly widespread.

Callum: 17:25

yeah, it can be that that Velcro type fine crackles or you might hear nothing or there might be a bit of a bronchial breathing sometimes. how about in the. Infants, does it present differently there?

Alyssa: 17:37

So I think in infants it mainly presents with, cyanosis and respiratory distress. I don't think I've ever seen a case in an infant,

Callum: 17:45

No, me neither. I imagine similar, I guess not seen it. And then, I guess other diagnostic tests you do. So chest actually often found this sort of diffuse bilateral and distal sugar and glass changes. it can be a low bar or it could be nodular as well. I think that's more advanced. CT is really You know, extremely useful because sometimes the subtle changes in early disease can be missed in a chest x ray. And again, you'll see ground glass consolidation. It might be more central predominance. And, that, that can be hard to pick up. The other thing is, to be aware of clinically is, as you progress in the disease and you get later disease, because it's like now, the mechanisms are poorly understood, but you get these small, like blisters or like air pockets on the lung and then they burst. And so you often get pneumophoresis or, other issues like that. so that's quite a common complication that I was worried about is like pneumothorax and I've been seeing a couple of people with that get really sick, need big chest strains and so on. Do you understand more about why that's happening?

Alyssa: 18:49

No, that was actually news to me. I don't think I've seen that before. Yeah, and I think like you said, because it's, it is really hard to understand, how this yeast causes disease because it's so difficult to research. yeah. But I think probably the main kind of take home message is thinking about how it can present differently between different groups, and, don't, I think that very classical sort of presentation in HIV populations that you described of more of an insidious onset with exertional hypoxia is really not necessarily the picture that you get in, in non being a low threshold for suspicion. When you've got a patient with, who's unwell with pneumonia who has a risk factor for the PCP.

Callum: 19:42

I've had quite a few phone calls where they phoned up and said, we've got someone with COVID Pneumonitis. And then when you dig into the history, you're like, like this sounds this doesn't sound like COVID, we don't see that much Pneumonitis these days. The other thing I would say is flipping around. And if you're seeing a patient who's presenting with an insidious onset. Syndrome, a bit like this, and that, it's not getting better if normal antimicrobials, do an HIV test, because the number of people that have seen that this is their first presentation of HIV, so just because we're saying, this, they might not know they have HIV, but they may well have

Alyssa: 20:18

Yeah, absolutely. Yeah.

Callum: 20:20

And when we see late diagnoses, and review them quite often, you'll see that they presented with symptoms before and there was missed opportunities to test earlier because it wasn't thought of in the differential. So I think, yeah, I and that earlier diagnosis and pick up and starting treatment earlier, you're gonna have much better outcomes than if you have a later treatment. Yeah, you're suspecting it. You've maybe listened to a podcast about it recently and thought, Oh, I wonder about PCP in this patient. How are we going to diagnose it?

Alyssa: 20:52

So as we've already said, you can't grow it. So you can't even try to do cultural sensitivity. So the main ways of diagnosing it are seeing it down the microscope. So microscopy molecular detection using PCR and then antigen detection. So should we talk a bit about microscopy first?

Callum: 21:12

Yeah, I don't know. I've never seen it or, looked at it for a microscope. I don't think locally we, we really do that. I don't know. Is that a commonly used test and how does

Alyssa: 21:20

So I think it's like the historic gold standard, but it's. really being replaced now by molecular methods of diagnosis. So I do remember seeing it in Bristol probably about 10 years ago, and at that time they were just phasing it out and bringing in molecular assay to replace it. But it is still considered the gold standard. Although it's not hugely sensitive microscopy, yeah, is essentially detecting the cyst or trophic forms of pneumocystis in clinical specimens, that usually is sputum or VAL. And there are different stains that you can use. It's mainly used, it's mainly done using immunofluorescent stains, so using monoclonal antibody that fluoresces to, to detect it. I don't know why it's usually green. And this will stain both the cysts and the trophic forms. So you'll see these kind of like green circles light up against a dark background. And then you can get different histopathological stains, such as gray cotton, glory methamin, silver, or geiser geiser stain. And chalcofluor fluorescent stain. immunofluorescent stain. It's the fluorescent stain that binds to B 2D glucan in the fungal cell wall, where these aren't specific for pneumocystis veii like the immunofluorescent stain is specific for it. And they're slightly less sensitive. And the Grey Cockamorie stain stains them black. And they can often look like little ping pong balls that might be squashed. So one side of them is slightly squashed. You don't see budding when you look at them under the microscope. You just see them on their own. And they're often found in this sort of cluster like honeycombs.

