So I have a question for Dr. Cromwell on the pediatric ARDS update. Just kind of, I know the topic is very controversial, kind of maybe you can share your experience a little bit with us about, you know, for patients with severe ARDS prone and supine positioning. As I said, I know it's very controversial, but maybe you can share your experience with us, and then that hopefully will open up to a very lively discussion. Thank you. Okay. So, as you know, there's no evidence from PALIC-2 to support supining or proning for severe ARDS. I think there's a current trial prospect, right, which is a four-arm trial randomizing prone supine conventional or high-frequency oscillatory ventilation that's ongoing that's hoping to answer this exact question. I think it is a relatively inexpensive option, although, depending on the size of the patient, it can be quite labor and resource intensive if you have an adult-sized patient. And so there's various levels of comfort with that. I think we don't do it quite as often as we probably should, at least in Atlanta, I don't think we do. I think usually someone will come up with a reason why they don't want to try it, although I do feel like, especially since the pandemic, we're more inclined to at least try than we had in the past. Thank you so much. My own experience as I don't like to use it, I really don't believe in it, but then that is just my own opinion, so an opinion not supported by a robust data. But my inclination is with the challenges, or maybe I am biased because I practice in a community hospital where the resources is limited. As a fellow, we used to do it a lot, but my own experience also is that the first 24, 48 hours, it makes a difference, and then they just revert back to square one, I would say. Thank you so much for answering that question. I think Kyle has a question. Yeah, well, I agree. I'll be very interested to see the results of prospects now that we're focused really on the severe cohort because what you described is what we saw in the previous proning trial, but it was with all comers. The first proning trial, it was all comers, right? It didn't show benefit, hence the severity selection with prospect. All right. 20 years later. 20 years later, yes. And now that we understand similarly, that showed the difference in adults. We'll stick with ARDS for the moment, although I will have a hyper-inflammatory question to follow shortly. But you mentioned following plateau pressures a few times and how it's important that we do that, but yet we don't do it enough to truly get a plateau pressure where the patient needs to be paralyzed as well. And so, obviously, there's some data in adults saying paralysis for 48, 72 hours is probably beneficial in ARDS. I don't know that we have that data in kids. We also know there's significant risks to paralysis. So can you talk about that risk-benefit, keeping patients paralyzed so that we can follow plateau pressures and track them versus not? Yeah. So, I mean, I think a lot of people, especially for the most severe patients, are probably paralyzing their patients. We don't have good data to support that in kids. There's no trial. There is work out of CHLA and Robby Kamani's work, right, where they're trying, and Nader's done the, yeah, CHOP is in this too, like looking at how well like a peak inspiratory pressure is a surrogate for like a plateau pressure. But you're right. We're not good about doing it. And the patient should be paralyzed when you do that measurement. So yeah. Yeah. I kind of have three questions, but they're all under the bucket of immunomodulation. The first is related to toposide and HLH. I understand the point of like sometimes just the overwhelming HLH response dictates being on something like a toposide. But I feel like that subset of patients, even if you effectively get the HLH under control, ultimately dies of morbidities, or I mean, not universally, but frequently dies of morbidities related to immunosuppression. And I was curious, kind of the way you risk stratified and identified the cohort that might benefit from something as significant as a toposide. Can you hear me? I'm not coming through well. Here. Borrow mine. Oh, okay. Thank you. So that's interesting. I actually use a lot of a toposide for HLH, and we don't have that experience. I think what you're probably referring to is when we gave literally everyone a toposide. So we're now entering an era of response-adapted therapy where, like I mentioned, a lot of times people are now starting with dexamethasone, some cytokine inhibition, and then if they are still not responding or they show up in like severe progressive HLH, you start out with like a dose of a toposide. So I think what we learned, particularly from HLH 2004, is that there is a group of patients where giving 10 doses of a toposide is way too much. And really what we're seeing is that most people that are using a toposide are using, I think, the max we used in our phase one with HLH-REXO, where we used rexalitinib, atoposide, and steroids, the max dosing that we were typically giving patients of a toposide is actually more around four doses. And that is also, so really, I think we're getting into the era where we're