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Sara Dong: Hi, everyone.

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Welcome to Febrile, a cultured podcast about all things infectious disease.

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We use consult questions to dive into ID clinical reasoning, diagnostics, and antimicrobial management.

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We're here with another Febrile StAR episode.

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These episodes feature topics and authors from the CID Journal State of the Art Reviews.

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So let's meet our guest stars.

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Daniel Chastain is a clinical associate professor and ID pharmacist at the University of Georgia College of Pharmacy in Albany, Georgia.

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Daniel Chastain: Hey, I'm Daniel.

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I'm excited to be here.

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I really appreciate the invitation to talk about the risk of opportunistic infections with steroids.

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Sara Dong: Megan Spradlin is a Senior Instructor within the Division of Medical Oncology and Division of Hospital Medicine at the University of Colorado School of Medicine.

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She is also the Director of Quality and Patient Safety for the Division of Medical Oncology.

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Megan Spradlin: Hi, I'm Megan.

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I'm excited to talk about steroids today.

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Sara Dong: Hiba Ahmad is a board certified clinical oncology pharmacist in genitourinary medicine at the University of Colorado Cancer Center.

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Hiba Ahmad: My name is Hiba.

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I'm happy to be here.

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Sara Dong: And then last but not least, Andres Henao Martinez is faculty in the Division of Infectious Diseases and Department of Medicine at the University of Colorado.

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Andres Henao-Martinez: Hi, my name is Andres Henao, faculty at UC Colorado.

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I'm very excited to be here, and talk about science and steroids with risks of infections.

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Sara Dong: Alright, now that you've met our guest stars, as everyone's favorite cultured podcast, we love to hear a little piece of culture, just something non medical that brings you happiness.

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Hiba Ahmad: In my free time, I just love being outdoors, hiking, skiing.

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If I wasn't in my current profession, I'd love to be an interior designer.

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Megan Spradlin: When I'm not at work, I also like to be active, hike, play pickleball, volleyball.

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Daniel Chastain: My family and I like to travel.

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We like to experience different cultures and hopefully become more culturally aware.

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We have a three year old son, so certainly trying to expose him to different parts of life and different people.

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Andres Henao-Martinez: I have a number of different hobbies, but one of them is classic films and classic cinema.

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One of my favorite, you know, filmmakers are Andrei Tarkovsky and Antonioni.

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So, that's a little bit of piece of me to share with the audience.

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Sara Dong: Well, I always like to start off by saying thank you for creating your state of the art review article, and it is entitled,
I should say, Unintended Consequences, Risk of Opportunistic Infections Associated with Long Term Glucocorticoid Therapies in Adults.

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Before we actually jump into some of the content, I think it's helpful if you give us a little bit of introduction and sometimes people
talk a little bit about either their process when they were starting out, maybe what sparked your interest in talking about this topic.

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Daniel Chastain: First, uh, certainly a big thank you to Andres for really suggesting that we submit a proposal to CID.

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I think that, you know, we all, all saw the call for proposals.

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Andres is more of the believer in things getting through.

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I'm more of a think, oh, that's a, you know, that's a really good idea.

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It'd be nice, but, you know, no chance that that ever, ever gains traction, but, you know, sure enough, get an email and it's like, hey, let's submit a proposal.

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So put together an outline and submit it.

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And that was, you know, positive feedback on it with, I guess, probably really more so the outline was focused on what are the risks and then how do we prevent opportunistic infections.

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And so as we started to put together the article, the common denominator among all these things are prednisone equivalents and, you know, this equivalency of steroids.

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And so as I started to figure out where that came from, everything went back to this pharmacology textbook, and there was really no primary literature that you
could necessarily find other than some mention of glucocorticoid receptor binding, and to make a long story short, that ended me up in data from the 60s, 70s, Dr.

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Fauci's data, I think in late 1970s, that everything was starting to focus on, you know, differences in steroids beyond just
their dose equivalences, in terms of, you know, is dexamethasone the same as methylprednisolone is the same as prednisone.

