My name is Asya Golnik, and I'm an intensivist at St. Jude Children's Research Hospital, and I'm going to be talking to you about primary and acquired immunodeficiencies and how they're relevant in the PICU setting. Many of these slides are adapted from a prior presentation given by Dr. Mark Hall, who has given this lecture in prior review courses. I have nothing to disclose. The objectives of this talk are to know the components of the innate and acquired immune systems, to recognize the signs and symptoms of primary and acquired immunodeficiencies, and to plan appropriate treatments for patients who have these disorders. So first, generally about the immune system, the role of the immune system is to recognize non-self, and that includes both pathogens and tumors. It is an integrated defense to infection with the ultimate goal of eliminating pathogens from the body. We will talk a lot about cellular defenses, but you have to note that there are other components of the immune system that includes barriers, such as the skin and mucociliary clearance. Also, there are non-cellular elements of the defenses, which include acute phase reactants, such as complement and CRP, and then immunoglobulins, which are made by B cells. And finally, the cellular defenses, which are composed of innate and adaptive immune cells. Innate immune cells include neutrophils, monocytes, macrophages, dendritic cells, and NK cells. This is part of your immune system that is present from birth and serves as the first line of cellular defense to infection. Importantly, it is nonspecific. These cells recognize broad classes of pathogens or molecules via cell receptors, such as toll-like receptors. And their response to a stimulus is of the same magnitude with each stimulation, meaning that there is no requirement for prior exposure, and the response does not increase in magnitude after exposure. And these cells have effectors, which include cytokines and chemokines. So contrast that with adaptive immune cells, which include T and B lymphocytes. These typically require antigen presentation for action. Remember that innate immune cells present an antigen, and the adaptive cells recognize this antigen. They typically perpetuate and modulate the immune response. Also, cells like the CD8 cells will actually kill directly. And this is an immune response that develops following exposure to an antigen. So this provides memory to that exposure. And the affinity of the response increases with increased experience, meaning there's a specific response to a specific antigen that you've seen in the past. Effectors of this response also include cytokines and chemokines, but also antibodies, which are made by B cells that mature into plasma cells, making antibodies. And that is important for upsonization, which is something we're going to talk a lot about. So there are a number of cytokines that you may want to remember. Common ones on these lists among the pro-inflammatory are IL-1 beta and TNF-alpha, which are part of the innate immune response, and IL-2 and interferon gamma, which are part of the adaptive immune response. And then the anti-inflammatory cytokines include IL-10 and TGF-beta. So let's talk about some features of primary immunodeficiencies. These patients typically present with recurrent, persistent, or severe infections. These can be unusual infections or opportunistic ones. And sometimes they will have a history of poor response to what is typical appropriate therapy. They'll also have sequelae of chronic infections, such as bronchiectasis or clubbing. They will typically, but not always, have failure to thrive. Type of presentation may be granulomas, which is a problem with walling off infections. And because their immune response is irregular, they may have autoimmune disease and also present with malignancies because they are not able to not only recognize pathogens, but also abnormal tumor cells. And of course, these patients may have a family history of immunodeficiency or unusual infections. So let's talk about some specific cellular defects. First, talking about the neutrophil, it's helpful to review normal neutrophil action. So neutrophils will travel through the blood vessel. They will begin rolling from an interaction of the neutrophil proteins with the P-selectin glycoprotein. And this will cause them to slow down and roll along the endothelial of the blood vessel. There will then be an upregulation of integrins, which will stop the neutrophil, will cause adhesion. And then the neutrophil will migrate through the endothelial into the tissue. They will then chemotax towards the site of infection. And they will then phagocytose the bacteria and kill that bacteria within the cell, and then downregulate and apoptose when they're no longer needed. Let's talk about some specific disorders of neutrophils. For all of these slides, the blue font is what you should know about the disorder, and the red font is the typical infections that they get. So first, disorders where there are not enough neutrophils or present with neutropenia. The first example of this is severe congenital neutropenia or Kauffman syndrome. These patients present with profound