understanding you don't, now that we have these other things to choose from, we don't have to keep patients on a toposide that long, and it does need to be kind of individualized therapy where you try to pull back that immunosuppression. That may be part of my institutional experience is the dosing and frequency of a toposide. We do lean a lot more on rexalitinib. Yeah. Yeah. I mean, we always want to get away, like we always want to try to not use a toposide, but there's still patients that literally blow through everything. And it doesn't matter what cytokine inhibitor you give, if you don't target that T cell population, they're going to continue to fall apart on you and they're going to die just from, so it's like you got to pick, do you want them to die from the fire at the beginning or do you try your best and try to get them off of immunosuppression and deal with kind of some of the infectious complications later on? But I agree with you. I think what had happened in the past, and even when I talk to people, especially oncology doctors that are treating patients with HLH, their biggest question, usually what they're telling me is that they're following the HLH-94 protocol. And I'm like, Levi, can we, maybe don't do that, especially in like a secondary HLH patient. If it's a primary patient and they're not well-controlled, then yeah, it makes sense. But especially like an EBV patient or something like that, they may not need that much atoposide. You may actually be killing them with the atoposide. Yeah. And as far as CARs and immunostimulation, I feel like from an immunomodulation and immunosuppression or hyper-inflammation standpoint, we're pretty generous with using agents to try to modify that response. Yeah. But even in precise, I think it's still paused, the immunostimulation arm. Yeah, yeah. But I'm just curious if anyone, yeah, close, anyone has pursued anything along that line other than kind of withdrawal of immunosuppressive medication? I have not seen anything. So I was querying Jen and Katie at Nationwide because I've done my own queries and I have not seen that anybody else has been doing anything other than GM-CSF and then interferon gamma and then the adults are using PD-L1 inhibition. And as far as I know, there's not been anything in PEDS where people have looked at that. I do find, so I do like to talk about immunoparalysis because it's kind of, it really is an interesting concept and it's very real. I don't know that we know what to do with it yet or have the adequate data to be like, yeah, GM-CSF. And in my patient population, because I've been talking to other people, I take care of mainly oncology and transplant patients. I do take care of some general pediatric patients, but the majority of my patients are going to be oncology and transplant patients. And trying to convince an oncologist, like a leukemia doctor or a transplanter, that I'm going to give their patient GM-CSF, oh, forget about it. Like, it's not going to happen. So usually what I do, like convincing them that this is a thing that's happening is one thing because it's something in our literature that's not translating to other people's literature. And then also just a lot of times what we end up doing is removing the immunosuppression or holding chemo. That's the best thing I know to do. The other thing is just being very vigilant about looking for a nidus of infection. Because a lot of times what happens is that there's an infection, but it's not showing up in a blood culture. It's not showing up in a urine culture. It's somewhere. It's in the tissue somewhere, but it's not like out and everywhere else. And so getting infectious disease also on board is also really hard. Because they're like, there's not an infection. Come off all of your antibiotics. And you're like, no, I can't do that. And then also convincing them that you're like, but what if it's a cannibal infection? What if it's a fungal infection? Because there's a reason why they still look this sick. So it's a lot of us sounding crazy whenever the patient has immunoparalysis without a whole lot of things for us to do, other than just trying to be as vigilant as we can, I think. But has anybody, I've had maybe a handful of patients that have actually treated with GM-CSF, and I didn't see a huge difference. And it was in the general pediatric population. I have yet to have a single oncologist let me use GM-CSF in my world. Has anybody had experience with using GM-CSF? Were you in the PRECISE trial, Prachoa? We're trying to become one, but there's a lot of headaches with the contracting and the pharmacy stuff. So the GM-CSF arm is closed now. So that's an observational arm that's happening. And the TRIPS arm, which is the anakinra arm, is still active. I don't think I can say. It's a secret. And then very briefly, I don't want to take too much time. As far as immunomodulation in ARDS and the adult DEXA-ARDS study, I was curious what y'all are doing from dexamethasone or other steroid treatment in ARDS. If you're kind of risk stratifying the pediatric cohort for inflammation in any way, using it at all? So the problem is there's no rapid bedside tools to really say who should be in what arm. So there