So our next speaker is Dr. Jennifer Muczynski. She is an associate professor of pediatrics in the Division of Critical Care and Nationwide Children's and an associate division chief for research at Nationwide. And she's going to talk about caring for the immunocompromised child, solid organ, and stem cell. We know a lot about that. So I guess you get me as a little bit of a palate cleanser in between all Dr. Basu all the time and kidneys. So here we go. We're going to talk a little bit about immune function building on what was discussed yesterday and start to get into some of the infectious disease content for the day. I was all prepared to come up here and say, well, Asapna, I'll see your 6% and raise you whatever. But in actuality, per the content specs, transplant care is one of the conditions. And infectious disease is another condition. Each of those is about 5% to 6% of the 54% of specific conditions. And so definitely something to pay attention to. But I guess sedation is still up there. So we'll try to keep everything on time. As folks have this morning, I have no relevant disclosures. The adjectives are up here for you to view. But we won't take much time on them. So when we're talking about caring for the immune suppressed child, as I mentioned yesterday, I know some of the congenital immune deficiencies and some of the disease states for acquired immune deficiencies were covered. Here we're going to talk specifically about exogenous immune suppression. And so I could take the entire 20 minutes or more to go through each of these drugs individually. And I would probably bore you to death if I did that. So I'm not going to do that. This table here is a helpful reference for you to have in the slides. It is helpful to know what the mechanisms of action of each of these drugs are. And specifically, it's helpful to know any of the side effects that are specific to each individual drug. So all of these drugs are going to suppress immune function. That's their intended effect. But each of them will have very specific side effects that are kind of easy things to test on. And it's good for you to know in your practice. I am going to call attention to one particular type of therapy, only because it is a little bit newer. And coming down to, Pike, what you will see in many of your institutions. And that is CAR T-cell therapy. So CAR T-cell therapy, what you can see there is what it stands for. And it's basically that you take the patient's own T-cells out, genetically modify them in some way in order to attack something specific. Typically, it's used for cancer right now, certain types of ALL. Then it's really harnessing the patient's own immune system to attack the disease process. The downside of that is that you are using the patient's immune system and can get an overwhelming immune response. This would be termed the cytokine release syndrome. What's important to know about CAR T-cell therapy on tests and in real life, when you're treating cytokine release syndrome, recognize that if you give steroids, like we often give to decrease inflammation, that can actually decrease the intended effect of the CAR T-cell therapy as well. And so typically, other biologics such as tocilizumab or that anti-IL-6 drug are going to be your first line with steroids reserved for the most severe cases, particularly those involving neurotoxicity. So that's an important point specific to the CAR T-cell therapy. So putting the drugs aside for a moment, as I said, we're going to dovetail into the infectious disease portion of the day. So we're going to talk a little bit about the bugs. The table here can be a very useful reference. And it's something, again, that's helpful to think about the particular types of infections that your patients are probably most at risk for based on their particular type of immune dysfunction. And this has to do with the specific immune cells or arms of the immune system that are used to fight these specific types of infection. Recognize this is guideline only or rule of thumb only because in reality, the immune system works together. And so it's not necessarily as cut and dry as what's in this table. This table can be a starting point. When we talk about particular infections specific to the immune-compromised host, there are a few that come to mind that are common that you will see, likely in real life, in addition to on tests. So CMV is something that is going to be commonly encountered within transplant populations that have to do with the fact that CMV is nearly ubiquitous in the population. And so if you have a CMV-negative patient who receives a CMV-positive transplant, particularly stem cell transplant, you're going to have risk factors for that. And so that's obviously something that is continuously monitored and can sometimes cause, particularly pneumonitis or hepatitis or GI inflammation are going to be your more common symptoms of CMV. Varicella is another virus that's good to know about. One, because it's out there in the population sometimes, particularly with waning immunization rates, and can be particularly problematic for your immune-compromised patients. And so recognizing how varicella and these other viruses can manifest differently in an immune-compromised host compared to an immune-competent host, it becomes important. Similar to HSV, again, thinking about what the risk factors for disseminated HSV are and how that manifests. What does that look like for your patient? Adenovirus is another very specific virus to this patient population. And again, it's a virus that's out there. It's in the world. It's nearly ubiquitous. But for the immune-compromised host, can be particularly problematic and can cause things that are different than what you might see in somebody who is not immune-compromised. In particular, adenovirus in the transplant