Our objectives for today are to review the mechanisms of action and side effects of common immune suppressive drugs used in the oncology and transplant populations, to identify common pathogens responsible for infections in patients at various times following solid organ and stem cell transplant, and to recognize common complications of transplantation in the pediatric patient. The child in the Pediatric Intensive Care Unit can be suffering from immune deficiency from a variety of different sources, including congenital immune deficiencies, acquired immune deficiencies, as well as exogenous immune suppression from a variety of different drugs to treat different disease processes. For the rest of this presentation, we're going to focus on exogenous immune suppression. Let's start with a question. This case is of a 12-year-old boy who is being treated for severe rejection status post-liver small bowel transplant. He is currently intubated, has fluid overload, hypertension, and oliguria, with signs of acute renal failure. The question is, which of his anti-rejection medications is most likely responsible for his acute renal failure? We're going to come back to this question in a moment. The first drug class we will review are the corticosteroids. Now, most folks wouldn't necessarily consider corticosteroids to be immune suppressive chemotherapy, but the reality is that corticosteroids, particularly those with high glucocorticoid content, are potently immune suppressive. One of the mechanisms of immune suppression involves binding of the corticosteroid to the steroid binding protein in the bloodstream, and then binding to the glucocorticoid receptor on target cells, where they directly suppress NF-kappa B and AP1 signaling in the nucleus. Suppression of these signaling transduction pathways results in suppression of pro-inflammatory gene transcription and promotion of anti-inflammatory gene transcription, thus switching the inflammatory response to a more anti-inflammatory direction. Corticosteroids also specifically promote lymphocyte apoptosis. Now, this property can be advantageous when treating leukemia, lymphoma, and certain autoimmune disorders, but certainly glucocorticoids do promote lymphopenia and low antibody levels. There are lots of side effects that one must consider, including hyperglycemia, hypertension, impaired wound healing, neuromuscular weakness, and agitation. But it's always important to consider, when talking about corticosteroids, that the type of steroid does matter. Looking at the corticosteroids that are commonly used in the PICU, one notes that dexamethasone has potent glucocorticoid or anti-inflammatory activity and little to no mineralocorticoid activity, compared to methylprednisolone or hydrocortisone, which has a predominance of mineralocorticoid activity. These relative activities are important to note when selecting different steroids for different purposes in the PICU. We will next consider chemotherapy and other immunosuppressant drugs that you may see in your PICU patients. This slide here is for your reference. It includes a list of different drug classes, the drugs in those classes, and their mechanisms of action. We'll get into the specifics of these drugs over the next several slides. Many chemotherapeutic agents work by blocking cellular reproduction. These so-called antiproliferative drugs are sometimes used to target immune cells and cause immune suppression as their therapeutic target. But they are often used to treat rapidly dividing cancer cells. And because immune cells are also rapidly dividing, immune suppression is a side effect. The first class of antiproliferative drugs we will discuss are the alkylating agents. These drugs block cellular proliferation by interfering with DNA replication. While each of these agents causes marrow suppression, these drugs each also have unique toxicities. So for example, cyclophosphamide causes hemorrhagic cystitis, whereas cisplatin and carboplatin can cause nephrotoxicity as well as neurotoxicity. Cycloplatin is unique in that it is a hepatic P450 inhibitor and also has MAOI-like activity. And so drug-to-drug interactions may be common and need to be taken into consideration. Antimetabolites block the molecules necessary for DNA and RNA synthesis. They include purine analogs, such as azathioprine and mercaptopurine, which have side effects including myelosuppression, nausea, vomiting, and mucositis. As well as pyrimidine analogs, 5-thyrouracil, which has side effects of myelosuppression, rash, and diarrhea. Methotrexate is a folate analog that blocks the synthesis of thymidine, purine, and pyrimidine and includes toxicities of myelosuppression, particularly bad mucositis, as well as nausea and pneumonitis. These toxicities can be mitigated with lucovorin rescue. Pyridine inhibits inosine monophosphate dehydrogenase, which is needed for purine synthesis. It's often used for rejection prophylaxis in solid organ transplantation and for treatment of some autoimmune disorders. Diarrhea is a major side effect. Other notable toxicities include red cell aphasia, leukopenia, and