is adult literature, right? The Cape Cod study for at least community-acquired pneumonia with dexamethasone. We don't have any pediatric trials in this. And again, the party line on PALIC-2 is without the information, you can't be for or against it. So some of our attendings, you know, other people will use it. Sometimes not. It's a hit or miss. Thank you. So just before, I have a quick question. And this is for, you can stay, you know, just stay, you know, for your question. I have a question for Dr. Hines. My interest is you talked about immunomodulation and immune dysfunction. In your own experience, at least with most of these hematology, oncology patients, where do you think or what primarily is the determinant of mortality? Is it the systemic inflammatory response syndrome that the patient exhibit or the complementary anti-inflammatory response syndrome? Which harm actually plays a greater role in morbidity and mortality? And what do you particularly target when you are treating this patient? So you're talking about oncocritical care? Excuse me? You're talking about oncocritical care? Yes. And you're asking, is it the fact that you can't get rid of the infection or the inflammatory response related to the infection? Yes. That's kind of, yeah. So we, and then if so, your answer to the question then would kind of determine or help, you know, I mean, and I know that the focus is on, you know, are you doing immunomodulation to try to correct this? Yeah. So I will say one of the things that is so interesting about studying this stuff is that it's paradoxical. So you would think that the patients that are highest risk for hyper-inflammation would actually be patients that are immunocompetent. And what's weird is that the patients that almost are at higher risk for hyper-inflammation are actually those that are immunocompromised. And part of that is an inability to clear antigens. So there's like this feedback loop that continually goes so that they continue to have a response, continue to have a response, continue to have a response. And if you actually look at the literature, whether you're looking at ARDS literature or sepsis literature, you will see that they have higher amounts of cytokines, whether it's serum or within their lungs, that kind of supports this idea that if they look more inflamed, it probably is because they're more inflamed. So that's part of it. The other part of it is that low cell numbers, they kind of have a difficulty not having the right cell numbers there and actually those cells being able to control the immune response. So like I said, there are all those checks and balances. And so you don't have the cells that are responsible for checking the immune response and bringing things down. So there are multiple reasons why this can happen. And that's why it's also weird that you'll see hyper-inflammation in primary immunodeficiencies. It happens all the time. And so I actually see more hyper-inflammation in oncocritical care patients in my clinical practice compared to what I would see in a general pediatric population. And as far as which thing kills them, it depends on the patient. It also depends on the infection. So there are definitely times where I have patients where they are presenting very acutely to the ICU. They're falling apart. And it's within that first 72 hours of critical illness. And what's killing them in that moment is actually their inflammatory response, their SERS response. And so modulating that makes sense. And that's where it becomes very key to get them off of that as soon as possible because later on what I end up worrying about is did they actually clear their entire infection or are they going to have a reactivation later on in some kind of viral infection, CMV, EBV, adenovirus, et cetera. So it depends on the patient. It also depends on where you are in your critical illness, kind of how, which part you're in. So all of it happens. Thank you so much. I will take the next question from Dr. Hart. Hey, this is for Dr. Hain. So I have two questions. First one would be GMCSF. So I know, like, the arms closed on GMCSF. But, like, a lot of data for GMCSF comes from models from H1N1 epidemic before, like, you know, probably 10 years ago or more than that. So when you give the GMCSF, like, a lot of immature cells, like bone marrow is already suppressed. There is not enough production of mature cells in there. So when you give GMCSF, like, you see the cell count raising actually every day or, like, they may need an extra, like, you know, another repeat dose or something. So do these immature cells, like, help to fight the infection better? That's one thing. And when these cells actually, like, you know, are, like, just released into the bloodstream, they all probably go into the lungs, like, worsen the hypoxia, hypoxemia, and, like, worsen the ARDS because they're all just, like, trying to attack or, like, you know, trying to do that. So what's your experience? What's your take on that? That's my... With GMCSF, what you're kind of... So the second part of what you're referring to is IRIS, which is the immune reconstitution syndrome that sometimes you can see. This is also what we worry about when we actually