So, I am Dr. Hines from Melissa, and I do work at St. Jude. So, I mainly work with oncology patients, but I do take care of general pediatric patients as well. And I am the director of our histiocytosis and immune dysregulation team. And so, this is, these are actually things that I think about a whole lot more than I think the general intensivist does, and then I just acknowledge my co-author on this chapter, who is kind of my little immunoparalysis guru, which is Katie Blind. So, if you have lots of questions about immunoparalysis, I'll probably get you to email Katie. So, I do have some disclosures. I do receive research funding from NCI for HLH clinical trial using roxalitinib, which we will discuss briefly in this, in this presentation. I'm also a consultant for Novartis and Sobe. Sobe makes anakinra and imipolymab, which will also be discussed. And we will be discussing off-label uses of medications. Here are the objectives. And I'm just going to go right on in, because it's going to be hard to fit everything in 30 minutes. So, as I was set up really well by Jocelyn, there people are getting smarter about how we think about the things we take care of, because we know that there's a significant amount of heterogeneity in these patient populations that we take care of. And so, we've done a whole lot for, when you talk about severe sepsis, as far as modifying how we fluid resuscitate, how we take care of these patients with intubation, vasopressor support. But there's only so much of that that you can do before you've kind of reached the top. And I think we've gotten there. And so, you kind of have to start thinking about the pathobiologic basis of these diseases. So, there are a couple of different ways this has been done, as Jocelyn mentioned, which are the phenotypes and the endotypes. And that's kind of helped us wrap our brains around how do we start targeting therapies for specific patients. And what we have found, particularly with the a priori clinical immunologic phenotypes, so you can see them listed there, is that these are clinically relevant, because they are associated with differences in mortality. And you can see that patients that develop multi-organ failure with any of these phenotypes have a mortality rate of around 18 to 20% compared to patients that do not have these phenotypes and multi-organ failure with 0 to 2%. So, that's a huge difference in mortality that we could potentially target. So, what we've learned from really sepsis research and critical care research is that there's a lot of heterogeneity, particularly in immune response in the setting of critical illness. And they can be described in different ways, whether you're looking at them from a genetic basis and looking at how people's immune cells are producing different types of endpoints versus just clinical phenotypes, how this patient looks. And they are associated with different outcomes. And they are associated with different pathologic, pathobiologic basis that can be targetable. So, I'm going to bore you guys with some immunology. So, a lot of intensivists don't think about immunology very often. So, here we go. On the bottom, you have the innate immunity, which includes your antigen-presenting cells, NK cells, macrophages, neutrophils. You have your adaptive immunity that's on the top there, which is your T cells, including CD8, CD4 T cells, and then B cells. And usually what happens is that you'll have something that stimulates the immune response. I have here a bacterial infection. And so, those PAMPs or DAMPs, depending on if you're dealing with trauma, will activate TLRs, or the toll-like receptors, which starts off the immune response. And so, you then have release of tons of pro-inflammatory cytokines, including IL-6, IL-1 beta, IL-18, interferon gamma that gets released by NK cells. And so, those are really kind of the cells that kind of talk and start the immune response. And then, you'll have your antigen-presenting cells that will take that antigen from the pathogen and present it to those T cells to get the adaptive immune response going. And this response is more specific because you have more specific cellular responses that can happen where you actually have specific targeting and killing of target cells, for example, or you can have an antibody response that's produced by the B cells. And then, there's further propagation from that adaptive immune response using things like interferon gamma, GM-CSF, IL-2, and IL-2 receptor. And I'm mentioning all of these cytokines because unfortunately, you have to know them nowadays because there's targetable ways to treat this. And so, the other thing I'm going to mention is that until the antigen is clear, you're going to have continuation of your immune response. So, when you're talking about as long as those antigen-presenting cells are going back to the T cells saying, hey, there's still something here, hey, there's still something here, you're going to have propagation of the immune response. There is a checks and balance with your immune response when you're talking about sepsis, for example. And you have the systemic