My name is Asya Golnik. I'm a pediatric intensivist at St. Jude, as you heard. And these slides are a combination of my own and ones from Mark Hall, who used to teach this class, as well as some of my own colleagues from St. Jude. So I'll start with immunodeficiencies and then go to PT-monk emergencies. I'll probably spend more time on that second topic. I'll explain where I'm going to skip over so that you can just read them on your own and try to get through at least at the time and maybe sooner. So no disclosures. This is my funding, which isn't relevant. So for the first talk, which is about immunodeficiencies, I'm gonna talk about components of an acquired immune system, some of that echoing what Scott talked about earlier, signs and symptoms of primary and acquired immunodeficiencies and then treatments. So briefly, starting big picture, and then I'll show you how this is organized for how you can use it in studying. So components of the immune system, review from your medical school. We wanna recognize self and defend against infections and eliminate pathogens. So we have barriers, non-cellular immunity, and then cellular defenses, and the innate and adaptive immune system as well as the components that are there. I realize this is review, so I'm gonna skip through that pretty quickly. So innate immune system are your neutrophils, monocytes, macrophages, dendritic cells, and NK cells. They're present from birth, your first line of defense, and they recognize a broad class of receptors that are nonspecific. And the magnitude of their response is proportional to the stimulation, which is actually really relevant for when things go poorly. And then their effectors are cytokines and chemokines. On the other side, the adaptive immune systems, B and T cells they require antigen presentation. They perpetuate and modulate the immune response. They have memory, they're specific, and on top of cytokines and chemokines, they also have antibodies, which opsonize. And so this is important as you think about where things go wrong, and then what are the consequences of that when it occurs. So starting with immunodeficiencies, if you think about primary immunodeficiencies, they classically present with very similar presentations. So they obviously have persistent infections. The type of infections often signals to what's wrong, and that's in the slides that I'll show you how to go through that. They're often unusual or opportunistic infections and have poor response to appropriate therapy. They also have sequelae of chronic infections, so they can have bronchiectasis or clubbing or other signs, often failure to thrive. And then some specific things like granulomas, they might have autoimmune disease because the mechanism there for the immune dysregulation is similar. They have a higher risk, some have a higher risk of malignancy. And then often there's gonna be a family history, which should trigger you that this is a familial situation in a question stem. So I'm gonna skip quickly through the specific cellular defects. The slides are there for you to review, and I mostly wanna show you how this is organized, which is hopefully gonna help you study this, because unless you're an immunologist, you're probably not gonna spend a lot of time in your career thinking about primary immunodeficiencies outside of the boards. So for each of these slides, the way that these are organized is to focus on the thing that is abnormal, so in this case neutrophils, and what is the abnormality. So here you can see the disorders where you have not enough neutrophils. And the disorders are listed there as well as their presentation with the types of infections in red. And I highlight that because I don't know how you take tests, but for me it's a lot of recognition of triggers in question stems. And so sometimes these things help you understand if they're talking about a specific immunodeficiency or a mechanism that is abnormal. So for example, in neutrophils, there's several disorders, innate disorders that present with inadequate numbers of neutrophils. And they're usually treated with GCSF. You can have adequate numbers, but that they don't work well. And if you think about what the mechanism of what neutrophils do, so you can have breakdowns in each part of that process. So if the neutrophils aren't able to get to the site of infections, you're gonna have often recurrent bacterial infections with neutrophils. And those types of innate immune deficiencies are treated with prophylaxis. Alternatively, they may be able to get there, but they can't phagocytose. And again, recurrent bacterial infections. You can see the treatments listed here. I'm not gonna go through these one by one because you're gonna fall asleep. And then they can get there. They may be able to start, but they can't complete the full phagocytic cycle. So you can see what happens if you can't phagocytose. If you can phagocytose, but you can't do the oxidative burst, meaning you can't actually kill the bacteria. They're in there, but they're alive. And granuloma is something we hear about. So if you see that, that's the mechanism. You think neutrophils. And again, prophylaxis for treating many of these. So neutrophils. Same concept for when we think about lymphocytes. Again, these are organized by the type of cell and what goes wrong, highlighting the types of infections that you're gonna