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And so as we, you know, got all of this experiential data or experimental data and then into the clinical data, our goals really kind of became, how do we take this mess, all
this data, and put it into something meaningful and really try to figure out how we can come up with some sort of guidance for clinicians to really kind of help them prevent

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opportunistic infections or even have some sort of guidance for for them to implement in terms of patient care and CID did a really good job in the the editorial staff did a
really nice job of, of really pushing that shared decision making part within the, uh, within the paper and, and ensuring that, you know, we always went back to, it's more to

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the discussion and we should certainly be including patients in our discussion in terms of, of gray data, gray areas, and when prophylaxis is needed or when you should stop it.

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Hiba Ahmad: And I just want to thank all the co authors for kind of bringing me on board as an onc pharmacist.

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You know, glucocorticoids in general are one of the most widely prescribed classes of medication.

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So from like the oncology perspective, we regularly prescribe them in patients with cancer.

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So they have direct anti cancer effects, anti inflammatory effects, and then they can be used to prevent or even treat certain adverse effects associated with anti cancer therapies.

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Recently, we're especially, especially using those glucocorticoids to counter the immune mediated adverse effects in patients treated with immunotherapy.

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So in this space, you know, we're using them all the time, but the question is, what is that threshold of, you know, when we prophylax a patient?

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A lot of times we're seeing opportunistic infections arise even with lower prednisone equivalent doses and stuff like
that, so there's a lot of questions around that and when to start and when to stop and how to taper and stuff like that.

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Megan Spradlin: Yeah, and I can speak a little bit about some of the quality work I've done in the past year and a half.

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So my project's really been focused on solid tumor patients and reducing the risk of pneumocystis jirovecii, PJP, pneumonia, particularly our oncology patients that are on high dose steroids.

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So as Hiba alluded to, we, uh, we use steroids all the time, dexamethasone, prednisone, and we're going to be using more and more as more solid tumor cancer
therapies include immunotherapy in their regimen because steroids are kind of the management for any adverse event related to immunotherapy, like toxicities.

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I've spent the last year and a half just recognizing that everyone's intentions are good, and we don't want to put our patients at risk of infection, but due to multiple providers being involved
in the patient's continuum of care, sometimes, depending on the patient's clinical response, we taper off of steroids, and they get worse, so we have to send in another prednisone prescription,

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and we're just missing, unfortunately EPIC's not sophisticated enough at our institution to calculate the prednisone equivalents in, in alert providers when their patients are at risk.

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So you're really relying on individuals to, to recognize that even with multiple prescriptions that their patients are at risk of these infections.

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Sara Dong: And you gave a sort of a brief case, and for Febrile, we usually center around either clinical examples
or case scenarios, so I'm going to mention that one, but I think we'll end up sort of talking more, more generally.

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The brief case that we have is a 70 year old man with a six month history of peripheral ulcerative keratitis is
treated with adalimumab, methotrexate, and a 10 week prednisone taper that started at 80 milligrams once daily.

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This patient, he was hospitalized with acute hypoxic respiratory failure due to Pneumocystis pneumonia.

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He is successfully treated with 21 days of trimethoprim-sulfamethoxazole.

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I am sure that many of the Febrile listeners are aware of some of these risks that you guys are mentioning.

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You know, we talk often about osteoporosis, hyperglycemia, immunologic defects, and like you also have been mentioning and that we'll get to is that we know
patients have increased susceptibility to infection, but most of us and others that we work with might not have the best framework for defining that risk.

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So before we sort of necessarily talk about the specific case, I was wondering if maybe you could give us an
introduction and talk about those immunologic effects of glucocorticoids and, and how we might best think about that.

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Daniel Chastain: Glucocorticoids significantly weaken the immune system, and in particular CD4 cells, and therefore that's the higher risk of infection.

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And within the paper, I think table one really does a good job of talking about each individual cell line that's affected.

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And figure one also does a nice job of summarizing that a little bit as well, and I mean, we could spend the next week talking about, you know, some of the experimental
data that we have in terms of how it affects different cell lines and different types of CD4 cells, but if we focus on what the clinical consequences of this are, or

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of this effects are, that we know that glucocorticoids shift white blood cells typically within four to six hours after that the first dose, and as a result, you see
increases in neutrophils because they're being taken out of tissue back into circulation, and then you see monocytes and eosinophils and lymphocytes all decrease.