neutropenia, recurrent infections with Staph aureus and pseudomonas. Contrast that with cyclical neutropenia, which present with a few days of neutropenia that occurs one or two times a month, and ulcers and cellulitis. And finally, Schwachmann-Diamond syndrome, which has a classic recognizable phenotype, which means it can present in questions. And they have neutropenia, pancreatic insufficiency, and skeletal abnormalities, and will have recurrent infection. For all of these, the treatment is with GCSF. So you can also get disorders of neutrophils where their function is impaired, thinking back through that normal function of neutrophils. There are disorders where the neutrophils can't get to the site of infection appropriately. One example is leukocyte adhesion deficiency, where they are missing the CD18 molecule, which is the adhesion molecule. This is another one that has a classical phenotype. They present with delayed cord separation and recurrent bacterial infections. Also there's hyper-IG, or Job syndrome, which have abnormalities in neutrophil chemotaxis, meaning they can't get to the site of infection. They present with recurrent staphylococcal infections, specifically in the lung, which results in pneumoceles and brachiectasis. And they also have a recognizable clinical phenotype of coarse facial features, eczema, and retained primary teeth, and as the name suggests, will have high IG levels. For these, appropriate antimicrobial prophylaxis is the treatment. Neutrophils can also not work well in other ways. For example, they may not be able to phagocytose bacteria, so that would result in Chediak-Higashi syndrome, which is a rare autosomal recessive disorder of impaired phagocytosis. These patients also have a recognizable phenotype of albinism, peripheral neuropathy, and then recurrent bacterial infections of the lung and skin. And treatment is symptomatic treatment, and then there's potential for transplant. There are also situations where cells, neutrophils, can phagocytose but can't produce an oxidative burst, meaning they can't kill what they are phagocytosing. An example of that is chronic granulomatous disease, which is typically X-linked recessive. It is a mutation in the NADPH oxidase, resulting in an inability of producing the oxidative burst. These patients have recurrent skin and lung and liver infections. Typical pathogens are Staph aureus, aspergillus, and serration, as the name suggests, will present with GI granulomas. Testing for these, there's a specific test for CGD. Previously, the nitro blue tetrazoleum test was used. And so if you see that, it is referring to chronic granulomatous disease. And more recently, the cytochrome C reduction assay is used. For all of these disorders, again, antimicrobial prophylaxis is important for treatment. So here's a sample question. A 32-day-old female presents with abdominal dissension and fever. The physical exam, which you can see in that picture, demonstrates a tachycardic fussy infant with peri-umbilical erythema and a persistent umbilical stump. Laboratory analysis reveals a white count of 87,000. What is the most likely underlying condition leading to this presentation? Your options are severe congenital neutropenia, leukocyte adhesion deficiency, chronic granulomatous disease, or primary HLH. I'll give you a minute to think about that. So the right answer is leukocyte adhesion deficiency. Again, that retained umbilical stump being the tip-off point. Going through the other answers, severe congenital neutropenia, you will have neutropenia and recurrent bacterial infections. This patient has a robust white cell count. As I mentioned, for LAD, you will have a neutrophil adhesion defect, and that also results in delayed cord separation and bacterial infections. Chronic granulomatous disease is X-linked recessive, typically. So this patient is the wrong gender and also presents with granulomas. And finally, HLH typically presents with shock, and we'll talk about that in a little bit. So moving on to another class of cells, so lymphocytes. Again, you can have disorders of insufficient quantities of lymphocytes. An example of that is DiGeorge syndrome or 22q11 dilation. This is also called velocardiofacial syndrome. This presents with thymic apoplasia, meaning you do not have T cells. You have clonotropical heart lesions, velopharyngeal incompetence or clefts, and hypocalcemia because of a loss of the parathyroid gland. Diagnosis is genetic through FISH. In treatment, importantly, these patients need to receive irradiated blood products. Any patient that has a T cell defect needs to receive irradiated blood so that donor leukocytes can't be given to the patient and attack the patient's native cells, causing transfusion-associated GVHD. If the blood is not irradiated and transfusion-associated GVHD does occur, that carries a very high mortality. Similar for these patients, they can't get live vaccines and will need antibiotics. Another example of lymphocyte deficiency is severe combined immunodeficiency or SCID. Also adenosine deaminase deficiency. This is a combined immunodeficiency, meaning it's a failure of both B and T cell lineages. These patients typically present with