1121CHAPTER 93 Critical Illness in Children Undergoing Hematopoietic Progenitor Cell Transplantation in the general population Therefore, this may be an appropriate option in select patients Conclusio[.]
CHAPTER 93 Critical Illness in Children Undergoing Hematopoietic Progenitor Cell Transplantation in the general population Therefore, this may be an appropriate option in select patients Conclusion The literature continues to be confusing regarding the nomenclature of these noninfectious pulmonary complications of transplantation It is important for the critical care physician at the bedside to treat the patient appropriately without becoming anxious over the particular name of the disease Although corticosteroids and etanercept, a TNF-a receptor antagonist, may prove to be beneficial in some cases (i.e., IPS), at the present time, there is no definitive treatment for critically ill children with any of the noninfectious pulmonary complications The NIH recently hosted a workshop to identify knowledge gaps and research priorities in the understanding of pulmonary complications of pediatric HCT The executive summary identified three main priorities: (1) build, characterize, and study prospective observational cohorts; (2) improve mechanistic understanding of pulmonary disease in HCT recipients and translate it to potential therapies; and (3) improve clinical outcomes It is hoped that this workshop will encourage investigators to continue the work needed to improve outcomes in this fragile population With our current understanding, the best care we can offer is excellent supportive care, paying close attention to fluid balance, preventing hospital-acquired infections, and using lung-protective strategies during mechanical ventilation Dilemmas in the Diagnosis of Pulmonary Complications As HCT patients with pulmonary complications are frequently tenuous, placing these patients at risk for complications from diagnostic procedures is a difficult decision Although it is difficult to treat these critically ill patients without a firm diagnosis, it is also disconcerting to expose these patients to an invasive diagnostic procedure that may worsen their condition and still not result in a diagnosis Therefore, the debate continues in the literature and at the bedside regarding the risk/benefit ratio of invasive diagnostic procedures such as BAL and lung biopsy St Jude Children’s Hospital published data regarding the diagnostic yield of BAL at their institution.137 BAL identified the cause of respiratory symptoms in 53 (67.9%) of 78 of their allogeneic HCT recipients and (63%) of 11 autologous transplant patients The most common finding diagnosed on BAL was bacterial infection (52%) The patients tolerated the procedure well, with complications noted in less than 20% In their series, transbronchial biopsy contributed additional information, which might have changed management, in only of patients They also noted that 14 of 16 patients who underwent open-lung biopsy already had a positive BAL The authors concluded that BAL had a beneficial risk/benefit profile and was useful in identifying patients who had an infectious etiology to their lung injury However, biopsy did not add significantly more information and carried an unacceptable morbidity rate of 47% A meta-analysis including 72 BAL studies and 31 studies of lung biopsy in both pediatric and adult patients found that BAL was superior to lung biopsy for diagnosing an infectious etiology of lung injury while lung biopsy was superior for diagnosing noninfectious lung injury.138 Either technique lead to a diagnosis in over 50% of the procedures Complications were reported in 8% of BAL procedures and 15% of the biopsies Complications of lung biopsy were higher in children than adults (P 003) It was 1121 also noted that the addition of BAL galactomannan testing significantly improved the ability to detect invasive fungal infections The authors concluded that a reasonable approach was to begin the diagnostic workup with BAL, particularly if infection was suspected, and proceed to biopsy if a noninfectious etiology became more suspect Hepatic Complications Hepatic complications of HCT have been a common cause of morbidity and mortality since the inception of the procedure.139–143 The complications include hepatic infections (viral, fungal, and bacterial); cholestasis; drug toxicity; sinusoidal obstruction syndrome (SOS), which is more commonly known as venoocclusive disease (VOD); and GVHD HCT patients may also have an underlying liver disease going into HCT such as, but not limited to, tumor infiltration, chronic hepatitis, iron overload, or extramedullary hematopoiesis.139,143–145 Viral hepatitis can be caused by any viral pathogen, including hepatitis B, hepatitis C, cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, herpes simplex virus (HSV), and varicella zoster virus (VZV) The diagnosis of these pathogens is based on clinical manifestations, with identification of the virus determined (1) histologically, (2) by culture of blood or tissue, or (3) by the presence of viral antigen or nucleic acid within serum or liver tissue Treatment is dependent on the identification of the viral pathogen HSV and VZV are treated with acyclovir, whereas CMV is treated with ganciclovir or foscarnet Unirradiated leukocytes from the marrow donor have been used to treat EBV-associated lymphoproliferative disorders after allogeneic bone marrow transplantation.146 Fungal involvement of the liver is often seen in conjunction with widespread dissemination There may be granulomas, abscesses, cysts, fungus in biliary ducts, or