Callum: 23:12

As such I really hadn't, didn't know much about microscopy. I think I probably read it in an SMI at some point. But do you think there's any role for that now? Is it, I wonder if it's a ref lab test? Might help or do you think it's just completely replaced by what we're going to come on to next?

Alyssa: 23:26

Yeah, so I think it's probably being phased out. And one of the issues is that then you de skill your microscopist, so if you did want to do it, people aren't going to be as, used to doing it, so then that's going to reduce the sort of inherent sensitivity. I think the histopathological stains and the calcifluor white they're non specific, so you might be doing that anyway on your on your tissue samples and then you might pick up the pneumocystis. But I do think the main diagnostic method really is PCR now.

Callum: 23:59

So we talked about molecular PCR, when can we perform that and any sort of hurdles to think about?

Alyssa: 24:06

So PCR can be performed on upper respiratory tract samples, sputum, BAL. And you need to consider the sensitivity and specificity of PCR at these different sites. So PCR on BAL is really sensitive. So negative result from the BAL sample, generally you can exclude PCP in this patient. Then if it's positive, because it's so sensitive, if it's a low level positive, could that be reflecting sort of colonization or maybe even assay contamination? So a positive PCR on a BAL, you really need to interpret it in the context of the fungal burden. So if there's a high high burden of fungi, then that's much more likely to be, pCP as opposed to colonization. And I think using PCR on other samples such as sputum and other respiratory tract samples was historically thought to just reflect up an airway colonization if you got a positive result. There was this recent systematic reviewer meta analysis by Lottie Brown in CID published this year. which actually found that PCR on upper respiratory tract samples is highly specific. So it's now thought that PCR positivity of upper respiratory tract samples probably more reflects higher burdens of fungus in the lower respiratory tract as opposed to colonization. So I, I think. PCR can be used on any respiratory sample, but you just need to interpret it in the context of, the patient's presentation, their beta c glucan result that we'll come on to in a moment and the burden of the fungal infection that they have.

Callum: 26:07

that is really interesting. I'm just thinking about an example where we had someone. trying to remember the case, it was maybe a year or two ago before this paper came out and we were really suspicious of PCP and there was a bit of debate at the time because we, I can't remember exactly why, but we couldn't get a deep respiratory sample. They were, they had a non productive cough, which is common with this, as we said earlier on. So it's non productive and historically would have done induced sputum. Getting a physiotherapist and to do that, but that sort of a service has been withdrawn locally. So we couldn't couldn't get any deep samples and I can't remember how, I think it might have been by accident that the PCR was done on a viral throat swab it was positive. And there was a debate about what that meant and people talking about colonization. And I felt at the time that actually it was still useful because although we have to accept it's got a lower sensitivity, if it is positive, what does that mean? Probably. So actually, yeah, maybe this could be practiced, I need to go read the paper and properly maybe do another episode about it. But in that paper, they're quoting a sensitivity of 89%. That's something to sniff at. 95 percent confidence, all of 71 to 96. 5. But if you can't get a deep sample, then maybe that's fine. And then the specificity of 90 percent is just about as good as the other samples, if not better. Wow. Yeah. Okay. That's really interesting.

Alyssa: 27:43

I think in our centre, generally, We've only ever performed Pneumocystis PCR and BAL because it's felt that if you get a positive or a negative on a sputum sample, then what does that mean? But then often, as we were saying, the majority of our patients with PCP and non HIV patients, and they're often quite sick. And often they're too sick to get a deep respiratory sample, or you don't want to delay their treatment whilst waiting for that. So actually, I think this paper really highlights that actually PCR on sputum and upper respiratory tract samples can be helpful, because if it is positive, it's telling you that pneumocystis is there, and it's probably there in higher amounts in the lower respiratory tract, as opposed to just telling you that they're colonized.