potentially progressive multifocal leukoencephalopathy. Tumica alkaloids prevent microtubule assembly and function, which prevents mitosis. Toxicities include peripheral neuropathy and hyponatremia. Topoisomerase inhibitors prevent DNA replication by blocking the enzymes that are necessary to allow the double helix structure to unwind. Toxicities include myelosuppression, diarrhea, hypotension, and in the case of atoposide, can cause fever. Antibiotic drugs are those that cause cellular damage by a variety of mechanisms. Actinomycin binds to DNA and prevents RNA transcription. Toxicities include merosuppression, mucositis, and diarrhea. The anthracyclines, including donorubicin and doxorubicin, can cause significant cardiac toxicity that is related to cumulative anthracycline exposure. This can result in arrhythmias or significant cardiomyopathy. While not a drug, total body irradiation can be used in preparation for hematopoietic stem cell transplant. Radiation doses can be split into several smaller doses that are non-ablative, meaning that they can suppress bone marrow but not necessarily destroy it. While lungs and other thoracic organs are often partially shielded, radiation-induced lung injury and cardiac dysfunction can occur. Other acute toxicities include rash, mucositis, diarrhea, and edema. Next, we'll talk about drugs that are specifically designed to target and suppress immune cell function. Calcineurin inhibitors are typically used for post-transplant rejection or graft-versus-host disease prophylaxis. They may also have a role in treatment of selected refractory autoimmune disease. These drugs specifically target T-cells by blocking IL-2 production. IL-2 is necessary for lymphocyte survival as well as for T-cell activation and pro-inflammatory cytokine release. In addition, these drugs polarize T-helper cells away from an inflammatory Th1 phenotype and toward a Th2 phenotype, which is more anti-inflammatory. There are lots of toxicities, including, importantly, nephrotoxicity. And nephrotoxicity is notable, particularly because these drugs are often used for post-transplant rejection prophylaxis after kidney transplant. The mechanism of calcineurin-induced nephrotoxicity involves constriction of the glomerular afferent arteriole. Because of this, labs often look pre-renal, with a BON that is much higher than expected, even if the patient is actually total body fluid overloaded and not intravascularly dry. A potential antidote is actually aminophilin. Aminophilin works in this setting by dilating afferent arterioles via the adenosine receptor blockade. This effect can be achieved with lower doses than what might typically be used for asthma, for instance, though it's important to note that there may be drug-drug interactions between the aminophilin and the calcineurin inhibitors themselves. Another potential side effect of calcineurin inhibitors is posterior reversible encephalopathy syndrome. This can cause seizures, headache, altered mental status, and vision change, and characteristic images on MRI, as you see on the slide. These can be hypertension-related or a direct drug effect. Symptoms typically resolve with strict blood pressure control and or stopping the drug, although anti-epileptic drugs may be needed, at least in the short term. mTOR inhibitors, such as sirulimus or rapamycin, are similar to calcineurin inhibitors. These drugs inhibit T cell activation and clonal expansion by blocking IL-2 signaling through the mTOR protein. These include interstitial pneumonitis, hyperglycemia, thrombocytopenia, and hyperlipidemia. Antibody-based therapies are even more highly targeted toward specific immune cell subtypes. These include drugs such as OKT3, which block CD3 positive T cells. These include both CD4 helper T cells and CD8 cytotoxic T cells. Other antibody-based therapies exist that target the IL-2 receptor or that target CD20 found on B cells. Antibody-based therapies can also target cytokines themselves. An example of this is tocilizumab, which targets the cytokine IL-6 and has gained recent attention for its treatment of cytokine release syndrome, as well as other hyperinflammatory conditions. Other examples include infliximab, which targets TNF-alpha and is often used for rheumatologic or autoimmune diseases. Antithymocyte globulin is an example of a polyclonal therapy directed against T cells. ATG can be used for prevention of rejection, or graft-versus-host disease, in solid organ or occasionally bone marrow transplant. It's typically given very early in the pre-transplant period and can cause cytokine release syndrome, as well as anaphylaxis, and so close monitoring during infusion is important. As opposed to causing immune suppression, CAR T cell therapy employs a very different approach. This approach involves harvesting a patient's own T cells, genetically modifying them to attack target tumor cells, and then reinfusing them. A cytokine release syndrome that causes overwhelming inflammation and can lead to shock and organ dysfunction can be common. As we discussed on the previous slide, tocilizumab, or anti-L6, can be used as the