population can be more common and more severe in children than in adults. And so as pediatric intensivists, important to recognize adenovirus and recognize that there are some specific treatments for that. That's covered in the larger slide deck. The next three viruses here are viruses that you really are only going to see symptomatically in the transplant or severely immune-compromised patient population. And each of them will have slightly different signs and symptoms. And it's worth knowing about that. It's also worth knowing what you do about them. For many of these viruses, there isn't a specific therapy or a drug that you can give to make it go away. And so the management really has to do with balancing the need for ongoing immune suppression with the need to try to bring some of the immune system back as the only way to fight these viruses. That's really a mainstay of therapy for most of these viruses. Even ones that do have antivirals available, you really need your own immune system to effectively mount an attack against them. And so the rule of thumb for all of these is multidisciplinary care with your transplant teams and really thinking about how much can we safely decrease the immune suppression in order to try to allow the body to recover and actually fight these viruses. So that's a little bit on viruses. They said there's much more detail in the full version of the talk. The next category of infections that we tend to think about in this patient population are fungal infections. Again, any patient in the ICU is at risk for fungal infection. I like to say that any patient in the ICU probably has some degree of immune compromise, whether we consider them severely immune compromised or we've intentionally immune compromised them or not. And so these are infections to think about just in your practice and to recognize the signs and symptoms of both local as well as disseminated fungal infections. Particularly, certain types of fungal infections you will see with severe neutrophil dysfunction. But really, you can see it with any type of immune compromise. Mucormycosis is a little bit of a different category altogether and is one that is very important to recognize. And because it's one that can start with very subtle signs or symptoms, you might see just a dark spot somewhere or a skin rash that doesn't look quite right. But the challenge with mucor in particular is that it's highly, highly invasive, including that it is angioinvasive. And so typically, you're going to see this often on the face because you can inhale the spores and starts in the sinuses, can easily invade into the brain, down into the lungs. Highly fatal fungal infection. And so it's one that you can see with very subtle signs and so it's one that the only way to combat is by early recognition, aggressive surgical debridement, and antifungal. So it's one to know about and one to know how to recognize. Cryptococcus is a little rarer. That India ink stain that's in bold, it's just one of those things you put in your brain together. Just link them together. That's how you diagnose that, right? And it's, like I said, it's one that can disseminate particularly to the CNS. So understanding which of these infections will impact the CNS specifically can be a useful tool. And then histoplasmosis, for anyone who lives and works around here, Ohio, anywhere in the Midwest, so where I practice, histoplasmosis is endemic. And so it is almost always on our differential. Particularly, one of the challenges is that histoplasmosis, when it is disseminated, can look like lots of different things. And so you have to think about it. Disseminated histoplasmosis might look like mods from any other type of sepsis. It might look like hepatitis initially. You're typically going to see, usually, some combination of pulmonary disease and hepatic disease, but can progress to fulminant mods that looks like lots of other things. So the only way to recognize it really is to have it on your differential and test for it. OK, so we're going to talk a little bit about specific transplant populations. So the figure that I have here on this set of slides, again, is a helpful rule of thumb to think about at what point in the course of a stem cell transplant is a patient at risk for certain types of infection. And it has to do with the time course of what happens when you get a stem cell transplant. So if we think about what happens in a stem cell transplant, the first thing that has to happen is you have to get rid of the patient's own bone marrow. So that's the conditioning regimen. That's your myeloablative chemotherapy. And then the, ideally, donor bone marrow is going to repopulate. And this is a rule of thumb. We'll talk in the next slide a little bit about the fact that these are not hard and fast days. There's actually a range. But you can get some sense of which cells tend to come back first and which cells tend to lag behind. And this will then lead you to which types of infections your patient is most at risk for at different periods of time. Now, recognize your patient is at risk for all of them at all times. So all of them should be on the differential. But how you prioritize that differential can differ based on where your patient is on that spectrum of reconstitution of their immune system. And so a figure like this is one to just kind of look at and think about putting to memory. The caveat to that, as I mentioned, is, of course, a stem cell transplant, particularly nowadays, is not just a stem cell transplant. There are so many different varieties of stem cell transplants right now. Particularly, beyond just is it the patient's own stem cells or somebody else's, so your autologous versus allogeneic. But also, have the cells been manipulated in some way? So there are now stem cell transplants that might be