Callum: 28:36

yeah, all the sort of medical stats, sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio, positive and negative, getting your head around that is a big part of medical training, isn't it? But what I like in this paper is they've included the positive and negative likelihood ratios. And for all three different ways of doing it, BAL, induced sputum or upper respiratory tract samples, if you've got a positive, it makes it much more likely.. But the negative likelihood ratio, so that was one issue is that, if you do a throat swab and it's negative, does it actually help you because you're not getting the deep sample? And for BAL is 0. 014 range for induced sputum 0. 02. And not as good for upper respiratory tract samples at 0. 12, but still, 10 percent as likely is it so it's really helping you in your differential diagnoses. If it's negative, it's not as good. But yeah, great. Okay. I need to go. I'm going to sit and read that paper. And I'm, I think I actually needed something to present at journal club coming up. So I've just got my paper, which is great.. You mentioned androgen detection how, what about that?

Alyssa: 29:41

Yeah, so as we said earlier, the cyst form of Pneumocystis has got beta D glucan in its fungal cell wall. And beta D glucan detection in blood is something that we commonly use to help diagnose fungal infection. So when patients with PCP. The B 2D glucan is often vary rates, so you'll see quite high high levels of B 2D glucan in these patients. But it's important to remember it's, this is a kind of panf fungal test, so it's not specific for PCP. And then equally, I think the main value of B2C Gluard is its negative predictive value. So if you have. Negative BCD, we have particularly serial negatives, then it's highly unlikely that the patient has PCP.

Callum: 30:36

I was like thinking about pre and post test probabilities, it's probably the way I often think of tests the most, so as with all these tests we've talked about there, if you're a pre test probability, so before you do the test, you think it's highly likely to be PCP and you get a negative result. It's still possible to have

Alyssa: 30:53

Yeah.

Callum: 30:54

You do a B2D Glucan and it's negative, but everything else points towards it being PCP, don't give up and keep pushing for that BAL or whatever else you're going to do. But if your pre test probability was pretty low, then actually just doing a B2D Glucan, if it's come up in the differential, but nobody believes it, that's going to be actually probably more helpful because your post test probabilities can be very

Alyssa: 31:13

Yeah. Yeah. So then it's quite good for ruling it out. Yeah. Yeah.

Callum: 31:18

yeah. And it's a much easier test to do in some ways if the patient's not productive, but, or maybe you should just do a fruit swap.

Alyssa: 31:24

Or like an oral pharyngeal wash.

Callum: 31:27

Okay. Yeah. Yeah.

Alyssa: 31:29

And I think, and we would have touched on this in the fungal diagnostics episode, but fungal diagnostics are imperfect. As as with all diagnostics, but I think it's, particularly true for fungi. This algorithm that I've put in the Notion notes really helps your thought process when diagnosing PCP. And I think it's important, like you said, to, you have to have a risk factor. You don't get this disease in people who, have completely normal immune systems. So if you've got a patient who's at risk, who's got clinical syndrome, which could be compatible and pneumonia, essentially. The subsequent diagnostics, whether that's microscopy or PCR or B2G glucan antigen detection, or the radiological features, all has to be taken in context together. So I think if you had, a low positive on the BAL for PCP PCR and a negative BCD glucan, and, the patient didn't have convincing clinical signs, then that low positive probably reflects colonization. Whereas if you've got a low positive on your sputum, PCR with a high beta glucan, then you're much more likely to be thinking, yeah, this could be PCV. So it's about taking those things together, not just one test in isolation.

Callum: 33:04

So we've got that patient, we were suspecting it, and we sent the tests, and we've confirmed, we think this is PCP, how do we treat this?

Alyssa: 33:13

As we were saying earlier, pneumocystis, jirovecii atypical fungus, so you do not generally reach for the antifungals. Most of them are not going to be effective. So by far the main drug of choice for PCP is cotrimoxazole. And I think that's widely accepted that is the best agent for treating PCP and is your first line drug. And that's both for treatment and for prophylaxis. Of PCP in patients who are at risk. I mentioned earlier that, that because the cystic form has got BC glucan in the cell will, the echinocandins will have some activity against this. So they might be useful as an adjunct in therapy, but not as a standalone treatment.