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And again, particularly the focus being on CD4 T cells being most impacted.

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Higher doses certainly have a much more faster effect.

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And the long part of this is that, ultimately, this weakens your immune response, it impairs phagocytosis, it impairs T cell activity, and also
wound healing that I think we tend to forget about in some cases, and so Table 4 within the text is, there's a lot of data that exists within there.

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The graphical abstract, the visual abstract does a really good job of that.

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There's a bar graph or a column graph rather that's in there.

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It really suggests that maybe there's a more complex picture than just all steroids suppress the immune system.

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And so this this bar graph and this table really look more so at similar cortisol suppression, but really focusing on differences
in, say, dexamethasone, methylprednisolone, having a stronger effect on lymphocyte depletion compared to prednisolone or prednisone.

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So maybe, yes, there's a global impact of glucocorticoids on the immune system, but there may be more to the story in terms of individual steroids in and of themselves.

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Andres Henao-Martinez: To complement, you know, Daniel's approach to the paper, we've been interested in
fungal infection, opportunistic fungal infection from the past, and that's what we share an interest in.

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We have developed projects together.

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So it's hard to individualize risk factors for these infections in each patient.

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And as we can see, a lot of patients have more than one risk factor.

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The one risk factor that come across, obviously, is immunosuppressive medications and steroids are typically very common.

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And that we use in clinical practice for multiple uses, so you know the list of indication for steroids is very long.

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Sometimes it's easy to approach, you know, how you give and prescribe steroids, but other times it becomes a little bit more erratic and the indication may be not as straightforward.

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You know, the interest is kind of born in kind of trying to isolate the steroid risk for this infection, although we know a number of times it's multifactorial.

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And we have a lot of experience in how, you know, an infection like HIV and AIDS causes immunosuppression, and sometimes we do not
appreciate immunosuppression in people on transplant, but we also are kind of very interested in population that are non HIV, non transplant.

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As we appreciate that that's a population that is difficult to define, difficult to characterize.

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It can be an oncology patient.

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It can be a patient with autoimmune disorder.

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That becomes a little bit more difficult to study.

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As Daniel mentioned, you know, the type of study that is given and the doses might not be standardized and may be different indication of different population
that, that, that, It's difficult to characterize, but just to give an example, like steroids become very apparent and very predominant risk in some population.

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For instance, in people with non HIV, non transplant that develop pneumocystis, we know that close to 80 to 90 percent of them had steroids
as a risk factor, so it becomes very predominant in some particular infection that we can obviously touch base later on, but that's kind

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of where our interests align for digging a little bit more on this and maybe open up some research questions for, for future projects.

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Sara Dong: And I feel like the association of, you know, having a patient who's received prednisone and thinking about pneumocystis comes to people's minds quite quickly.

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They're taught it, it's, you know, ingrained in tests and, and clinical wards, but are there other risks of an opportunistic
infections for patients who use steroids that you want to make sure that we highlight for folks who are listening.

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Andres Henao-Martinez: You want to mention maybe Megan can come up because even though we do know in the
ID world and some providers that PJP is highly linked to steroids, some providers might not be aware.

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And I think Megan can describe some quality improvement projects that she has developed, trying to
recognize even for pneumocystis, and then we can obviously discuss, uh, risks for other type of infections.

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Megan Spradlin: Yeah, I just wanted to highlight that what we've seen across UCHealth wide since 2016, we've
had over 130 cases of steroid related PJP cases, and this is in the non HIV, non transplant patient population.

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And actually, the steroid related PJP cases are more common than seeing this in the transplant and the HIV patient population, because those patients are so heavily prophylaxed.

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Yeah, for

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Andres Henao-Martinez: other infections, I think, and I can let Daniel discuss this a little bit more, but obviously we do know that there
is a risk for tuberculosis, increased risk for tuberculosis reactivation, and even some links to increasing non tuberculosis mycobacteria.

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People can also develop shingles after these infections.