therapy of choice in this setting, with methylprednisolone or other steroids as a second line really reserved for refractory cases. Cytokine release syndrome can be accompanied by neurotoxicity, characterized by altered mental status, seizures, and cerebral edema. And in this setting, treatment of choice involves tocilizumab plus dexamethasone, as well as anti-epileptic drugs. So we've come to the end of our discussion of drugs, and come back to our question from the beginning of the lecture. Now this, remember, was a 12-year-old boy who is being treated for severe rejection, status post-transplant, and has acute renal failure. The question was, which of his anti-rejection medications is most likely responsible for his acute renal failure? And if you selected tacrolimus, you are correct. Moving from drugs to bugs, in the next several slides, we'll discuss infections to which children with immune compromise are particularly susceptible. When we think of infection risk in individuals with immune deficiency or immune compromise, there are a few general rules of thumb. These are depicted here in the chart on the slide. For children with neutropenia, we tend to think of infection risk related to bacterial or fungal organisms. Children with lymphopenia are also at risk for fungal or bacterial infections, as well as viral infections, particularly for T cells. Children with T cell deficiencies are also at risk for atypical organisms and protozoa. Those with B cell deficiency, including asplenia, are particularly at risk for encapsulated organisms, as well as those patients with complement deficiency. Those encapsulated organisms, of course, being strep pneumo, haemophilus influenzae, and Neisseria meningitidis. While it can be helpful to think about these rules of thumb, it's also very important to understand that there's a tremendous amount of crosstalk among different arms of the immune system. And so it's likely that a patient with one immune deficiency may also have deficiencies in the other arms. An example of this is the fact that T cell repolarization can affect innate immune cells indirectly. Conversely, innate immune cells often do direct the activity of T cells. It's part of what they do. An example from the transplant setting are studies that have shown that tapering of calcineurin inhibitors, which again target lymphocytes, have been shown to improve monocyte and innate immune cell function. This improvement in monocyte function has been measured by monocyte HLA-DR expression, as well as cytokine production capacity. And so while you can think about these rules of thumb, you can also consider that any patient with any immune deficiency may be at risk for multiple types of infection. Moving on to specific infections. In terms of bacterial infections, patients with immune compromise are at risk for gram-positive infections, particularly those with an indwelling central venous catheter. Infections can be caused by Staph aureus, including MRSA, coagulase-negative staph, enterococcus, and of course pneumococcus as well. Common things still be in common, even in immune-compromised patients. Empiric therapy should include MRSA coverage, and depending on your local antibiogram, may also need to include VRE coverage as well. These patients are also at risk for gram-negative organisms, particularly in patients who have altered mucous membrane or gut barrier function. This can be important in the setting of severe mucositis or graft-versus-host disease, where you may have a higher propensity of translocation of intestinal bacteria into the bloodstream. These patients also have prolonged hospitalizations, frequent antibiotic exposure, and frequent contact with the healthcare system, and are at high risk for healthcare-associated organisms and multiple drug-resistant organisms. And so when considering empiric antibiotic therapy for these children, it's important to consider your local antibiogram, as well as the patient's personal history of growth of multiple drug-resistant gram-negative organisms. And don't forget about C. diff. Again, these patients are exposed to a lot of antibiotics and have immune compromise. They are at risk for C. diff. colitis, which needs to be considered when you have a potential abdominal source of infection. C. diff. in a healthy person can be very severe. It can be especially severe in someone with immune compromise and potentially life-threatening. Moving on to viruses, cytomegalovirus, or CMV, can be acquired congenitally, vertically, or throughout life. Drug-resistant recipients can acquire CMV through the organ or bone marrow transplant itself, or through transfusion of blood products. The highest risk is for individuals who are CMV-negative, who then acquire CMV de novo after the onset of immune suppression, as opposed to those individuals who have CMV reactivation. Now, in a healthy host, a new CMV infection might cause a mild monolike syndrome. But in an immune-compromised host, CMV can cause a significant pneumonia, retinitis, hepatitis, GI inflammation, meningencephalitis or myelitis, as well as myocarditis. Diagnosis of CMV infection