Callum: 34:05

Yeah, I think, have you used that clinically? I think we've talked about it in our MDTs as an option. What's the sort of evidence base behind the kind of candid angle? Is it, is that something that there's, we've got clinical data to, to back it up or is it more of a theoretical thing? If you don't know, I can just take that question out.

Alyssa: 34:19

So I think it's quite limited at the moment. I think there are, case reports and case series of the kind of pandens being used as an adjunct or as an alternative in patients who can't tolerate cotrimoxazole. But it's established practice in guidelines yet.

Callum: 34:34

Hopefully we'll get some data about that soon. So in the treatment, I think it differs between HIV and non HIV patients. So treatment in HIV. So that's high dose. Cotrimox is offered for 21 days. What do we mean by high dose cotrimoxazole? This is confusing because sometimes the dosing recommendation guidelines is weight based, sometimes it's dose based, sometimes it's tablet based, and sometimes they talk about weight based of the trimethicone component of cotrimoxazole. Why? Anyway, Jay Mobile to answer why, because he's told me before and I can't remember, but long and short of it is when we say high, it's our standard dose of cotrimoxazole for say, a bacterial infection is 960 milligrams twice a day? Not weight based, but for most people, so say 96. Nine, say for a 96 kilogram person, that would be 10 milligrams per kilogram of cotrimoxazole, wouldn't it? A relatively low dose. In UCAS dosing consult, at dosing guidelines, they talk about high dose cotrim, and there they talk about double dose, so one eight two zero milligrams twice a day. Which is interesting for certain organisms or certain sites of infection bacteria we're talking about when we're looking at PCP. The high dose in vir commas is 120 milligrams per kilogram per day in divided doses, which is often three times a day and of como cotrimoxazole. And that's equivalent to 20 milligrams per kilogram of the trimethoprim component. And if you get it confused, so cotrimoxazole is made up of one part of trimethoprim to five parts of sulfonamethoxazole. So if you wanted to if you wanted to convert from that milligrams per kilogram of trimethoprim components, you times it by six. I find that a really confusing way of doing it, is the trimeframe component. I wish they would just do it by codrem. That's a huge dose say, now, a hundred kilogram person, it's just because the maths are super easy. That's, what, a hundred times a hundred and twenty, which is twelve thousand milligrams. So divide that by three, it's four thousand milligrams. Three times a day,

Alyssa: 36:57

yeah, next.

Callum: 36:59

compared to 960mg twice a day, so we're talking about a big dose. I think in the BIVA guidelines, the British HIV Association guidelines, they talk about three days of 120mg per kilogram and then you drop to 90mg per kilogram per day.

Alyssa: 37:15

Yes, you start off on that higher dates and then you drop to what's still a high dose. It is a huge dose and it's going to have issues. So in generally in sort of patients with severe PCP. You start with intravenous, and then once they're, improving, I think that the general sort of strategy is then to switch to tablet form, or if it's fairly mild PCP at presentation, you can start with the tablet form. But the intravenous form, it's going to be big volumes, and the tablet form is going to be a lot of tablets.

Callum: 37:50

Yeah, I think most tablets are 480mg. You can get 960mg tablets as well, I believe, which is a sort of double strength tablet if you ever see that in guidelines. Yeah, it's a huge dose and that volume load and I always worry about, you've got this patient and they come in and they've got, a respiratory disease. Maybe they're comorbid, particularly or non HIV patients. Maybe they've got a bit of heart failure. You're giving a huge fluid load, you're giving a huge salt load, you're using that cannula a lot. And we know that cotrimoxazole is excellently bioavailable. I certainly push to try and oral switch these patients. As quickly as possible or whether we really need to give them IV in the first place because of all those sort of risks that are involved. Now at this point, I'm going to have to say something because if James was here and he's abandoned us, although we're doing this about him, so I can't really say he's abandoned us, but he would, I think, come and throttle me if I didn't mention this time that there's some controversy about the dosing and I'm, we're not going to dwell on this or go into depth because I think James is so passionate about this topic I would hate to talk about it without him. So he's going to come back and we're going to do a deep dive addendum episode, on code room dosing in PCP. But there were some newer studies saying actually, could we give lower doses and seem to find equivalent outcomes. And when you look back at the original data to support this higher dosing, it's quite sketchy. But as always, once you've established practice, it's very hard to change practice, which is, the accepted standard of care. Anyway, that's a sort of a teaser for that and I won't go into that in any more detail lest we have an hour and a half long episode. So that was the first line treatment in HIV positive patients. What about the other treatments? So say you've given them this very high dose of cotrimoxazole and they get a massive AKI and hyperkalemic and their fluid overloaded. Or they've got an allergy or other issues which will come on to you. What else can we use?