inflammatory response syndrome or SIRS, which kind of revs up the immune system to clear infection or tissue damage. And this includes that production of pro-inflammatory cytokines, the expansion of the immune cells, particularly T cells and B cells, and increased antigen presentation. When you're talking, but then you have the other part that's supposed to kind of even it out, which is this compensatory anti-inflammatory response or CARS, which slows down the immune response to prevent damage to the host because the immune system definitely can cause damage to your body. And this includes production or propagating production of anti-inflammatory cytokines, such as IL-10, apoptosis of lymphocytes that are no longer needed. Decreased antigen presentation, including decreased monocyte HLA-ADR expression, and which also leads to decreased antigen presentation. So moving on to the highs of the immune system. What does hyperinflammation and critical illness look like as far as we know based on the phenotypes we've studied? And so I am presenting here kind of a spectrum of inflammation. We'll talk about the hyperinflammatory here in a little bit, but we're going to stick to the spectrum of hyperinflammation over here on the right. And you can see there is, I include both macrophage activation syndrome and hemophagocytic lymphohistiocytosis, or HLH, because I think of them a touch differently because I treat them actually a little bit differently. But there is certainly phenotypic overlap. And so hopefully I can simplify it enough that you can take this back to your clinical practice. What are things that I think about in patients that I'm like, ooh, this is not going to go well? I think they may have more inflammation than I really, that may need a little bit more intervention. So things that make me suspicious, patients that have, that are on multiple vasopressors or you're having to increase vasopressors significantly and quickly, that makes me suspicious if they have severe myocardial dysfunction, cirrhositis, severe capillary leak syndrome. If they start having like a bump in their liver enzymes, particularly if they have a direct hyperbilirubinemia, that makes me a little bit more suspicious. And this is something that's not usually seen in pediatric sepsis. It's seen a lot in adult sepsis for liver dysfunction. So that's something that always kind of makes me think. And then they'll also start having signs of anemia, thrombocytopenia, neutropenia, lymphopenia. Some of this is bone marrow suppression and sometimes it can be consumptive. And then DIC as well. Moving on to macrophage activation syndrome. So I have pretty much here a cutoff, a cutout of the innate immune system because I want you to associate macrophage activation syndrome with the innate immunity. And so what do these patients typically look like? They will have increased ferritin. Like I mentioned, they'll have maybe some liver dysfunction. They tend to, these are the patients that tend to have coagulopathy or DIC. And I typically think of these patients as like the prototypical severe MAS-like sepsis patients or patients with systemic JAA. So it's really the patients that almost have a predominant innate immune response. A lot of these patients don't always meet all of the HLH criteria, but they can. And like I said, driven by the innate immune response, mainly you will have some T cell response obviously that will get, that will happen in there. But it's mainly macrophages, neutrophils. So you're going to have tons of IL-6, IL-1 beta, IL-18. Those are things that are produced by the inflammasomes. And then ferritin and CRP are the kind of key biomarkers that I think about. And the estimated incidence of this in multi-organ failure patients in severe sepsis is around 5 to 11%. Why does this happen? I don't know that we have a clear understanding of it. But what we think is happening is that it's an over-exaggeration of that systemic inflammatory, excuse me, inflammatory response. And why does someone have an over-exaggerated systemic response? It could be the, what they're infected with. So it could actually be the infectious agent. But there's probably some other host things that are going on. So something with the patient themselves where they could have an underlying genetic predisposition and immunodeficient genes, HLH-related genes, complement-related genes. It also could be due to underlying idiopathic immune suppression, believe it or not. When we're talking about these biomarkers, CRP is stimulated to be released by IL-6. And that release is further enhanced by IL-1 beta. So you can tell that CRP is pretty specific to the innate immune response there. And then ferritin is usually being released by activated macrophages. So again, another part of that innate immune response. And we've seen that ferritin levels in particular are associated with mortality and critical illness. So it's a great biomarker. I love the carcilloferritin CRP contingency table. And so you can see that if you consider them together, it's really helpful because if you have a patient with a CRP, they have a cutoff here of four and a