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There are other fungal infections besides pneumocystis where steroids may play a role, I think we mentioned in some of the tables cryptococcus, although the link there
is not as strong as we have seen with pneumocystis, parasites as well, I mean the list is relatively long as you can expect from the suppression of the immune system.

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You can have a variety of different infections.

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Hiba Ahmad: Yeah, and the data shows incidents of infections during or within a year of checkpoint inhibitor therapy.

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It ranged anywhere from like, I don't know, like 18 to 27 percent, and a lot of them were bloodstream infections and most commonly caused by Staph aureus, E.

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coli, Klebsiella pneumoniae, um, Haemophilus influenzae, Pseudomonas.

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Um, there's a wide range of different infection risk for this patient population.

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It's not just the PJP.

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Megan Spradlin: I guess I forgot to mention this earlier, but I just wanna highlight of 130 cases that we've seen across UC Health
for steroid related PJP, this is an iatrogenic problem, like we are doing this to patients because we're forgetting prophylaxis.

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I think that's one of the things that is so jarring and alarming.

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Part of the reason I've been pulled into this work is because we've found that heme onc radiation oncology
patients are making up half of these cases, which is not surprising with how many steroids that we prescribe.

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So I think the fact that we're making up half these cases, it's iatrogenic and can be preventable, have kind of prompted
a lot of the work that we've done in this realm and I think the other piece is that it's associated with a high mortality.

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30 percent of these patients will end up with ARDS and in the ICU and die.

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Hiba Ahmad: The hard part about the prophylaxis component is, and we talked about this in the paper, it's you know dose and frequency and then patient specific as well.

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So for our patient population, they usually have a ton of comorbidities.

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And, you know, for the PJP prophylaxis realm, sometimes Bactrim is not the best option given their kidney function.

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It's not a benign medication.

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So then we have to, you know, dive deeper to see what other options we have with dapsone and getting G6PD deficiency testing and stuff like that.

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So it can become a little burdensome.

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So I think that's been also a barrier in sometimes deciding if prophylaxis is necessary or not because there's so many different factors that we have to take into account.

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Sara Dong: And I know we'll revisit prevention in a second, but just to review for people listening.

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So we're kind of walking through that infographic talking about understanding the risks, trying to assess, you know, the likelihood or risk of opportunistic infections.

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And then, you know, the next one is trying to quantify those risks, and so I'm sure all, many of you have either asked or been called about you know, a clinical team says, well, what is the risk?

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Like, what percentage are we looking at?

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Can I just take their steroid dose and how long they've been on it and somehow just kind of calculate a risk?

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So, what do you guys think?

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Like, we all are acknowledging that we can't do that, but are there other frameworks or tools that you use to think about sort of at least stratifying the risk a little bit.

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Andres Henao-Martinez: You know, as, as, as the article wanted to come across and this series is very well trying to have a goal is always have a shared decision
making, you know, especially in these areas where you don't have a lot of information, you don't have like a, you know, black and white type of decisions.

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And sometimes we, it's, it's an example of our patient, it's not easy, even, you know, even if he
presented before the episode of pneumocystis, it wasn't quite clear if this patient needed prophylaxis.

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So always sharing the decision.

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I think one of the take points from this article is to really describe that that dose alone and the duration might
not be enough for you to completely have an assessment of a particular patient and individual risks of pneumocystis.

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You really have to kind of have a more comprehensive evaluation of the patient that includes their age, the additional comorbidities, do they have diabetes, do they have cancer, do they have
additional comorbidities that can affect the immune system, and also importantly, other medication that can react as immunosuppressors in addition to steroids, as we have seen in our example.

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So, when you put all together, obviously there's We will all wish to have a calculator that can tell us
exactly the percentage risk, and we can discuss about future plans to try to develop something like that.

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But in the actual days, we're trying to highlight those additional risk factors.

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And what if this patient gets pneumocystis, is this going to survive, does he have a good pulmonary function, does he have an underlying lung disease?

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All those can play a role in actually goals of care.

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Is this patient with cancer that is terminal and might not be, wish to be placed on a ventilator?