Alyssa: 39:55

So then you're going to your second line options, which include the atoquavone Clindamycin plus Primquin, or IV Pentamidine. So those are the main second line options.

Callum: 40:10

Yeah, they they're second line for a reason. These are quite toxic drugs, I guess would fair to say. Yeah. It's a tovaquone or clindamycin bispurenquine. Is that right?

Alyssa: 40:21

Yeah.

Callum: 40:23

Yeah. None of these drugs are not toxic. And I guess, as we said earlier on, it's got some more similarity to. to human cells about cholesterol., I think people have tried using nebulized pentamidine as well. What, where would you go for sort of treatment guidelines? I tend to go to the BIVA guidelines, the opportunistic infection. Guidelines are local antimicrobial guidance. I've got some stuff, but it really just deals with first line,

Alyssa: 40:46

Yeah, and that's where I tend to go as well, is the VIVA guidelines, and then I either amend that to the non HIV patients, or there's also the ECIL guidelines for treatment of PCP and non HIV patients.

Callum: 41:02

Every specialty seems to produce their own guidelines sometimes for these types of infections. Like screening pre biologics, rheumatology, dermatology, GI, everybody seems to do it slightly differently, which is always interesting. I think IDSA got pretty good PCP. Guidelines as well. All these drugs are certainly second to third line and it's quite complicated. But it's not unusual that you're in a situation where you're having to look at those either because you've started them on cotrimoxazole and you've run into problems. I think it's one reason to think about the lower dosing because you get less toxicity that way. And, maybe that'll be the future. Who knows? But the other thing is that there are certain sort of things to think about before you start high dose cotrim. The first one is G6PD deficiency, so glucose 6 phosphate dehydrogenase. And if you have a deficiency in this, then you're, essentially, your red cells are less able to get rid of oxidants. And so you get this hemolytic anemia. And having seen this in someone with a severe G6PD deficiency it can be quite scary managing that. I think many guidelines recommend checking for G6PD deficiency before starting high dose cotrim. We didn't do it for normal dose cotrim, but it's not as much of a risk. But that and also primoquine or dapsone, which are the treatments we use. It also says that you shouldn't really delay treatment. So if you've got someone really sick of PCP, you just need to get them started and get a G6PD screen sent off. And then management, if they do have that, will be in conjunction with a hematologist. So I'll link in the show notes some papers about G6PD deficiency. We're not going to go into it because it's not a hematology podcast, you can grade it by severity. And really G6 PD deficiency varies quite greatly by ethnicity it particularly would worry about this in groups. I think it's Middle Eastern and Mediterranean ethnicity is the highest risk, but also some areas of Africa. Certainly something to think about. And if you've got severe G6PD deficiency and PCP it was already not that many treatment options and then you're really getting quite stuck. And then the other thing to think about is like sulfa allergy. So it's not uncommon to see people with sulfa allergies. And there's again, some guidelines about. What to do in those circumstances, which we go to depth into is getting quite small print, but there is some people looking at What to do with those patients because sometimes people get a rash and are labeled and as we've talked a lot about penicillin allergy, although you have a label of a soft allergy It may not be true and just like the pen fast score. I know that jason trubiano Presented some data ekmed in 2023 about they were working on something called the soul fast screen score, which was to look at these allergens to assess if it was a true allergy or not, which would be really useful if they once they serve, if that is if that works and it's validated.

Alyssa: 43:51

and I think another point to make is that all of these drugs have side effects and they're quite toxic, aren't they? So we know that cotrimoxazole has got the best data for efficacy, and it is definitely your first line, and that it can cause bone marrow suppression. But then your second line drugs, like the plimdomycin primerquin combination, can cause neutropenia. Pentamidine can cause bone marrow suppression as well. You might run into similar issues with your second line agents as well. And they're not, clinically as effective. So it can be tricky if for whatever reason you need to switch away to the cotrimoxazole. And it can be tricky and, making that decision as to when to do that and what to switch to.