tends to involve quantitative or semi-quantitative PCR. Strategies to prevent CMV involve donor screening, as well as use of leukocyte-reduced or CMV-negative blood products. Treatment involves ganciclovir, although there is some resistance to this medication. And foscarnit and sidofavir can be used for ganciclovir-resistant CMV, though these drugs are particularly nephrotoxic. There may be some role for IVIG or CMV-specific hyperimmune IVIG in terms of prophylaxis. A small infection can be primary or can be a secondary reactivation. Here too, a primary infection is much higher risk and can often be fatal in immune-compromised patients. These infections can be confined to the skin or can be disseminated. It's also been shown that the duration of fever and period of new lesion eruption is longer in immune-compromised patients compared to the immune-competent host. A primary infection can be associated with pneumonia that typically presents with a diffuse nodular pattern with perihylar infiltrates and can progress to ARDS, as well as hepatitis, DIC, encephalitis, ocular inflammation, and myocarditis. Diagnosis can be made by viral culture or direct fluorescent antibody detection in lesion fluid or by PCR. And of course, in the immune-compromised host, antibody titers really aren't helpful. Post-exposure prophylaxis can be considered using varicella zoster immune globulin. IV acyclovir is the treatment of choice for active disease in the immune-compromised host. In terms of prevention, in addition to post-exposure prophylaxis, vaccination can be considered as well as isolation, including airborne and contact precautions until skin lesions have crusted over or resolution of illness for any contacts of an immune-compromised patient. HSV can also be primary or secondary and can be confined to the skin or disseminated. Disseminated HSV can cause pneumonia, hepatitis, DIC, encephalitis, and or esophagitis or mucositis. This is typically PCR-based or sometimes by also direct fluorescent antibody biopsy or culture. Treatment includes typically acyclovir, although valciclovir is sometimes used, but with limited pediatric data. Adenovirus in the immune-compromised host can cause a severe pneumonia with ARDS as well as hepatitis, hemorrhagic cystitis, diarrhea, and meningoencephalitis. This can be due to reactivation of latent virus or to de novo infection, and typically kids are more susceptible to this particular viral infection compared to adults. Diagnosis these days is typically made by PCR. Treatment is a bit tricky because the drugs that we would use are particularly nephrotoxic. The first-line therapy typically is sidofavir with cytotoxic T lymphocytes as an emerging therapy for refractory cases. Brincidofavir is a drug that is currently in phase three clinical trials and may be available through compassionate use at selected centers that may have a more favorable side effect profile and some efficacy against adenovirus in immune compromised patients. Though, as I mentioned, those studies are still pending. JC virus causes progressive multifocal leukodystrophy. This can be a very severe, often fatal, demyelinating brain disease that's caused by virus reactivation. The diagnosis here basically is based on characteristic brain imaging and possibly PCR and biopsy. The treatment really is to reduce immune suppression if you can, as there is no specific antiviral therapy for JC virus. Each HV6 infection can result, again, from primary or secondary infection. It's commonly seen about two to three weeks after solid organ or stem cell transplant. This infection is characterized by fever, rash, pneumonia, marrow suppression, and encephalitis. Diagnosis is based on quantitative PCR and treatment can be considered with the antivirals listed there. BK virus can be an important organism to consider, particularly in those with renal injury. Up to 80% of the population is thought to have latent virus, and this virus can reactivate in the setting of immune suppression. Again, this virus causes renal injury, which can be particularly bad for patients who are recipients of a renal transplant. This virus can also cause hemorrhagic cystitis, particularly in stem cell transplant patients. Diagnosis is by the BKV blood test, as well as PCR. And the treatment really here also is to reduce immune suppression. There may be some efficacy for leflunomide, IVIG, or Sidofavir. Moving on from viruses to fungal infections, patients with immune compromise are particularly at risk for severe fungal infections. These infections can be caused by Candida species, which can cause either local or disseminated disease, including pneumonia or airway infection, renal disease, including abscesses, GI infection, liver or spleen abscesses, brain abscesses, or fungal sepsis. It's important to note that certain Candida species are normal colonizers of the upper airway. And so in an immunologically normal patient, one might consider an airway culture with Candida to be normal flora and not represent infection. However, in immune compromise patient, that same Candida really can, in fact, cause a severe