ferritin greater than 2,000. You pretty much select out the patients, at least in this particular cohort, that are the highest risk of mortality with a mortality rate of 50% in this group. And this was a severe sepsis group. Thinking about potential therapies, there's always the oldie but goldie methylprednisolone. I will say a couple things about methylprednisolone in that the doses that we even use in the ICU, that the two per kilo per day, is actually cytotoxic to cells, particularly T cells. So keep that in mind. You think you're doing nothing, but you're killing a bunch of cells. The other thing is that it does, in part, it controls the immune response also by promoting an anti-inflammatory response. So switching transcription to more anti-inflammatory rather than pro-inflammatory. And you can see most of the time when people are talking about sepsis, they're usually talking about the two per kilo per day or the moderate dose. High dose, post dose is usually mainly been used by rheumatology colleagues, particularly in the setting of refractory systemic JA. Moving now to anikenra. Anikenra, while you think it's a rheumatologic drug, it actually was initially tested in sepsis patients in the adult world. And what you can see is that there is a huge therapeutic window, massive. So it's a really very safe drug with very little side effects. I'm not going to go through all those. You can ask me in the chat or the panel later. But it is a really, really great drug and has been used both in the setting of MAS-like sepsis and in systemic JA and STILs. This imipolimab seems kind of random here, especially since that's not something that you think about with innate immunity and activation. But sometimes patients can get so sick that you almost have to hit two things at the same time. So the adaptive plus the innate. And that's what happens sometimes in patients that are refractory in systemic JAA. So you may see your rheumatologist pulling this out in a patient that has refractory systemic JAA. As far as anikenra, there is a current trial that's going on called the PRECISE trial. I'm sure many of you are actually sites for this trial for the targeted reversal of inflammation in pediatric sepsis-induced MODS. And so you will see that CRP and ferritin cutoff look very familiar from that carcillocontingency table. And what they do is they take these patients that look like they have hyperinflammation based on ferritin and CRP and randomize them to Anakinra on several different doses. And you can see the wide variation there all the way up to 16 milligrams per kilo per day IV for seven days versus placebo. So hopefully we'll have more to come on Anakinra and PEDS, macrophage activation-like syndrome. Okay, moving on to HLH, which is actually my favorite. So HLH, if you remember what the HLH criteria are, this is a phenotype of patients that present with fever, cytopenias, including neutropenia, splenomegaly, ferritin, low fibrinogen, increased soluble IL-2 receptor. They may or may not have some hemophagocytosis on a marrow. They can present with liver dysfunction as one of the predominant organs of failure. And just for you to know, there is a new publication on the diagnostic criteria, if you're really excited about HLH, where they've actually taken out NK cell function. It's been found to be completely useless, and I agree. So usually what we see with the biomarkers is you're looking for signs of overwhelming T cell activation in the setting of HLH. And so these patients will have really high interferon gamma and soluble IL-2 receptor. And so the testing that we usually will send out is soluble IL-2 receptor and CXCL9, which is downstream of interferon gamma. And these are the patients, when I think of HLH in this overwhelming adaptive immune response, it's usually in patients that have biallelic mutations or monallelic mutations in HLH-related genes. They can have, I also, patients that have secondary HLH for EBV. This is the patient population that I think about. And then also patients with HLH secondary to malignancy or lymphoproliferative disorders. So what actually happens in HLH, and I'm gonna go through this quickly because it will make so much more sense for why we use what we use for HLH-related treatment. So in a normal immune response, you have a viral infection. You have expansion of your T cells to try to fight this infection off. You have a pro-inflammatory response like normal, but you have intact cytotoxicity. And so you can actually get rid of the virally infected T cells. And so you clear your infection. Your body does what it's supposed to do. It contracts all those cells that you don't need, and the patient gets better. So you have a normal kind of revving up, but you also have a slowing down of the immune response. What happens with HLH is that you'll have a viral infection, for example. And usually there's cytotoxicity, particularly in primary HLH or familial HLH is not intact because of gene mutations. And so what will happen is that they will continue to have this viral infection. The body will continue to try to fight it off. So you have a huge