Callum: 44:37

Yeah. These are all, these are decisions often made with conjunction of support from colleagues in an MDT format when you're getting to second and third line therapy. So we've not gone hugely into depth in that. But certainly there's lots of, there's lots of papers are talking about that, but I guess the main issue is we just don't have the clinical trials to support decision making there.

Alyssa: 44:57

How would your treatment approach differ than, Callum, between treating PCP and someone with HIV compared to treating PCP in someone who doesn't have HIV? Yeah,

Callum: 45:12

and the treatment is a little bit different. Again, it's high dose cotrimoxazole. I guess in these circumstances there might be other things going on. In terms of the people that I've treated of HIV PCP have generally been a bit younger with less comorbidities. And in non HIV, they maybe have a higher rate of sort of other organ disease, renal impairment, which sometimes hampers your ability to give your first line treatment more. And the second line options are the same as in HIV. The main difference really is that role of steroids. So they are recommended in HIV, but they're not recommended in non HIV cases. They can be considered. I think that's because there was some trial data suggesting that it just didn't have the, that it didn't have the mortality benefits, but there is good evidence in HIV, which is summarized in the BIVA guidelines. Is that your

Alyssa: 46:00

that's my understanding as well, in that yeah, there's good evidence for the mortality benefit of adjunctive corticosteroids in HIV patients with HIV and PCP who are hypoxic. Whereas you just don't have that data in the non HIV population. So I know some of my colleagues will extrapolate that and will give patients corticosteroids. And some of the rationale is to reduce that inflammation in the lungs. But it's really be considered on a case by case basis. And also one thing I've always thought about is, quarter case steroid uses is a risk factor for PCP. They've got their PCP because they've been on steroids. Do you then give them more? I don't know. So yeah, I think it, I think that really depends depends on the case. And like you said, there's the IDSA guidelines, the ESIL guidelines which stands for European Conference on Infections in Leukaemia. So they've got some good guidelines for PCP that will talk through some of this in more detail.

Callum: 47:08

Just touching on the pathogenicity, essentially pneumocystis, it binds your type one alveolar epithelium and that is when it transforms from that trophic form to the cystic form. Which is bigger. And that adherence isn't the singular cause of alveolar damage. What really caused the damage is the inflammatory response that causes a significant lung injury and that leads to impaired gas exchange and hypoxia and respiratory failure. And that is, part of the reason why we might use steroids. Okay. So that's a sort of overview of the treatment. As I say, I think we'll come back and take a bit of deeper dive into the. Coaching dosing, because that is quite a topical debate. But the treatment, I guess is, to summarize, difficult to tolerate and catching it earlier, it makes it much easier to treat and late disease, quite get complications. These patients might be in the intensive care units and it can be Scott, I think quite high. Mortality. I think I there's not data. Yeah, the steroid dosing, I think it's usually prednisolone you use. You start with 40 And I guess the other thing, prevention is better than cure, isn't it? So we talked about these high risk. patients earlier on. I guess what's your, what's the approach to prophylaxis? This is something that I guess we get involved in writing guidelines on as infection specialists, it's not the people doing it often.

Alyssa: 48:35

Yeah, so I think I think it's quite clear in patients with HIV, who use prophylaxis. So people who have a CD4 count less than 200 should be on PCP prophylaxis. First line for prophylaxis is similarly cotrimoxazole, and that should be continued until their CD4 count is sustained above 200. Whereas it's much more grey with non HIV populations. Solid organ transplant, I think the highest risk is in their first six months post transplant. So they're likely to be on PCP prophylaxis during that period. But the risk varies slightly with which organ is being transplanted. And, what other anti rejection drugs they're on as well. So you might end up extending the prophylaxis beyond that six month period. Then we were talking earlier about the risk of corticosteroid use. High doses for long periods put patients at risk of PCP. Establishing, what dose and duration combination you need to start prophylaxis is tricky and needs to be taken into context with other, other risk factors, such as if, the corticosteroids is part of a a treatment for an autoimmune condition where you're also using a biologic agent which has some some risks. And I don't think there are super clear guidance on prophylaxis for non HIV populations. Thank you.