pneumonia and needs to be considered as a potential causative organism for infection. Candida infections are diagnosed by culture or particular stains. And when a Candida infection is identified, particularly when it is disseminated, one needs to evaluate for abscesses with an ophthalmologic exam, as well as ultrasound or CT scan of the liver, spleen, and kidneys. Beta D glucan can also be used as a screening test for invasive fungal infection. Treatment involves source control, which can be very important in the setting of fungal infections, particularly central venous catheter associated infections caused by fungi. In the setting of Candida albicans, fluconazole can often be used, although there is some emerging resistance. In terms of others, resistance patterns are variable. So it's important to know your local antibiogram. Amphotericin B is often a good broad-spectrum empiric therapy, although does have some associated renal toxicity. Other choices include caspifungin, mycofungin, and boriconazole. Flucidazine may be added for persistent disease, although need to watch out for hepatic and bone marrow toxicity. Aspergillus infections can be local or disseminated. The most common infection caused by aspergillus is pneumonia, which can be a necrotizing pneumonia with abscesses and fistulae that can erode into blood vessels and cause a significant pulmonary hemorrhage. Aspergillus can also cause sinusitis, eye involvement, brain abscesses, osteomyelitis, endocarditis or pericarditis, pyelonephritis, or solid organ abscesses. Diagnosis can be made by tissue culture or stain or by aspergillus-specific IgE serology. It's important to note that galactomannan assays may be less helpful in kids because of a high false positive rate. First-line treatment involves boriconazole or isovoconazole, though pediatric dosing data are a bit unclear. And so therapeutic drug monitoring is recommended if it's available. There also is some emerging azole resistance. And so again, need to consider your local antibiogram and be aware of this resistance pattern. Infotericin B can alternatively be used, although fluconazole typically does not have great coverage against aspergillus. Itraconazole may also be effective, but again, need to wait for sensitivities. It's not a really great first-line or empiric therapy for aspergillus. Mucor mycosis causes a highly invasive, often fatal infection that can affect the lungs, sinuses, brain, kidneys, or skin. Diagnosis is based on culture, stain, and typical imaging appearance. Treatment involves amfotericin B, reducing immune suppression as much as you can, and often aggressive surgical debridement. Cryptococcus typically involves an inhalational route of infection that can disseminate and cause CNS disease. Diagnosis of lung disease typically is by antigen test of a sputum or BAL specimen. The India Inc. stain in the CSF is a prototypical stain for cryptococcus identification for CNS infections. The treatment of cryptococcal infections include amfotericin B and flucidazine. And lastly, histoplasmosis, which is a fungal infection that is endemic in the Midwestern US. In healthy individuals can be asymptomatic, but in immune-compromised individuals can cause an acute progressive disease with fever, pneumonia, adenopathy, and hepatosplenomegaly. Diagnosis is based on culture and stain, as well as antigen tests and potentially serologies. And treatment includes amfotericin B and intracortisol. Immune-compromised patients are also at risk for tuberculosis. And so it's important to understand the travel and exposure history for your patients. It's also important to understand that a PPD may or may not be positive, even in the setting of infection. These infections can be pulmonary and or extra pulmonary involving the liver and CNS. Diagnosis is by a characteristic findings on chest X-ray or CT, sputum or gastric aspirates for AFB culture and or PCR. The quantiferum gold test really isn't recommended for diagnosis in kids. Treatment of latent TB typically involves single drug therapy, while combination therapy is used for active disease. Mycobacterium avium complex can cause an isolated lymphadenitis or disseminated infection characterized by fever, lymphadenopathy, hepatosplenomegaly, diarrhea, and cytopenias. Diagnosis again is by AFB culture or PCR. And treatment can involve excision and or macrolide ethambutol and rifampin therapy. And finally, patients with immune compromise are also at risk for certain protozoal infections, including toxoplasmosis, which tends to be thought of as transmitted by cats as primary hosts, although it's estimated that up to 30 to 50% of humans may also be carriers. Toxoplasmosis in immune compromised hosts can cause encephalitis, retinitis, myocarditis, and hepatitis. Diagnosis typically involves PCR or biopsy, as serologies may not be helpful in this setting. Treatment includes sulfadiazine, pyrimethamine, and luguborin. And if there's a mass lesion, sometimes steroids are considered. Cryptosporidium is a parasite that's transmitted by the fecal-oral route that primarily causes a diarrheal illness that can be severe