infarcts from vascular occlusion Typically, Candida species are noted; however, any fungal pathogen can be involved Fungal infection often presents with right upper quadrant abdominal pain The diagnostic workup discovers positive serum tests for fungal antigens or DNA, radiologic findings of fungal infection and, if necessary, histologic evidence (including special stains).144,147 If there is a suspicion of active infection in the liver, liposomal amphotericin, voriconazole, or caspofungin should be given until engraftment is established.144,148 Bacterial infections of the liver occur less commonly but present similarly Gallbladder stones from poor oral intake, cytoreductive therapy causing exfoliation of gallbladder mucus-containing cells, and increased biliary excretion of precipitable material (cyclosporine A [CSA], antibiotics) all contribute to a 70% incidence of gallbladder sludge in this patient population.149,150 Sepsis can also lead to cholestasis and hyperbilirubinemia This is mediated by endotoxins, interleukin-6 (IL-6), and TNF-a.144,151 Rarely, persistent biliary obstruction can be caused by lymphoproliferation from EBV- or CMV-related biliary disease, duodenal hematoma as a complication of endoscopy, inspissated biliary sludge, or leukemic relapse in the head of the pancreas.144,152 Numerous medications required for HCT can have direct toxicity on the liver, including antibiotics, fluconazole, and CSA Histologically, drug effect should be suspected when there is significant hepatocellular necrosis and minimal inflammation VOD after allogeneic HCT was first reported in 1979 and now is recognized as a major cause of morbidity and mortality in the first 100 days of transplant.153 The disease process begins in 1122 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology the sinusoids due to endothelial injury and affects venules only late in the course of the disease.144 The pathogenesis is believed to result from hepatic venule and sinusoidal endothelial injury.154 Histologically, subendothelial edema, endothelial cell damage with microthrombosis, fibrin deposition, and expression of factor VIII and von Willebrand factor within venular walls is observed.155 Hepatic necrosis occurs, and collagen deposition in the sinusoids, venular wall sclerosis, and collagen deposition in the venular lumen is seen as the disease progresses.156 Risk factors may include elevated transaminases before the conditioning regimen,144–146,157–159 age younger than to years,160 use of methotrexate for GVHD prophylaxis,161 presence of oral mucositis,162 interstitial pneumonitis,163 and/or RBC transfusion iron overload.164 Certain preparative regimens have also been found to have a higher incidence of VOD, including those with high doses of total body irradiation, cyclophosphamide, or the combination of busulfan and cyclophosphamide, or etoposide and carboplatin.158,159,165,166 A trial of adults undergoing HCT using everolimus and sirolimus for GVHD prophylaxis was terminated prematurely because of an unacceptably high rate of severe VOD and thrombotic microangiopathy.167 The authors believed that busulfan use in conditioning may have been a contributing factor Clinically, VOD presents with hyperbilirubinemia, painful hepatomegaly, and fluid retention The incidence varies based on risk factors and the criteria used but reportedly are as high as 55%,157 with mortality rates ranging from 3% to 67%.168 Significant variability in mortality results from differing conditioning regimens and definitions of VOD Two sets of criteria have been used for VOD Jones et al.158 first described VOD and modified this criterion as hyperbilirubinemia greater than mg/dL within 21 days of transplantation with at least two of three other findings: hepatomegaly, ascites, or 5% or greater weight gain McDonald et al.157 in Seattle defined VOD in their series as two of the following criteria occurring within 20 days of transplantation: hyperbilirubinemia greater than mg/dL, hepatomegaly or right upper quadrant pain, or sudden weight gain of more than 2% body weight Clinically, most patients with VOD develop symptoms between days and after transplantation, peaking around 10 days after onset, and returning to baseline 10 days later if they are going to recover.158 Multiorgan failure is seen frequently in patients with VOD.157,159 Severe VOD (S-VOD) is associated with the development of multiorgan failure, including renal failure, pulmonary insufficiency, cardiac failure, and changes in mental status.169 Liver ultrasound with Doppler study demonstrating reversal of portal flow is a late finding in VOD160 but is not part of the diagnostic criteria Liver biopsy can be performed to diagnose VOD, but it is recommended that it be reserved for patients in whom the diagnosis is uncertain and other diagnoses must be excluded, such as hepatic GVHD.170 Transvenous liver biopsy and hepatic venous pressure gradient measurements can be performed safely171 and have been found, in a limited study, to have predictive value, with hepatic venous pressure gradient greater than 30 mm Hg associated with poor outcome.172 Hepatic venous pressure gradient levels greater than 10 mm Hg have been found to be highly specific for diagnosis of VOD.173,174 Given that the pathogenesis of VOD is thought to involve endothelial injury and coagulation factor deposition, attempts have been made to reduce the hypercoagulable state with several agents, including heparin, prostaglandin, and bile salts The Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) and Pediatric Blood and Marrow Transplantation Consortium Joint Working