failure to thrive as infants. Infections that these patients get are candidiasis, viral infections, and opportunistic infections. They also will need irradiated blood, can't have live vaccines, and will typically be treated with transplant, although there's a recent study showing success with gene therapy. Another example of insufficient lymphocytes, which also has a distinct phenotype, meaning it's easy to test on, is ataxia telangiectasia. These patients have neurodegenerative disease, skin findings, and recurrent sino-pulmonary infection with encapsulated bacteria. They will have low T cell and antibody levels, so this is a form of combined immunodeficiency. This is because of a defect in the ATM gene or the ataxia telangiectasia mutation, which causes a decrease or absence of the protein in white blood cells. These patients are treated with IVIG and antibiotics. You can have deficiencies in B cells. An example of that is X-linked agammaglobulinemia, or Burton's. This is a mutation in Burton's tyrosine kinase, which results in no mature B cells, meaning no plasma cells, and as a result of that, no antibodies. These patients present with recurrent sino-pulmonary infections in infancy and youth with pneumococcus, haemophilus, meningococcus. Those bacteria have something in common. They're all encapsulated organisms, and that's something you'll hear over and over again. You need antibodies and opsonization to clear encapsulated organisms. So diseases where there's a problem with B cells or antibody production, a problem with opsonization or clearance, will frequently present with recurrent infections with encapsulated organisms. Also these patients are susceptible to opportunistic infections, and they are diagnosed by quantitative immunoglobulin levels. They will have low immunoglobulin levels, and you can do specific assays, and treatment is actually just giving them immunoglobulins. You can also have disorders where B cells are present but don't work appropriately. So an example of that is hyper-IgM syndrome. This is an X-linked disorder, a mutation of a specific gene. Here B cells are there, but they can't class-switch, meaning that they, remember, you will first make IgM, and then over time, to the specific infection, you will make IgA and IgG. In this disorder, the B cells can't do that, so they will only make IgM. There is also a problem in this disorder with T cell receptor signaling, so this is a type of combined B and T cell disorder. These patients will have recurrent respiratory infections with bacteria and cryptosporidium. They'll also have liver disease and an increased cancer risk, and treatment is with immunoglobulins, antibiotics, and possibly transplant. Another example of this is Wiskott-Aldrich syndrome. This is an X-linked disorder with a mutation in the WASP gene. Again, this is one that has a specific phenotype, so it can be tested. They present with eczema, thrombocytopenia, and immunodeficiency. They have reduced antibody production and T cell signaling, so again, a combined immunodeficiencies, and present with recurrent bacterial infection with encapsulated organisms, again, an opportunistic infection, and here, similar treatment. And then there are disorders where the lymphocytes get overstimulated. So an example is X-linked lymphoproliferative disease. There are two types with mutations related to lymphocyte activation. So these patients are actually normal until they get infected with EBV, which results in a lymphomatous transformation, typically a B cell lymphoma. And these cells, as a result of that, will present with lymphadenopathy, hepatic failure, and if they have marrow infiltrate, marrow failure. And so these patients will need chemotherapy, and they can also be treated with rituximab, which is a B cell-specific anti-CD20 antibody, and then will need to go on to transplant. And finally, let's talk about HLH. So this is a severe hyperinflammation and setting of immune dysfunction. Here, NK cells are either malfunctioning or deficient, and this causes dysregulation of cellular cytotoxicity. Patients present with fever, splenomegaly, cytopenias, high ferritin, low fibrinogen, and high triglycerides, and elevated CD25. And then the disorder is manifested by hemophagocytosis and reduced or absent NK cytotoxicity. So you need five of eight of these diagnostic criteria to meet the diagnosis of HLH. And these patients typically present in shock, frequently more than half requiring ICU care on presentation. So how does this happen? Let's talk about the normal immune response. So CD8 T lymphocytes are exposed, for example, to a viral infection. There will be an expansion. They will make cytokines. And then after that is done, the NK cells will facilitate cytotoxicity, there will be a contraction, apoptosis of these cells. However, in HLH that expansion happens normally to an infectious or other trigger. However, that cytotoxicity doesn't occur and so there's this dysregulated proliferation and cytokine storm which results in macrophage activation, a high level of cytokines, hemophagocytosis, and tissue infiltration presenting with the symptoms. So there are two types of HLH, both are dysfunction of NK