Callum: 50:12

On the for cellular organ transplant, it would be routine to give cotrimoxazole for the initial period when they're more severely immune compromised and drop it down. It will depend on indication to indication and what that specialty is. guidelines have said. I guess the main takeaway I've heard is you should consider it as a risk. If they've fought to be high risk, you should consider prophylaxis and there'll usually be specific guidelines for each indication. As you say the HIV guidelines are a bit more clear there was the old sort of previous guidance, which were from 2011 just on opportunistic infections in total, which are slowly being replaced with individual guidance. So there's 2024 guidelines on pulmonary infections. So fairly recently. Published. And as you say, that's the sort of indications for prophylaxis. So you could try and extrapolate that. Obviously your first time prophylaxis is going to be courtroom. You can either do 960 or 480 once a day. Or you could do 960 free times a day. Relatively, yeah. Advantage, less tablets at this advantage. I don't know of anybody else, but I think remembering to take a tablet on right. If you take it every day, it becomes one of your routine again and it can be a bit more complicated. I guess it's probably going to come down to patient patient preference. So we'll link all these guidelines in the notes. But I think the updated. Either guidelines are useful. And maybe we can we can do a bit more of a deep dive into that in the future when we're talking about HIV in general, because they're I guess just to wrap up resistance or to finish resistance, I guess we know a little bit about that, intrinsic and acquired resistance, but I imagine it's quite tricky to study given that we can't culture it.

Alyssa: 51:48

Yeah, no, exactly. It's a difficult one with PCP. So Like you said, we know what it's intrinsically resistant to. It doesn't have a gosterol in the cell membrane, so your polyenes, so amphotericin, and your azoles aren't going to be effective against it. And we know that only the cystic form has got BCD glucan, so your echinocandins might have some activity but trophic form. And then acquired resistance. I think there is evidence that mutations can occur in dihydrofolate ductase and dihydroteroate synthase, which can lead to resistance to cotrimoxazole with first line therapy. How you suspect that resistance, if you have a case which is just not improving on cotrimoxazole. And I don't think it's clinically available at the moment, but I imagine that in the future there'll be PCR assays that will be able to detect common mutations that confer cotrimoxazole resistance. But yeah, like you said, you can't culture it, so it's I think it's gonna be entirely molecular the way that acquired resistance is identified in the future.

Callum: 53:09

Yeah. There's a small section in the Beaver Optionistic Infection Guidelines 2024, and I'll just quote and they say mutations in dihydro. Teroate synthase gene that confers sulfur resistance in other organisms have been described in pneumocystis, but their clinical significance is unclear. And they give a reference for that. And they say people develop PCP whilst on prophylaxis, you can still give them high dose to treat. And as if a lot of, um, resistance, and UCAS are doing a lot of work on this is. What's in the lab in the in vitro is one thing but or detecting the gene either, but it's about clinical outcomes that we need the clinical data because, you might do a PCR and find a gene, but does actually mean it's going to fail. You don't know unless you do the clinical study. So, perhaps I'll get better of time and we will have more molecular ways of screening for resistance as we do have many other things. So yeah, so just to recap what we've gone over so we talked about pneumocystis gyrevecchiae the taxonomy, some of the naming controversy in CETL and PCP who gets it, and then the, epidemiology globally, the clinical syndromes that you get and a little bit about extra pulmonary site, but mainly talking about pneumonia. How to diagnose it in the lab, do a PCR, and then treatment in particular, some difficult to treat groups, and finally, the resistance. So that was what we might call a pretty cool pod.

Alyssa: 54:35

Yeah, that was a great PCP, yeah.

Callum: 54:39

Okay thanks as always.

54:41

This Mycology series of episodes is sponsored by the British Society for Medical Mycology. The 59th BSMM annual conference is due to take place in Norwich from the seventh to the 9th of September, and aims to bring together clinicians and researchers in the field of medical mycology. Registration is only two 40 for trainees and includes accommodation and meals. Abstract submission is now open and we welcome abstracts on research, clinical cases and auditing QI projects in medical. Visit www.bsm.org to register and submit your abstract. 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 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.