109: StAR: Corticosteroids

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.

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.

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. 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.

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.

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.

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

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

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.

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

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.

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.

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,

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

This patient, he was hospitalized with acute hypoxic respiratory failure due to Pneumocystis pneumonia. He is successfully treated with 21 days of trimethoprim-sulfamethoxazole. I am sure that many of the Febrile listeners are aware of some of these risks that you guys are mentioning.

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.

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.

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

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. And again, particularly the focus being on CD4 T cells being most impacted. Higher doses certainly have a much more faster effect.

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. The graphical abstract, the visual abstract does a really good job of that. There's a bar graph or a column graph rather that's in there.

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

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. 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. We have developed projects together. So it's hard to individualize risk factors for these infections in each patient.

And as we can see, a lot of patients have more than one risk factor. The one risk factor that come across, obviously, is immunosuppressive medications and steroids are typically very common. And that we use in clinical practice for multiple uses, so you know the list of indication for steroids is very long. 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.

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. 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.

As we appreciate that that's a population that is difficult to define, difficult to characterize. It can be an oncology patient. It can be a patient with autoimmune disorder. That becomes a little bit more difficult to study.

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.

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

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. 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.

Yeah, for 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. People can also develop shingles after these infections.

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. You can have a variety of different infections.

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. 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.

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

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. So it can become a little burdensome. 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.

Can I just take their steroid dose and how long they've been on it and somehow just kind of calculate a risk? So, what do you guys think? 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.

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.

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. So always sharing the decision. 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.

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.

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. But in the actual days, we're trying to highlight those additional risk factors. 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? All those can play a role in actually goals of care.

Is this patient with cancer that is terminal and might not be, wish to be placed on a ventilator? All those things really need to play a role when making that decision, we need to play this patient on prophylaxis. 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.

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

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. Is that a fair starting point for most people? Perhaps in some form or fashion, is that an easy, an easy way to think about it? 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?

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

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. And I think that population is going to grow with time. 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? What's that net immunosuppression really look like?

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.

And we've been focusing on prophylaxis. But in your paper, you talk about having a multifactorial approach to thinking about prevention strategies beyond just whether or not we provide prophylaxis. Is there anything else from sort of thinking about prevention that you guys would like to mention?

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? 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? What are the reactivation disease?

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? And I think there's, you know, there's, there's arguments on both sides of those. The data don't necessarily support antigen screening in patients without HIV.

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.

So it's another way that we can use technology to nudge people to consider prophylaxis. We've looked at other strategies in oncology as far as working with our pharmacists to figure out a way to educate patients. 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.

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. Yeah.

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

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

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. 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.

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. 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.

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

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

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

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. 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.

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

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. 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.

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

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? Could we have prevented it, you know, up front? And so, are there ways, you know, there's a lot of clinical decision support.

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. 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.

And so, if we can ever get in front of it, maybe that, you know, prevents a negative outcome in the end. 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? You know, what does it mean to be lymphopenic on a steroid and, you know, a biologic, or even not on a biologic? Is there any point in getting CD4 counts? Does that matter?

You know, if anybody's doing steroid related research and you have those data, I think that'd be fantastic to see. 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. I think the other place that also kind of becomes interesting is, I believe it's pronounced EULAR. Um, but it's the, I have, I'll have to look and see what they, what their exact definition is.

European If you'd asked me four weeks ago,

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? 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.

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. 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.

I think our group is interested in looking at, you know, characteristics even more. 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. 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 we have a little bit of data that can give us a little bit of light in that direction.

And we also are trying to refine that calculator. 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. 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.

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

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. 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.

And so once the infection is established. Uh, it's going to be difficult and a number of times it can be very detrimental to the patient themselves. 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. Don't be fixated on threshold for doses and duration. You just take a comprehensive look at the patient.

Always have a shared decision making and need to realize conversation about those risks. 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. Or they have additional risk factors.

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

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