give granulocyte infusions is we worry about IRIS. And, I mean, that's always a theoretical risk when you do something like that. The doses that are being used are probably less likely to cause that type of response because it's not, like, it's not the crazy dose that oncologists a lot of times will use. Usually when we use it in the oncology setting, sometimes we'll see IRIS with, like, the really, really high dose. But even with someone that's received myeloblated chemotherapy, you are going to have some amount of a response as far as the number of cells that are going to be spit out from the bone marrow. As far as... The other part of it is not just the number of cells that you get. It's also... One of the key things is actually the phenotypic shift that I kind of mentioned in the talk, which is you're trying to switch these cells from a exhausted phenotype to a non-exhausted phenotype. So take the cells that are actually already out there in the tissue and switch them to a functional state rather than a non-functional state. And so that's kind of the point of the GM-CSF. It's also the point of interfering gamma. It has a similar function in switching the non-exhausted phenotype. Yeah, I mean, if you're just talking about doing ex vivo studies and you want to prime, like, neutrophils to have a respiratory burst, one of the simulations is GM-CSF. So it's not necessarily that you're trying to pump immature neutrophils or bands out of the cell. You're also... It's physically acting as a primer and as a stimulant to try to wake them up from their suppressed and exhaustive state. Okay. I have one more question. Sorry. So for HLH or, like, you know, microphage activating syndrome, so is there a data... Like, instead of... We know, like, we know the pathways and, like, you know, immunomodulators sort of help to change the treatment management options. So is there a difference between just steroids versus steroids plus immunomodulator? I know you use the steroids first and then you later, like, someone not... Why can't you use both at the same time? Is there a difference in the outcomes? That's the... Yeah, I mean, I... Okay. I was, like, I feel very quiet. So I will... So you're asking a very complex question. It's going to get a very complex answer. So if you have a patient... I feel very comfortable with starting with anikinra or steroids. If you have a really sick patient that's, like, dying in front of your eyes and you're, like, doing a Hail Mary, I will use, like, sometimes two up to three agents at the same time. And again, this is my... Like, what I'm comfortable doing. I don't think a whole lot of people would be comfortable doing that. But I would do... Like, I definitely have patients that I'm, like, okay, so you're going to get steroids, anikinra, and I'm going to give you a dose of Tosi. Hail Mary. And hopefully things will turn out okay. Because, like, in that setting, usually you are so desperate and you're trying to think, okay, I'm either crashing this patient onto ECMO if they're even an ECMO candidate or they're not an ECMO candidate. I'm just trying to do my best. And so that's when... So yes, severity of illness kind of plays a role in how many agents you need up front, potentially. So there are two different ways you could go about it. You could go about it as in you add agents. So layering is one way you can do it if you have the time to do it. If you don't have the time to do it and your patient is dying on you, then you can definitely add multiple agents all at the same time and then peel them off. So you may only need that one dose of Tosi. Never give another dose of Tosi again. Keep them on steroids and anikinra and then start peeling that off pretty quickly after that once they've stabilized. As far as choice of steroids versus anikinra or another targeted agent, it depends on your comfort level. And it also depends on the issues going on with the patient. So there are other things about the patient that may steer you away and make you choose anikinra instead. For example, sickle cell patient, the hematologist is worried that you're going to cause them to have a sickle cell crisis in 48 to 72 hours if you give them steroids. So in that patient, my first line would be anikinra because that would be a relative contraindication to steroids. More specifically to us, it would be I have a patient that I'm already thinking about an icardipine drip. Do I really want to do steroids on top of it? I already have a patient that I have them on a crazy insulin drip. Do I really want to add another thing on top of that? Or would something more targeted be okay for this patient? So you do have those patients that have a relative contraindication to steroids. If you're talking about cost, steroids are significantly cheaper than anikinra. Usually anikinra is going to cost you at least $1,000 to $2,000 a day. If you're doing it especially Q6 IV, for example, most people are going to run a bill of $1,000 to $2,000 a day. Steroids are dirt cheap. So you also have that to consider whenever you're making your decisions.

pediatric ARDS

hyper-inflammatory responses

ventilation strategies

immunocompromised patients

immunomodulators

oncocritical care