depleted of certain types of cells that are going to change how your immune system is repopulated once it's repopulated. And so it's important to have close communication with your transplant team and not just know that your patient had a stem cell transplant, but what kind of stem cell transplant and what does that mean for their expected time course and risk for infection. The other thing to note, the different conditioning regimen is also going to be different based on the reason for the transplant. And so in general, when you're doing a stem cell transplant for a genetic condition compared to a malignancy, that conditioning regimen is going to be much more intense because your patient has started out usually with an intact bone marrow altogether. And so it takes much more to knock out their bone marrow than it does for somebody with leukemia, as an example. And so the reason the transplant is happening is going to influence the conditioning regimen. The intensity of the conditioning regimen is going to largely influence all of the other side effects that we're about to talk about. And then, of course, there are drugs that in certain patient populations can or can't be given in order to try to increase the time or increase the speed of that immune system recovery. Another really important point, any infection that is in the body at the time of engraftment or that pre-engraftment period or that time before the cells come back itself can and often does delay engraftment and might even cause graft failure. So when we talk about graft-versus-host disease, so we just talked about you want to have the immune system come back depending on the type of transplant. When that immune system comes back, if it's recognizing the self as foreign, now you have a problem. And that's one of the reasons why many stem cell transplant recipients need to be on ongoing immune suppression in order to prevent graft-versus-host disease. The drugs that are going to be used for this typically are going to be drugs that work against T cells, because T cells are your major mechanism for graft-versus-host disease. T cells are typically your major mechanism for graft-versus-host disease. Acute graft-versus-host disease can manifest in multiple different ways. Some of the classics would be skin rash. GI, GVHD is very common. So diarrhea that isn't otherwise explained can very much be GVHD. As we're in the ICU and we kind of aren't really paying attention to the stools, and all of a sudden you walk in and nurse says, oh, there have been like five or six loose stools in a post-transdental transplant patient who is at risk for graft-versus-host disease, that may be highly relevant. The acute management of this typically is going to be high-dose steroids, plus-minus a whole host of other biologics that are coming down the pike that are specific to GVHD. Other things that are potentially specific to stem cell transplant, although not exclusively, so VOD, which is now sinusoidal obstructive syndrome, or SOS. This really does have a lot to do, again, with that pre-transplant conditioning regimen, the intensity of it, what drugs are used. And what it is fundamentally really is endothelial damage. It's endothelial damage that is specific to the sinusoidal endothelial cells that cause obstruction of those sinusoids that impairs blood flow through the liver, basically. And so this triad of symptoms is what you will see. The findings on ultrasound typically will be reversal of flow in the portal vein. And treatment is going to be multifactorial. Largely, it's going to be good critical care. But then it's also going to include diffibrotide, which is a, so actually, the mechanism of action of this is in the name. I love when drugs do this. It's not very common. But the drug name itself tells you what it does. So what you're trying to do is break down fibrin. So part of the cascade, they'll talk about in the next slide about TMA, hint, hint, is that endothelial dysfunction is going to cause a little microthrombi if you break up the fibrin. This is a drug that, in my career, has been a game changer for VOD. Even with diffibrotide, there are other aspects of management that you can find reviewed in this paper and the companion. There are sets of guidelines. Ascites is one that is very common that can be to the point that you actually cause abdominal compartment syndrome. That would need to be managed right away in order to save the kidneys that somebody back there think are actually important organs. It's not even paying attention. So that's a very quick version of VOD or SOS. TMA. So thrombotic microangiopathy, I'm just going to say familiarizing yourself with the various different versions of thrombotic microangiopathy and what that is will do you some good. These are a spectrum of illnesses or maybe an umbrella basket term. There are lots of things that fall under this term of TMA. The basic underlying pathophysiology tends to start with endothelial dysfunction. So it tends to be a multi-hit phenomenon where something injures the endothelial cells. Maybe here it's the transplant or the conditioning regimen for TAMOF. It might be sepsis. So something injures the endothelial cells. For TMA in particular that's transplant-associated, typically it's thought of as a complement-mediated phenomenon, kind of like atypical HUS. So you can think of the pathophysiology of this very similar to atypical HUS, which helps because then what you test for and how you treat it is also the same. So you activate complement. You're going to cause ongoing endothelial injury. So it's going to cause this feed-forward loop that will activate your platelets, cause microthrombi. That's what's going to cause your anemia and your MODS. So this is what you see. Very similar to atypical HUS. And this is how you treat it. Again, very similar to