see. So unlike with neutrophil deficiencies where you have recurrent bacterial infections, these are slightly different. You're gonna see opportunistic organisms. And so if you don't have enough lymphocytes, I think dysgeorge is something you see on tests a lot because there's also all these other symptoms, congenital anomalies that can trigger that. For severe combined immunodeficiency or SCID, you're gonna get these opportunistic infections that you see in other patients who are chronically immunosuppressed. Importantly there that you have both BNT cells. So often presenting right with severe presentations in infants. So you can have lymphocytes but not enough of them. An example of that is ataxia telangiectasia. Another one that comes up because it has a lot of physical findings that are listed there. And you're gonna get recurrent infection with encapsulated organisms. And another example of not enough B cells in this case is X-linked or Burton's agam algal bulimia. Remember back to your board days from pediatrics, you can't have, if you don't have B cells, you don't make antibodies. So again, you're gonna have recurrent infections with encapsulated organisms. Shockingly, the treatment for this is to replace antibodies, so IVIG. And then you can have enough, just like in neutrophils if lymphocytes are present but they don't work well. Here is an example of what happens in that scenario. Bacterial recurrent infections. And depending on your T cell defect, if you have a primary T cell defect, it's important to understand what's going on with B cells as well. And so another example of lymphocytes present but don't work well. And again, I want you guys to have the slides, understand how they're organized, spend time to go through them when you have time. And then I do wanna spend some time here because I think this comes up a lot. And it's good to be able to recognize these when it happens on questions. So what happens when lymphocytes are present but they're overstimulated rather than under or dysfunctional? And so you get X-linked lymphoproliferative diseases. This can be innate or can get triggered by a virus, in this case often EBV. And they're treated with chemotherapy and immunosuppression. So that kind of links to the idea of HLH, which comes up on board questions all the time because it has a pretty specific presentation. So this is a disorder of the immune system where you have dysregulation of cells that down-regulate inflammation. So you have a hyper-inflammation phenotype due to immune dysfunction. And so these are the diagnostic criteria. Of the eight, you have to have at least five to meet the diagnosis. I think it's important because not all of them are often present in a patient realistically at the bedside and on question stems. But classically, this is a patient that's presenting with shock, they have fever, splenomegaly, cytopenia, they're very inflamed, so high ferritin, low fibrinogen, and high triglycerides. And then if you're very lucky, they'll talk about evidence of hemophagocytosis. But usually, of course, you don't know that at a patient presentation. And so most of these patients, patients presenting with HLH are extremely ill and so present with critical illness, including on board exams. And so importantly, when the questions come up, you wanna try to understand is this primary or familial. Often those patients are gonna have a family history of immune disorder or death from infection or shock. They present younger. And that's important because those patients ultimately will need to be, if they're gonna survive treatment, they need a transplant. As opposed to acquired or secondary HLH where the primary mechanism is a trigger and you have to treat the trigger for them to get better. And that, I think, is important for real life, but also as you think about answering, understanding these questions on board exams. So those were cellular elements of the immune system and disorders of their dysregulation, inequity numbers, or hyperactivity. And so this was mentioned by Scott, so I'm not gonna spend a lot of time, but you can also get, obviously, disorders of your non-cellular elements. So think about cytokine, excuse me, complement, and what happens if you have inadequate numbers of complement or when they are dysfunctional. And again, if you think about what the complement does, remember it organizes into a membrane attack complex. And so if you can't do that, you can't kill particularly encapsulated bacteria. So you're gonna get infections with those types of bacteria. The other component of the non-cellular immune system is immunoglobulins. So again, opsonization, neutralizations of antigens. We covered, or the prior slides covered some of these disorders, but you have to think about if you have a primary disorder, whether how bad the deficiency is, and whether it's in all components, all immunoglobulins, or only a subset, and that will impact how severe the presentation is. So depending on whether it's all immunoglobulins or a subclass, the presentation will be different. And then if the immunoglobulin deficiency is secondary to a cellular deficiency, you're gonna have other elements of the immune system that are affected, obviously, like in severe combined immunodeficiency. And as in many of these, immunoglobulin disorders can be acquired if you're losing protein. So thinking about a patient with kylothorax