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All those things really need to play a role when making that decision, we need to play this patient on prophylaxis.

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And so, when I get asked the question, I always kind of have a little bit more of an umbrella about the
comorbidities, demographics, additional clinical perspective for that patient to make that decision.

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Obviously an ongoing conversation, one to one, where you still want to need to try an extra medication that can also bring side effects.

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That all ultimately play a role in finalizing that decision to move on to prophylaxis when that threshold of dose and duration might not be there yet.

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Daniel Chastain: I mean, I agree wholeheartedly of the numerous different factors that are included.

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I wish there was greater emphasis on primary prevention, but I feel like oftentimes, it's typically, this case is kind of, kind of
hallmark in terms of Hindsight, we recognize multiple different risk factors for an opportunistic infection, pneumocystis in this case.

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And then it's, oh, I wish we would have done it.

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I wish we could have done it.

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Now, what about secondary prophylaxis?

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And so, The historic thought is somewhere between, you know, 10, 20 milligrams of prednisone equivalents for, you know, 2 to 4 weeks, depending on what day you read and going back to the, to the 90s.

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Is that a fair starting point for most people?

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Perhaps in some form or fashion, is that an easy, an easy way to think about it?

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You know, even if you get into the additional immunosuppressive therapies, you know, are they on the induction part of the anti TNF or is it more of a maintenance phase?

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So there's so many different factors that exist within this that it's almost impossible to quantify.

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And if anybody's out there sitting on piles of money that they're willing to put forth towards this, or that's really good at developing, you
know, machine learning, that's able to build this calculator, you know, hey, let's, let's talk because they're, they are very commonly used.

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And what's interesting to me is kind of our, our therapeutic, or we, we induce immunosuppression or treatment related immunosuppression outside of, of transplant outside of HIV.

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And I think that population is going to grow with time.

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And so does that mean that we have more and more consideration for opportunistic infections and more needs to calculate, to steal something from, you know, the transplant community?

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What's that net immunosuppression really look like?

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So if y'all, you know, if the transplant community is willing to share those platforms, by all means, you know, let's do it.

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Sara Dong: I was just going to say that my transplant part of my brain is constantly thinking about that net state of immunosuppression that you're referring to and how this whole
discussion is very similar framework for thinking about how all of these factors contribute to someone's infectious risk, not just purely their dose or duration of that one drug.

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And so this part, you guys are making my job easy because you already sort of transitioned to talk about prevention.

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And we've been focusing on prophylaxis.

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But in your paper, you talk about having a multifactorial approach to thinking about prevention strategies beyond just whether or not we provide prophylaxis.

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Is there anything else from sort of thinking about prevention that you guys would like to mention?

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Daniel Chastain: The primary prevention piece and the lack of data that surrounds it really is something that is much needed.

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Every commercial for any biologic or small molecule drug, we certainly appreciate the risk of, of TB reactivation or hep B reactivation.

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And there's always screening for those up front before those are, those are started, but we don't really expand that practice to steroids in and of themselves.

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So is that something that, you know, could be done up front before we, we induce someone with a high dose of, of solumedrol, methylprednisolone or put somebody on a long term taper?

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And then I think that there's also the question that, that I tend to think about in terms of what other things can we screen for?

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What are the reactivation disease?

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And, you know, depending on what, what camp you live in, in terms of cryptococcus, you know, is it a reactivation disease or is it an acutely acquired disease?

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And I think there's, you know, there's, there's arguments on both sides of those.

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The data don't necessarily support antigen screening in patients without HIV.

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The sensitivity hasn't ever been established, but is that something that could be investigated further to determine which patients are more
likely to benefit from preemptive cryptococcal antigen screening up front before we ever induce them on some sort of immunosuppressive therapy.

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Megan Spradlin: In our world, a couple of things we've tried to do from an intervention standpoint, or to I guess prevention standpoint, we have implemented a best practice alert, an
interruptive alert in the electronic health record that will trigger if a provider puts in a prednisone, 20 milligrams or greater for over three weeks, to nudge providers to consider prophylaxis.