in immune compromised host. The treatment is with nidazoxazide as well as supportive care. As we conclude our discussion of specific infections, let's consider another question. The case here is a six-year-old girl who develops fever after a stem cell transplant for refractory leukemia. She is neutropenic, she's being maintained on methylprednisolone and tacrolimus, and she is exhibiting a rising creatinine and fluid overload. Of the viruses listed, which is most likely to be the cause of the patient's renal failure? If you chose BK virus, you are correct. We're going to spend the last few slides talking about specific transplant populations. When we consider infection risk status post-hematopoietic stem cell transplant, we tend to think of three different phases. The first is the pre-engraftment phase, the second is the early post-engraftment phase, and the third is the late post-engraftment phase. The early pre-engraftment phase occurs between conditioning and about two to four weeks status post-transplant. The primary immune deficiency in this time period is neutropenia, with often a severe mucositis that can lead to loss of barrier function. And for this reason, bacterial organisms predominate as causes of infection, though you can also see viral infections, particularly with HSB in the setting of mucositis, as well as certain fungal infections, including candida and aspergillus. The second phase is the early post-hematopoietic phase, certain fungal infections, including candida and aspergillus. The early post-engraftment phase tends to be between about one and three months post-transplant. Here you have more cellular and humoral immune suppression because lymphocyte recovery lags behind neutrophil recovery post-transplant. You can also see early graft-versus-host disease and its associated treatment that further suppresses immune function. In this phase, patients are susceptible to a variety of viral infections, as well as fungal infections. Bacterial infections still do need to be considered as well, particularly in the setting of central venous catheters and intestinal translocation in the setting of GVHD. The late post-engraftment phase tends to be after three months post-transplant. Again, here cellular and humoral immune suppression is still occurring, as it may take up to a full year post-transplant for lymphocytes to fully recover. You can also have chronic GVHD and its associated treatment that can further suppress immune function. Patients in the late post-engraftment phase are particularly susceptible to encapsulated bacteria, as well as certain viruses, atypical organisms, including pneumocystis, and fungal infections, including aspergillus. And so to recap, the timeline for a typical hematopoietic stem cell transplant patient involves first intensive chemotherapy and or radiation therapy, followed by the transplant itself, followed by engraftment or return of marrow function that tends to occur about two to four weeks after transplant. Engraftment is defined by an ANC greater than 500 plus platelet count greater than 20,000 for three days in a row without need for transfusion. Again, notably lymphocyte numbers and antibody levels will remain low for several months post-transplant. It's also important to note that reconstitution of immune function following stem cell transplant does depend on several patient-related factors, and so it's not the same across all stem cell transplant patients. One of those factors is the type of transplant itself in terms of the source of the stem cells. Another important consideration is the conditioning regimen itself, which is often going to be influenced by the underlying disease for which the patient is being transplanted. These conditioning regimens can affect the immune recovery, can also affect end organ function so that if an infection occurs, there can be variable susceptibility to developing multiple organ dysfunction. GCSF or GMCSF is often used to promote marrow recovery. And of course, the presence of infection itself in the pre-engraftment period can delay engraftment. Other complications post-hematopoietic stem cell transplant include sinusoidal obstruction syndrome, formerly known as veno-occlusive disease. SOS is thought to be due to certain pre-transplant conditioning regimens that can damage the immune system that can damage hepatic sinusoidal endothelial cells and lead to obstruction of hepatic venous sinusoids. The clinical triad is hepatomegaly, jaundice, and weight gain due to edema and or ascites. On imaging, you tend to see reversal of flow in the portal vein on ultrasound. Treatment involves diuresis, management of intra-abdominal hypertension, and defibrotide. Consensus-based recommendations for supportive care and treatment for children and adolescents with veno-occlusive disease or sinusoidal obstruction syndrome were recently published in a three-part series and can be a helpful resource. An additional complication, of course, is graft-versus-host disease. Graft-versus-host disease occurs when the new immune system attacks the host. Now, sometimes you can get a graft-versus-tumor