or other losses. So again, you're gonna have an issue with opsonization, so encapsulated organisms, and treatment is often replacement of those. The last thing to note is asplenia. We see this either congenital in heterotaxy syndrome or acquired in sickle cell disease or trauma, or in a patient who's had a spleen removed for some other surgical indication. And so those, again, present with overwhelming infection with encapsulated organisms. And so this is a summary, again, for you to have in review of the types of organisms that you may see recurrent infections with, and then what is the mechanism or this component of the immune system that is possibly deficient to help you kind of pair the presentation to what is the underlying problem. So that's primary immunodeficiencies. A note about secondary or acquired immunodeficiencies, and this is echoing a lot of what Scott said, so I think that this is hopefully reinforcement. So, of course, there's some obvious causes, as in we're causing immunodeficiency with our treatment. So patients who have received either a solid organ or a bone marrow transplant, they are receiving rejection prophylaxis, so they're immunosuppressed. Any patient with a malignancy does not have a functional immune system, either because of their underlying cancer or because of the cancer-directed therapy, and so they're obviously immunosuppressed. And then, of course, patients with autoimmune diseases who are treated for those autoimmune diseases as well as patients with HIV rates. As Scott, I think, spent a lot of time on this, so I won't as much as talking about the immune effect of critical illness. So we, not only in sepsis, but in critical illness in general, you can have a pro-inflammatory response and an anti-inflammatory response. Those things are functional responses to serious illness, but when they become dysfunctional, meaning it's a pro-inflammatory response that is out of control or anti-inflammatory response that is not rebounding, you get the secondary effects on your immune system. And so you can have patients, for example, presenting with an HLH-type syndrome or hyperferritinemic response, or conversely, patients who are immunosuppressed. And immunoparalysis, which is something that Scott mentioned so I won't spend time on, but the main thing there is to stop. If a patient is receiving immunosuppression and you think that that is the mechanism of their problem, it's part of the management is to actually stop the immunosuppression. And then a lot of what we do in critical care is causes immunomodulation that we have to be cognizant of that might not be intentional, but is a secondary effect of our treatments. And so I think on the third day, you'll hear a lot about transfusions. Those are often immunosuppressive. Patients who are presenting malnutrition, and it could be malnutrition because of a patient in the community who is malnourished, but also patients, as you heard earlier, who are potentially on TPN or are getting insufficient nutrition by us, often will have immune suppression. Hyperglycemia or other complications of critical illness is pro-inflammatory. Hypothermia, for example, caused by us if we're treating a patient, is immunosuppression. And then many of our ICU medications have immune modulation effects that are important to consider, but are secondary to the primary intent. And then just to say that not every patient who presents with a recurrent infection at your bedside or in a question stem has a primary or secondary immunodeficiency. There are a lot of other non-immune causes of recurrent infections. So abnormal mucous membranes, patients with burns, with severe eczema, with Bullis disease or ectodermal dysplasia, patients who have obstruction of hollow viscous, so they have a foreign body, or ureter pelvic valves, for example, foreign bodies that we place as part of our medical management, vascular anomalies, and then congenital anomalies that might predispose somebody to recurrent infection, as well as neurologic conditions like aspiration. This is obviously stuff that we see all the time. And then finally, metabolic disorders. So I think it's the, when you're trying to understand is that they're trying to get me at a primary immunodeficiency in a question stem, it's those signal, recognizing the other symptoms, other presentations of the patient, a family history, and then the type of infection that they have would guide you into is this, are they trying to get me at a underlying error in the primary immunodeficiency, or is this something else? So a summary on that piece is that there are elements of the innate and adaptive immune systems that are affected by immune defects. And these often have a very classic presentation. They have a classic infectious presentation and findings. And so hopefully as you guys review, those slides will help you start to see the patterns that will then trigger something that you'll remember in a question. And also in addition to primary immunodeficiencies, a lot of interventions that are done medically or presentations of other illnesses might present as secondary immunodeficiencies. And a lot of what we see is actually as a result of the critical illness itself or the interventions that we do.

immunodeficiencies

pediatric intensivist

innate and adaptive immune systems

primary and secondary immunodeficiencies

immunoglobulin replacement