cells. The first is primary or familial HLH. This is autosomal recessive or X-linked. Most will present under two years of life and these are defects in NK cells genes such as perforin or granzyme mutations. Treatment for these disorders is chemotherapy. So the hallmarks of chemotherapy for HLH is dexamethasone, etoposide, and cyclosporine and ultimately these patients will require a transplant. Contrasting that with secondary or acquired HLH which is a similar reaction but in response to a trigger, typically infection, which can be bacterial, viral, fungal, or parasitic, malignancy, or autoimmune disease. And here the treatment is directed at treating the underlying trigger. Patients do sometimes need corticosteroids, IVIG, or anakinra, sometimes cyclosporine, and possibly etoposide at extreme cases. We've talked about cellular immunity. Now let's talk about some non-important non-cellular elements and how those can be abnormal. We mentioned the importance of acute phase reactants such as CRP, fibrinogen, complement, mannose binding lectin, and SAPs. You all remember the complement cascade. You don't need to know the details of the complement cascade for the boards but you do need to know the manifestations of complement deficiencies and also generally know that complements are important to effective immune response, that they're activated by several pathways including antigen-antibody interactions, mannose binding lectin, or MBL, and that there are some that are spontaneously active. So complement deficiencies can be present in one or more of the complement proteins. They can exhibit defects in upsonization and chemokine or cytokine function. Also another important element of complement function is to form the membrane attack complex so those proteins can be deficient. You can have a deficient MAC and so these pose a high infectious risk particularly with encapsulated organisms and Neisseria meningitis. So that's an important one to remember if you see a recurrent infection with Neisseria that is a trigger word for a problem with a complement. In diagnosing these you can either do complement levels or complement activity. We already mentioned a number of deficiencies of immunoglobulins. Remember these are responsible for upsonization sticking to the pathogen which allows for the pathogen to be neutralized. The back end, the Y end of the antibodies, the FC portion, which is what is recognized by innate immune cells that then clear the pathogen. These deficiencies can be severe such as the X-linked agammaglobulinemia or hyper AGM syndrome or they can be mild such as IgG subclass deficiency or IgA deficiencies. They can also be associated with other immunodeficiencies such as a common variable immunodeficiency and can be acquired through loss of immunoglobulin. We'll talk more about that a little bit later. And so as we talked about earlier immunoglobulin deficiencies will present with infections with encapsulated organisms because remember you need upsonization in order to clear encapsulated infections and can be diagnosed with quantitative immunoglobulins subclasses and can be treated with IBIG and antibiotics. Asplenia is important to mention. This can be congenital such as patients with heterotaxy syndrome or acquired such as in sickle cell disease or trauma with surgical resection. Patients are at risk for overwhelming infection from encapsulated organisms. Here the problem isn't making antibodies but that there's normal upsonization but they can't clear the pathogen once it's upsonized because you need a spleen in order to clear those pathogens. So think again encapsulated recurrent infections with encapsulated organisms and for that reason these patients need antimicrobial prophylaxis and immunization. So here's another question. A 16-year-old girl presents to the PICU with her second episode of severe pneumonia with strep pneumo requiring intubation both within the last year. Her height and weight are at the 60th percentile. She is developmentally normal with no known comorbidities. Laboratory testing shows a white count of 20,000 with the differential you see. Serum IgG levels are 20 percent of normal while IgA and IgM are 60 percent of normal. Enumeration of B and T cells are normal. This patient most likely has asplenia, complement deficiency, Wusker-Aldrich syndrome, or common variable immunodeficiency. So I'll let you think about that for a second. So the answer is common variable immunodeficiency. Just going through some of those answers there's nothing in her history to suggest asplenia. For complement deficiency remember the trigger there is Neisseria often. Wusker-Aldrich is X-linked so those are typically male. Also remember the phenotype of eczema and thrombocytopenia as well as recurrent infections. So that's a good answer. Common variable immunodeficiency is one that actually typically presents in the second or third decade of life. So they are not patients who present with failure to thrive or early infancy. They will have low antibody levels but normal B and T cells. So that is the right answer here. Another way to think about this is to think about which are the types of immune defects that present with which