proliferation, particularly of CD8 T cells, huge amounts of pro-inflammatory cytokines that are produced, and they just cannot clear this. So this keeps happening over and over and over again. So it's a feedback loop without a negative feedback loop. And you get the phenotype of HLH. And so there are a couple of different ways that you can actually target or treat HLH. One way is to treat the cytokine storm itself. The other way is actually to target those proliferating CD8 T cells. So the therapies we usually start with are gonna be dexamethasone. Again, oldie but goldie. Everybody feels pretty comfortable with steroids. Again, one of the reasons that it's effective in the setting of HLH is that it's actually cytotoxic to T cells. The other thing that we sometimes will use, particularly in patients that we think that have infection-drived HLH, particularly EBV, things like that, we will use Anakinra in those patients as well. Another newer drug, like I mentioned, is Imipalumab, which is a monoclonal antibody for interferon gamma, which is thought to be a key cytokine in the pathophysiology of HLH. And if you remember, I showed you it's that predominant T cell response, which is spewing out tons of interferon gamma. So it makes sense that this would be a potential target in the setting of HLH. And this has been studied in both, mainly in primary HLH. Ruxolitinib is another therapy that is currently being studied. And there's actually a fair amount of literature about the efficacy of this in the setting of HLH. And what it is is a JAK1-2 inhibitor, which inhibits the intracellular signaling of many cytokines, including IL-6 and interferon gamma. And then atoposide, while you want to avoid atoposide, there are definitely patients that absolutely will need atoposide in order to control their immune response, because there's only so much you can do sometimes with cytokine inhibition. And so if your oncologist comes to you and they're like, I really think we need this, let them do it, because there is a very specific reason, which is it ablates those activated T cells. As far as treatment of hyperinflammation, how do you know if your therapy is helping? Usually what I see is that patients will start to stabilize within 12 to 24 hours. With an improved fever curve, maybe you're actually able to stabilize on your vasopressor support and come down. Usually we'll see at least some stabilization of inflammatory markers. If the patient isn't stabilizing for you, then you may need to consider adding additional therapy. And there are definitely times where I layer therapies and have to add multiple therapies on one patient. And a lot of reasons that people feel very uncomfortable in the critical care world with using some of these drugs is that we're terrified we're gonna make the patient worse. And it's kind of counterintuitive to think about giving somebody that has an active infection an immunomodulator because you're trying to clear this infection. And so the biggest thing that I can say is that what's gonna kill your patient is actually, it may be the fire itself, so they have to survive the first 48 to 72 hours. The other thing is is that what will kill them is the infection later. So do they get infections later? So get them off of therapy as soon as you possibly can. So I usually will start reevaluating if I can start coming off things in three to five days. And then I wean something off every couple of days. Okay, talking about immunoparalysis or the lows in critical illness. So you can see here we're on the other end of the spectrum now, we're on the left side. And you can have immunoparalysis. It's been documented both to affect the innate immunity as well as the adaptive immunity. And it's been defined in the innate immunity as reduced TNF alpha release with stimulation, mainly LPS stimulation of macrophages. So that's one way to test it. The other way to test it is to actually look for decreased HLA-DR expression. And then for looking for possible adaptive immunity, immunoparalysis, you actually try to stimulate the T cells. And then they have a reduced amount of interferon gamma production. What do these patients look like? Usually what they look like is they'll have an initial improvement, but they'll get sick again. So that's one way that they present. So you're like, yay, they're getting better. And then like a week later, they're kind of falling apart again on you. Or you're expecting them to improve. They've gotten through the first 72 hours or so. You're like, okay, they should be getting better any time now. And then they just continue to progress and get worse and get worse. The biggest key is to look for a new infection. A lot of times these patients have an infection that's not being treated, or they have a new infection that's showing up, which could be bacterial, cannibal, or fungal, and viral or a viral reactivation, including make sure you're looking for DNA viremia, CMV, EBV, adenovirus. And a lot of times these patients, particularly if they have an adaptive immune issue, will have pretty profound lymphopenia that is prolonged. So like I said, this is usually how