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We know everyone's best interest is to take care of the patient, but unfortunately this is just one extra thing to consider prophylaxis.

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So it's another way that we can use technology to nudge people to consider prophylaxis.

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We've looked at other strategies in oncology as far as working with our pharmacists to figure out a way to educate patients.

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We found that that initial appointment when patients are being evaluated for immunotherapy and getting teaching is a very overwhelming visit and
30 to 40 percent of patients may need steroids throughout their course of therapy, but we found that that's probably not the appropriate time.

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So we're still trying to figure out the best time to do a little bit more education regarding steroids
and the potential side effects and haven't quite figured that out at our clinic or institution yet.

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Yeah.

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Sara Dong: And I want to make sure we sort of deliberately go back to that case example that we started with.

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For this patient, was PJP prophylaxis indicated?

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You know, now that he has been treated and completed his three weeks of treatment, would you provide secondary prophylaxis?

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Any thoughts on our case scenario?

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Andres Henao-Martinez: Yeah, I think, I think it was a challenging question to begin with.

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If we, you know, retrospectively have seen this case before I think obviously that the high dose steroids may have prompted some at least consideration from the beginning.

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Obviously, duration was also another point to consider, and the fact that the patient was also given an additional immunosuppressive therapy.

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I think, you know, obviously it's hard and retrospectively everything looks so easy, like, oh yes, this patient should be prophylaxed, but I think at the time, obviously it wasn't clear.

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So, again, this really highlights the complexity of trying to inform patients, trying to individualize those risks.

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This is an example in where don't follow only doses and duration because that can obviously put you in the wrong path and can, under prophylaxis people that really need it.

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And so by the 80 milligrams definitely it was a substantial dose in addition with the other one I think would probably favor a little
bit of prophylaxis at the beginning although the duration of the taper could have, you know, put you in a way one way or the other.

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And so for the second part it actually was involving the care of this patient and again the conversation comes to, you know, you already developed pneumocystis so we know you're at risk.

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And so lower the threshold for secondary prophylaxis, and patient was continued on both the steroids and the immunosuppressant medication, so I think we favor in that case to do secondary prophylaxis.

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Obviously, that conversation can lead to a different outcome if patient had a different goals of care or if they were considering
about potential side effects or a different insight that can really shift the conversation there in terms of prophylaxis.

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Hiba Ahmad: Andres is right.

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I mean, when you're looking back at the case, you're like, oh yeah, we would have prophylaxed patient,
but like, when you're actually in it and thinking about it, it's like, is that dose of prednisone?

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Yes, it's high, but like the patient's only getting it for three weeks.

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If you look at some, a lot of, you know, What we do, especially in the oncology world, I mean, it's going to be 20
milligrams of prednisone for more than four weeks is when we would start prophylaxis, so like that's the gray area.

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So it really is that shared decision making with like the dose, the frequency, duration, and that can just muddy things up.

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And of course, this patient had other PJP risk factors, so it made sense, but you know, when you're in it and wondering, I mean, it, it just, doesn't feel as straightforward as it feels right now.

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Andres Henao-Martinez: A number of these newer immunosuppressants, we are a little more cautious.

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I think we feel like we don't know much about them and so we're a little bit of risk averse and we want to be extra cautious
making some precautions, but with steroids it feels like they've been around for so long that we feel so comfortable.

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I mean, a lot of providers feel so comfortable prescribing steroids, so not necessarily translate into more awareness of potential risks down the road.

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Daniel Chastain: And I think in his specific case, I think there's the glucocorticoid steroid piece, but then there's also anti TNF.

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There's also his other immunosuppressive diseases.

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And so I think it's, you know, in that specific, I mean, we don't have labs and a lot of the other clinical findings that exist in terms of medical history,
extensive whatnot, but I think he's got multiple risk factors that stack up against an increased risk of a secondary or a second episode of pneumocystis.

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And so I think that, you know, again, hindsight's always, always much, much better, but at least going forward, I would advocate to put him on prophylactic therapies.

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If that's something he's interested in, if that's something he's willing to do, you know, then that opens the question of, you know, how much, how often, and then how long.