types of infections. So for that you can refer to this table with antibody deficiencies presenting with enterovirus encapsulated bacteria Ganongiardia. SCID presenting with a host of viral bacterial atypical and fungal infections. Phagocytic defects presenting with catalyzed positive bacteria atypical and fungal infections. And then there's a number of other types of positive bacteria atypical mycobacteria and some fungi. And then complement deficiency presenting with encapsulated organisms particularly Neisseria. Now let's switch gears and talk about secondary or acquired immunodeficiencies. So first some obvious causes. Patients who have undergone transplantation and are on rejection prophylaxis. Patients who have malignancy and either have bone marrow invasion or are being treated with chemotherapy or radiation that is immunosuppressive. Patients with autoimmune disease who are on immune suppressive medications. And of course patients who have HIV or AIDS. Those are obvious secondary or acquired immunodeficiencies. But maybe less obviously is what commonly happens in patients with critical illness which is an impairment of immune function. So we know that patients with critical illness often have a pro-inflammatory response with SERS, increased levels of cytokines, fever, capillary leak, and organ dysfunction. But at the same time these patients will have a compensatory anti-inflammatory response or CARS with a down regulation of their immune response. And so if both of these immune responses are modest and transient the patient will have an uncomplicated course. However if they are persistent and severe the patient will have a complicated course and have a higher risk of mortality. So to explain that this is an example of a normal monocyte. And remember monocytes will phagocytose bacteria. They will then kill that bacteria and present antigens from that bacteria on HLA-DR on their cell surface for recognition by other cells. They will also cause production of TNF-alpha. However contrast that with an immunoparalyzed monocyte which has decreased ability to phagocytose as a result of and also decrease intercellular killing. They will actually down regulate HLA-DR and have decreased antigen presentation as a result and will also have less ability to produce pro-inflammatory cytokines like TNF-alpha. This can actually be diagnosed quantitatively. So the decreased HLA-DR can be either diagnosed by the percent of monocytes with a robust HLA-DR response. That's a percent positive and that is typically less than 30 percent in immunoparalysis. Or the number of HLA-DR molecules per cell is the number there is less than 8,000. And also in laboratory studies you can actually demonstrate this failure to produce TNF-alpha with stimulation. So at baseline when you are not stimulated you should not have high levels of TNF-alpha but your production capacity meaning your ability to respond to infection is really important and these cells have a reduced production capacity of TNF-alpha. So there's a number of studies that demonstrate that immunoparalysis results in worse PICU outcomes and these patients have an increased risk of mortality in pediatric mods. Also the initial TNF-alpha response that capacity for response is able to predict mortality in children with critical influenza. Importantly they also have a higher risk of nosocomial infections. So studies showing that the TNF-alpha response at post type day one actually predicted the risk of post-op sepsis after cardiopulmonary bypass and that the early and longitudinal reduction in TNF-alpha response predicted development of nosocomial infections in pediatric trauma. And finally these patients also have prolonged organ dysfunction with studies showing that reduction the TNF-alpha response is associated with more organ failure in pediatric sepsis. So there are proposed treatments for immunoparalysis. Importantly in these patients if they are immunosuppressed you should stop the immunosuppression if possible. And then there are two experimental treatment that have data behind them. The first is interferon gamma which there are some data out of Europe. The problem with this treatment is that it is not as well tolerated. The treatment has side effects with fever and hypotension. Also GM-CSF granulocyte macrophage colony stimulating factor is a treatment that's actually used commonly in adults and children for reconstitution of the bone marrow after transplant or after chemotherapy and leukemias. And this treatment actually not only increases immune cell numbers but also increases the function of existing cells and is actually better tolerated. And so there are some small studies that show that GM-CSF in patients who have immunoparalysis improved the immunoparalysis or reversed the immunoparalysis both in septic adults and in pediatric patients who have evidence of reduced TNF-alpha response and MODS. So we talked a lot about monocytes. Lymphocytes are important too. These are some images showing lymphocyte depletion in spleens of children with MODS and lymphopenia. And there's evidence that prolonged lymphopenia, which is defined as an ALC of less than 1000 for a week, is associated with