effect here with the new immune system attacking the residual cancer. And so some of that may actually be helpful. In terms of preventing or modulating graft-versus-host disease, therapies tend to be targeted toward T-cells since those are the causative immune cells of GVHD. And so T-cell depletion or calcineurin inhibitors are often used. Acute GVHD can involve rash, hyperbiliruminemia, diarrhea, and because diarrhea can also be caused by lots of different things in the setting of bone marrow transplant, biopsy can often be needed to diagnose. GVHD is graded with the higher grades, often requiring ICU management. And treatment of acute graft-versus-host disease tends to involve high-dose corticosteroids. Idiopathic pneumonia syndrome can also happen after hematopoietic stem cell transplant. IPS is characterized by widespread alveolar injury without evidence of infection and can occur in up to 5% to 15% of allogenetic stem cell transplant. Timing tends to be around three weeks around the time of engraftment. And unfortunately, this syndrome can be fatal and there really is no good therapy. Bronchiolitis obliterans is a complication of chronic GVHD that results in a non-reversible obstructive lung disease that's characterized by hyperinflation on chest X-ray and a biopsy if it's done would show obstructed small airways. Treatment is to increase immune suppression if able, though here also bronchiolitis obliterans has a fairly poor prognosis. And lastly, moving on to solid organ transplantation. Infection risk in the setting of solid organ transplant is related to the degree of immune suppression, which is related to the organs that were transplanted. With lung and bowel transplantation, typically requiring more immune suppression. Many of the immune suppressants that are used are similar and are those drugs that we previously discussed, though end organ function is often different. And so lab work, imaging and therapeutic drug monitoring parameters may be different based on the type of transplant. Careful attention should be paid to drug-drug interactions and clearance of drugs as end organ function changes over time. An important goal of therapy is to prevent graft rejection. When we think about organ rejection, we consider hyperacute rejection, acute rejection and chronic rejection. Hyperacute rejection tends to be due to preexisting antibodies and can occur within minutes of transplantation. Strategies to mitigate hyperacute rejection include careful tissue typing and sometimes pre-transplant phoresis and or rituximab in order to decrease antibody load. Acute rejection is driven by cellular immunity and tends to occur over weeks to months. Monitoring for acute rejection tends to be by monitoring organ function with biopsies as necessary. Acute rejection is treated with pulse corticosteroids, increased doses of calcineurin inhibitors and or antibody-based therapy to target T-cells. Chronic rejection is often related to recurrent rejection episodes and can lead to fibrosis of the organ. Post-transplant lymphoproliferative disorder can occur in the setting of immune suppression related reactivation of EBV. This leads to polyclonal polymorphic B-cell hyperplasia that can progress to a high-grade lymphoma. Patients present with lymphadenopathy, mass lesions in the brain or intestines and potentially infiltrative disease in the liver. Risk factors include young age, an EBV seronegative recipient, a high immune suppression load, and this tends to occur in the first year post-transplant. Diagnosis is by a quantitative EBV PCR and by biopsy. Treatment is to reduce immune suppression, Rituximab, which targets B-cells may also be used. In terms of preemptive therapy, one may potentially use EBV load to titrate your immune suppression and or consider prophylactic encyclopedia. One of the key challenges of post-transplant care is that many of the signs and symptoms of severe infection overlap with the signs and symptoms of rejection, including fever, inflammation, and organ dysfunction. Now this sets up a therapeutic dilemma because if you have rejection, you want to increase your immune suppression. If you have severe infection, failure to wean immune suppression is associated with adverse outcomes. And so it's vitally important to have a multidisciplinary approach here with input from infectious disease colleagues, pathology, transplant specialists, pharmacology, and your clinical laboratory. In summary, immune-compromised children encompass a broad range of patients. A broad array of immune-suppressive medications exist, some with specific targets, all with significant side effects. The immune-compromised patient requires special consideration for prophylaxis or treatment for a wide variety of opportunistic infections. It's important for the intensivist to recognize certain conditions that are unique to the immune-compromised patient population. And certainly a multidisciplinary approach is essential for optimum care of these patients.

immune suppressive drugs

oncology

transplant patients

mechanisms of action

side effects

common pathogens

infections

complications