you diagnose it. Unfortunately, I don't know of any clinical lab, and hopefully somebody here does know of a clinical lab that will do testing for immunoparalysis. The poor man's way to kind of figure it out is looking at the ALC. And if it's less than 1,000 for three days, that's pretty suggestive. Proposed therapies for this would be removal of immunosuppression if they're receiving immunosuppression or reducing it. If they are a cancer patient, holding chemotherapy. GM-CSF has been looked at. We'll talk about that in a minute. And then obvious, and the most important thing is actually to treat the infection. I will say that these patients often get confused with having hyperinflammation because they do have really high CRPs because they have an underlying infection, but their ferritins will only be a little high. So they're like, they're inflamed, but they're not like HLH MAS inflamed, if that makes sense. So why do we think immunoparalysis happens? We think it's because of a kind of prolonged or exaggerated CARS. And so these patients will have reduced antigen presentation, just overall reduced function of an adaptive immunity, lymphopenia, and they have this exhausted immunologic phenotype. So they have the cells there most of the time. Sometimes they're actually reduced the number of cells, but even the cells that are there, it's like they just can't quite muster up the effort to produce some cytokines, to kind of get everybody on the same page to get rid of an infection. What are the groups that are highest risk for immunoparalysis? No brainer, those that are immunosuppressed, you can see them there. They make up about a third to half of the patients that have been diagnosed with immunoparalysis in studies. And then also the other group that we maybe don't think about are the patients that have this really exaggerated severe surge response up front, but then they'll have this over-exaggerated CARS that will happen. And the patients where this kind of happens are gonna be your burn patients, and then patients that are status post-cardiopulmonary bypass. Therapies that have been tested include GM-CSF and interferon-gamma. GM-CSF has been tested in the pediatric population, mainly by Mark Hall and his group. And then interferon-gamma has been looked at mainly in the adult population. I do not know of any pediatric studies that have looked at interferon-gamma. Then there's also PD-L1 inhibitors. I don't have that up here, but it's never been studied in PD... PD-L1 inhibitors have never been studied in pediatrics, and as far as I know, there's only been a phase one trial that's been completed in adults. And I don't know of a phase two that's ongoing quite yet. Looking at GM-CSF for reversal of immunoparalysis, again, this is a part of the PRECISE trial, and it's the GRACE-II arm. And what they're doing is they're defining immunoparalysis on day two of multi-organ failure. They're doing this by using the TNF-alpha production capacity as I showed earlier. And then these patients will get potentially randomized to GM-CSF, and you can see the dosing that they use there. And they do it sub-Q once a day for seven days, and then following outcomes. And just to kind of give you some perspective, this GM-CSF dose is about 50% of the dose that I would use in an oncology patient. So it's a low dose. How do we think that these therapies would potentially work is that it is thought to lead to a phenotypic shift in the cells. So they go from an exhausted phenotype to an active phenotype. And it also overall increases the number of cells, including granulocytes and monocytes. And it just improves the ability, so it kind of improves that antigen production, I mean, excuse me, that antigen presentation, because that definitely decreases in immunoparalysis and improves the ability of these cells to actually produce cytokines in an immune response in order to clear the infection that's there. So the final thoughts I have are that there are adaptive and maladaptive immune responses in critical illnesses, and there's a spectrum of that, whether it's a hyperinflammatory versus a hypoinflammatory response. And there's a growing level of evidence that we can potentially target these responses in our patients. Things in the future that Katie and I thought about or that we need to kind of understand, who are the patients that are most at risk for this? Is there a genetic risk factor in these patients? Or is it more of a what is the patient actually being infected with? So is it the infections or is it the patient? It's probably a mixture of both. The other thing is that we've got some reasonable data now looking at all of these therapies in the general pediatric population. So how do we kind of approach this as we think about more subspecialized groups? So the oncology patient population, cardiac, solid organ transplants, trauma burns. Because certainly these patients are probably gonna be a little bit different than the general population. All right. That's all I have. Thank you.

immune dysregulation

pediatric critical care

hyperinflammation

immunoparalysis

targeted therapies

cytokine storms