atypical HUS. So this table I don't put up here to go in detail, but it's, again, a really useful reference because those three things I just talked to you about have very similar signs and symptoms. All of them can present with MODS. And so if you have a patient who's post-stem cell transplant with MODS, it can be a little bit tricky to think about, OK, what's causing the MODS? And having a reference like this can help. Also, like I said, having very close communication with your transplant team about what this patient's specific risk factors for each of these things are. So you have this in your slide for reference. A couple of things that are specific to the pulmonary system, so moving away from MODS to SOD, single-organ dysfunction, these are just things to know about. So idiopathic pulmonary syndrome and bronchiolitis obliterans, you should know. They should be part of your vocabulary. You should have some sense of what they are as they are on your differential for respiratory dysfunction in this patient population. OK. A little bit on solid organ transplant. Yep, OK. So here, your infection risk is really going to be related to your degree of immune suppression. And your degree of immune suppression is going to differ based on different organs and the amount of immune suppression that is required to prevent rejection. And so in general, lungs, bowels, organs that have their own native immune system are going to require more immune suppression. Kind of makes sense. Each, the monitoring for your solid organ transplant, of course, is going to, I am so sorry about the auto forward, is going to depend, obviously, on the organ itself. So the way that you monitor a transplanted organ is going to be, in some respects, similar to how you monitored that organ dysfunction before the transplant. But there are some specific tools as well. In this patient population in particular, thinking about drug-drug interactions and your drug clearance is really, really important. So having your pharmacist involved, because as your transplanted organ is coming back online, if you will, your drug metabolism is going to be different. And that needs to be taken into account. So for all of organ transplant, obviously, we're trying to prevent graft rejection. It's important to know the three different categories of graft rejection and what those individually look like. So you have your hyperacute, what does that look like? Your acute, what does that look like? What causes it? How do you treat it? And then your chronic, what does that look like? What causes it? And how do you treat that a little bit differently? There's a little bit more in the full slide deck about this. Couple of slides just on specific complications that you might see after, particularly a solid organ transplant. So post-transplant lymphoproliferative disorder is one that you should at least know about. So this is gonna be a little bit different. So this is related to the immune suppression that your patient is on, tends to be thought of as a reactivation of EBV, and particularly is gonna cause a clonal expansion of B cells. So if you think of post-transplant lymphoproliferative disorder, and you think EBV and B cells, you got it. And so think about how that's gonna present, what some of the risk factors are. Again, if you have someone who has EBV negative to begin with, and then gets a transplant that's EBV positive, or gets exposed to EBV after transplant, that's gonna be a risk. Your mainstays for treatment here, again, that balance of can you safely reduce the immune suppression? And or do you give a therapy that's specific to B cells? And if you put in your brain rituximab, which is a monoclonal antibody against CD20, which is cell surface marker on B cells, so link rituximab and B cells in your brain, that's gonna be a mainstay of therapy for anything that's B cell mediated. So the bottom line for when you're taking care of transplant patients, one is your signs and symptoms of organ rejection or infection often overlap. And that can be really tricky, right? Because the treatment of those two things are diametrically opposed, right? So if I think my patient has organ dysfunction because of rejection, I'm gonna increase my immune suppression. However, if that organ dysfunction is because of sepsis, which we know also causes organ dysfunction, then I wanna decrease my immune suppression. And so this is really my biggest take home point for the care of the patient with immune compromise due to transplant is a multidisciplinary approach really is most important. And that is having a good understanding of the risk factors specific to your patient and having that bi-directional communication with your transplant team about the relative risks and benefits of managing the immune suppression in the context of your patient who is now critically ill and may or may not be infected. So my key take home points, immune suppressed children, broad group of patients. You should know about all of them. There are a broad array of immune suppression, excuse me, immune suppressive medications. Think about the specific targets for each of those medications and the specific side effects for each of those medications. The immune compromised patient really does require special consideration for prophylaxis as well as for a different differential diagnosis when you are suspecting infection and or when you suspect infection. And think about those conditions that are unique to that population that you might not see in other populations, but if you recognize them early and you manage them well in a transplant population, that is lifesaving. And a multidisciplinary approach is absolutely essential. That's all I got. Thank you.

immunocompromised children

solid organ transplant

CAR T-cell therapy

GVHD

infection management

multidisciplinary support