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And that is a, you know, a great series of questions that I, I don't know that there's great data to, to, to push it one
way or another besides being, you know, largely extrapolated from, from data with, you know, people with advanced HIV.

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You know, as we open one door, you know, 10 more open in terms of further places to explore.

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Sara Dong: And I think that's kind of what I wanted to end with, is opening it up to see what you all see as future directions.

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Like, what are the questions that we need to try to answer?

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How can we better think about these risks and of course, any other sort of take home points that you want to make sure that we emphasize.

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Hiba Ahmad: One thing that's been unclear and we don't really have great guidance on is how long to taper a patient and what dose,
what frequency, how many weeks, so that becomes difficult because what we see in our clinics is every provider is pretty different.

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Some are very conservative and they'll taper for, um, several weeks, eight to ten weeks.

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Some providers will just taper for three to four weeks, and it's hard to know.

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So I think that just highlights that it's a science, but also an art as well, because sometimes it's, you know,
you have to look at all these different patient conditions to decide how long you want to taper the patient.

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So we just don't have great guidance on that and how long we should be doing that and again, we just see it happening differently from provider to provider.

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Sara Dong: It would be amazing to have some sort of synchronization of how we taper steroids.

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It always feels a little bit like magic and hand waving.

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Hiba Ahmad: Yeah, we have an order set, but then even in the order set, you input your own dosage and the week.

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So you're, it's, the order set is basically, it's not really built to help you besides just typing everything out for
you, but you know, you have to decide how long you want to take for a patient, what dose and how you're going to do it.

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Megan Spradlin: I think also recognizing that this is a system issue and not unique to our institution.

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And, and with the advances in electronic health records, I would like to see a more sophisticated calculation or risk stratifier that could calculate,
you know, how many prednisone equivalents or dexamethasone equivalents the patient has been on over a period of time, and then nudge the provider.

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So it's not relying on, on every individual person to remember this.

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But it really is just a part of the system that can guide us and let us know when our patients are at risk.

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Daniel Chastain: A couple of things that I think of in terms of areas moving forward, I mean with ID, the hot topic has been antimicrobial stewardship, stewardship related initiatives, and
we certainly recognize the importance of, you know, targeted therapy, de escalations in broad spectrum to more, you know, narrow targeted therapies for certain infections, but I feel like

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in some cases we miss the prevention boat of, you know, yes, it's important to put people on the appropriate drugs from a treatment perspective, but what if we never got to that point?

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Could we have prevented it, you know, up front?

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And so, are there ways, you know, there's a lot of clinical decision support.

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Are there ways that, you know, alerts could be built into some of those clinical decision support to say, hey, consider prophylaxis in this individual,
or this individual is at high risk for, you know, this opportunistic infection or even vaccines for that matter, I think, in a lot of these individuals.

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Me personally, I tend to push a lot of preventive care, a lot more so than thinking about, you know, sick care, which, unfortunately, a lot of healthcare tends to revolve around.

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And so, if we can ever get in front of it, maybe that, you know, prevents a negative outcome in the end.

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The other thing that I think would be interesting, certainly a wish list of a calendar, but what do we do with, you know, a lymphocyte count in some of these individuals?

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You know, what does it mean to be lymphopenic on a steroid and, you know, a biologic, or even not on a biologic?

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Is there any point in getting CD4 counts?

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Does that matter?

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You know, if anybody's doing steroid related research and you have those data, I think that'd be fantastic to see.

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Is there any, is there any association or correlation with lymphopenia and, an event, an invasive fungal infection, an opportunistic infection from, from that perspective.

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I think the other place that also kind of becomes interesting is, I believe it's pronounced EULAR.

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Um, but it's the, I have, I'll have to look and see what they, what their exact definition is.

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European

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If you'd asked me four weeks ago,

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Sara Dong: we can pull up..

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Daniel Chastain: European Alliance of Associations for Rheumatology.

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So, I know that EULAR, put out a call for standardizing how we define steroids in papers and really push that prednisone equivalence.

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And I think it certainly does help.

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It makes things a standardized approach, but we often miss the boat in terms of Well, what if it was dexamethasone?