secondary infections and death. So it's not just about the quantity of lymphocytes, it's the function of them as well that's important. Remember there's a number of different types of CD4 cells. A few worth mentioning are Th1 cells which are pro-inflammatory. They make cytokines such as IL-2 and interferon gamma and they induce B cells to make more immunoglobulins. There's also Th2 cells which are anti-inflammatory and autoimmune and they make IL-4 among others. There are also Treg cells which are potently anti-inflammatory making IL-10 and TGF-beta and finally Th17 cells which are also pro-inflammatory make IL-17. And so there's evidence that down regulation of lymphocyte pathways actually predicts mortality and organ failure in pediatric sepsis and that global reduction in lymphocyte cytokine production predicts newer persistent infection in pediatric sepsis. So the function of these cells is equally important. And finally there are acquired hypoglobulinemias. We already mentioned a few of these. These can accompany critical illness and should be treated with IVIG replacements. So some conditions that might result in low immunoglobulin levels include lymphopenia. Remember that antibodies come from B cells. But also if a patient is malnourished, if they have kylethorax, they're losing antibody that way. If they have nephrotic syndrome or protein losing entropy, all ways that a patient might be losing protein and immunoglobulins that require IVIG replacement. And then to remember that there are a number of unintended immunomodulation that happens in critical illness. For example, patients in our ICUs frequently require transfusion which is likely immunosuppressive. Mention malnutrition. Beyond loss of low protein levels and immunoglobulin, this is an immunosuppressive state due to trace element deficiencies. Hyperglycemia is likely pro-inflammatory and hypothermia is likely immunosuppressive. There's also a number of medications. And this is not a list that you need to memorize. But just know that many of the medications that we use in the ICU actually have immunomodulatory effects. And most of those effects are immunosuppression. This is obviously not the intended purpose of using these medications. But it's important to know that these are the unintended consequences. And so another question. A five-year-old boy is one week status post-motor vehicle crash that resulted in polytrauma, including traumatic brain injury, pulmonary contusions, and a grade 5 splenic laceration. Laboratory evaluation reveals a white count of 6,000 with 80% neutrophils, 8% bands, 5% lymphs, and 7% monos. And his monocyte HLA-DR expression is 45%. Which factor places this boy at greatest risk for nosocomial infection? The grade 5 splenic lac, his absolute neutrophil count, his absolute lymphocyte count, or his monocyte HLA-DR expression? I'll let you think about that. So the right answer is C. It's his absolute lymphocyte count. His grade 5 splenic laceration actually is not a problem unless it requires removal of the spleen, which this does not mention. His absolute neutrophil count is normal, is appropriate. However, his absolute lymphocyte count is less than 1,000 a week out from his injury, which remember is a risk factor for infection. And finally, his monocyte HLA-DR expression is above 30%, so is normal. And finally, I want to end with reminding you that not all recurrent infections are immune-mediated. There are non-immune causes. So for example, there could be abnormalities in the mucous membranes or skin through burns, severe eczema, bullous disease, or ectodermal dysplasia. There could be obstruction of hollow viscous through inhaled foreign bodies, urethral valve abnormalities, or obstruction. There could be foreign bodies such as shunts, prosthetic valves, devices, or catheters, vascular abnormalities such as intercardiac shunts, pulmonary fistulas, and diabetes. There can also be congenital issues that cause recurrent infections such as cysts or sinus tracts, TE fistulas, abnormal ciliary function, CF. There are neurologic issues that we see a lot that cause aspiration and poor respiratory effort. And finally, metabolic disorders. And so it's important to think when you see a case with a patient with a recurrent infection to consider is this a primary immunodeficiency, is this acquired immunodeficiency, or is there another cause for recurrent infection. So in summary, we talked about how elements of the innate and adaptive immune system can be affected by specific primary immune defects. And these often have identified ideologies, have characteristic infections, epidemiology-associated findings, and specific therapies. There are multiple acquired immune deficiencies that increase a patient's risk of infection and critical illness. And innate and adaptive immune function is often secondarily impaired in the context of clinical illness with critical illness-induced immune suppression that is contributed to by common ICU therapies. Thank you.

immunodeficiencies

Pediatric Intensive Care Unit

immune system components

specific immune system disorders

acquired immunodeficiencies

secondary immunodeficiencies

treatment of immune system disorders