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What if it was methylprednisolone?

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What if someone got, you know, was on chronic prednisone and then they were admitted for a couple days and we gave them pulse dose methylprednisolone?

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And so I think a lot of the details within a specific individual's case often get lost within a manuscript or some sort of publication.

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In this case, maybe we need more granular information to be able to really figure out what that risk calculator, what that risk,
or ultimately what that net immunosuppression really looks like in individuals who don't have a history of transplantation.

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Andres Henao-Martinez: And I want to second, obviously, uh, Daniel's comments, I think, you know, preventing goes a long way and that's probably where we should focus on those patient at risk.

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I think our group is interested in looking at, you know, characteristics even more.

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What that risk means and trying to define the different factors that, that come together to make an individual, uh, immunocompromised or susceptible to these infections.

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We do have some data from a prospective study that are looking at different infection risks with different equivalent doses of steroids so stay tuned

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we have a little bit of data that can give us a little bit of light in that direction.

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And we also are trying to refine that calculator.

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Obviously, as Daniel mentioned, there is a lot of limitation to the data that we have available because it's known as granular, so it becomes a little bit difficult to use.

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characterize, even the infection themselves, but we develop a small simple calculator before and we're trying to collect data
from, uh, a large number of patients where we can at least have, uh, an approach, uh, and where we can inform back the risk.

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Obviously, it's difficult to study these infections because they're relatively infrequent, and so any prospective study, you know,
becomes challenging when you're trying to recruit a number of episodes for these infections, so it becomes, uh, uh, difficult.

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And so we often had to rely on retrospective data that has obviously a lot of limitations as well.

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But at least we tried to make a little bit of small contribution and see if we can at least have a
better understanding of the dynamics that, that plays a role in, in putting people individually at risk.

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With the ultimate goal to, you know, implement preventive measurements, because once the infection happens, we know that mortality, you know,
is very high, with pneumocystis, you know, especially in HIV and transplant people can reach up to 40, 50 percent, and so it's extremely high.

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And so once the infection is established.

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Uh, it's going to be difficult and a number of times it can be very detrimental to the patient themselves.

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And the last thing I want to reiterate, whenever you're thinking about these infections, you're using steroids, I think it's important to stay aware of potential infection risks.

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Don't be fixated on threshold for doses and duration.

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You just take a comprehensive look at the patient.

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Always have a shared decision making and need to realize conversation about those risks.

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And even if steroid doses, they don't reach that threshold, some patient might benefit from prophylaxis, either because they're giving dexamethasone a high dose, even weekly, as Megan mentioned.

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Or they have additional risk factors.

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So even though you're not going to have a clear guideline there, I think it's important to have, get out of that comfort zone, strategy,
recipe of doses and thresholds to really kind think outside the box when you're looking at this infection risk in people on steroids.

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Daniel Chastain: Kind of piggybacking off of what Andres was mentioning was, you know, if you see someone on steroids, can you question, do they still need them going forward?

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Can there be a plan put in place to get rid of them or decrease them?

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And then, you know, not to steal from the Staph aureus bacteremia group, but you always hear fear Staph aureus and respect Staph aureus.

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And I think we start to need, we kind of start to need to think of steroids in the same light of, you know, yes, they do fantastic things in some cases, and maybe
they make you feel great for a little bit of time, but they also have some detrimental downstream effects that often get, get overlooked and underappreciated.

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Sara Dong: Thanks again to Andres, Hiba, Megan, and Daniel for joining Febrile today.

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You can find their article linked in the episode description and consult notes from CID entitled Unintended
Consequences, Risk of Opportunistic Infections Associated with Long Term Glucocorticoid Therapies in Adults.

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Don't forget to check out the website, febrilepodcast.

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com, where you'll find the consult notes, which are written complements to the episodes with links to references, our library of ID infographics, and a link to our merch store.

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Febrile is produced with support from the Infectious Diseases Society of America, IDSA.

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Editing and mixing was provided by Bentley Brown.

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Please reach out if you have any suggestions for future shows or want to be more involved with Febrile.

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Thanks for listening, stay safe, and I'll see you next time.