Committees used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria to develop consensus guidelines for the management of patients with VOD.169,175,176 Ursodeoxycholic acid is recommended for prophylaxis in patients at risk for VOD.169,177–179 Defibrotide is not approved for prophylaxis for VOD.169 Due to the lack of evidence, the use of heparin, fresh frozen plasma, antithrombin III, glutamine, and prostaglandin E1 are also not recommended for prophylaxis.169 Early treatment with defibrotide is indicated for patients with S-VOD for 21 days or until resolution of multiorgan failure and/or signs of VOD, whichever comes later.169,180–187 Supportive treatment for fluid retention and multiorgan failure is an important part of management of these patients It is recommended to avoid acute fluid overload and restrict fluid in patients exhibiting evidence of fluid overload.175 Continuous renal replacement therapy is recommended if there is progressive fluid overload despite fluid restriction and diuresis and electrolyte disturbances that are refractory to medical management.175 Paracentesis (in the setting of intraabdominal hypertension/abdominal compartment syndrome or pulmonary dysfunction due to tense ascites) and/or thoracentesis (in the setting of pulmonary dysfunction) should be considered.175 Screening and empiric management for fevers or clinical instability should follow the standard of care HCT guidelines.176 Colitis and Other Gastrointestinal Complications Gastrointestinal (GI) complications that arise after transplantation often result from mucosal damage secondary to radiotherapy and chemotherapy regimens, together with immunosuppression following transplantation.188 Upper GI complications include diffuse mucositis, nausea, vomiting, and nonspecific abdominal pain Barker et al reported a 90.1% incidence of mucositis and 85.2% incidence of posttransplant vomiting in a retrospective study of 142 patients who underwent HCT.189 Lower GI/intestinal acute complications include C difficile colitis, viral and other gastroenteritis, typhlitis, intestinal GVHD, and intestinal thrombotic microangiopathy.189 In one case series, C difficile colitis was reported in 8.5% of patients, viral enteritis in 7.0%, typhlitis in 3.5%, and intestinal GVHD in 27.4%.189 The incidence of typhlitis in this series was much lower than the 32% incidence previously reported in the literature for AML patients.190 Viruses such as CMV, adenoviruses, and rotaviruses can cause diarrhea in the immediate posttransplant period Imaging findings include nonspecific bowel wall thickening, ascites, and adjacent inflammatory changes, especially in the ileocecal region.188 Neutropenic enterocolitis or typhlitis is a necrotizing inflammation of the colon in an immunocompromised patient There is a predilection for the cecum, thought to be due to the marked distensibility of the cecum, along with lower vascularity The clinical manifestations are a triad of abdominal pain/tenderness, fever, and neutropenia.188 The incidence of typhlitis can vary depending on the aggressiveness of chemotherapy and prophylactic antibiotics used.191 The typical time frame to be diagnosed with typhlitis after HCT appears to be 15.5 days.191 Plain radiographs or ultrasounds of the abdomen appear to be good initial imaging modalities CT scan can be used if the diagnosis is questionable with initial imaging Plain radiographs of the abdomen will likely demonstrate dilation of small-bowel loops with a paucity of gas in the right side of the abdomen In advanced cases with perforation, free intraabdominal air may be detected Ultrasound of the abdomen will likely reveal asymmetric, echogenic wall thickening of the cecum and terminal ileum CT will CHAPTER 93 Critical Illness in Children Undergoing Hematopoietic Progenitor Cell Transplantation demonstrate luminal narrowing and stranding in the pericecal fat.188 Management includes bowel rest, antibiotic coverage to include Gram-negative organisms, G-CSF to treat neutropenia, and optimal parenteral nutrition Antifungal therapy should be considered if there is no clinical improvement on initiation of antibiotics Persistent GI bleeding despite resolution of neutropenia and coagulopathy, evidence of perforation with peritonitis, and uncontrolled sepsis are potential surgical indications.190 Pneumatosis intestinalis can be noted in typhlitis, in which case it implies imminent bowel perforation.188 Corticosteroid therapy appears to be a significant risk factor for pneumatosis intestinalis, inducing atrophy of the Peyer patches in the intestine with resultant mucosal defects and dissection of intraluminal air into the submucosal or subserosal regions If detected in an asymptomatic patient, it will most often be resolved with conservative management.180,188,192 Intestinal acute GVHD usually develops after to weeks and can be accompanied by skin and hepatic GVHD Chronic GVHD occurs several months after transplantation.193,194 Symptoms include secretory diarrhea, fever, nausea, vomiting, abdominal pain, and intestinal hemorrhage.195 In addition to nonspecific findings, CT imaging may reveal bowel wall enhancement correlating with mucosal destruction and replacement with granulation tissue.188 Thrombotic microangiopathy (TMA) of the intestines can occur after HCT and is caused by intimal injury to the microvasculature followed by formation of microthrombi The injury is presumed to be due to chemotherapy, total body irradiation, or the pretransplant conditioning regimen as well as the use of drugs known to be associated with TMA, such as tacrolimus and cyclosporine A This is a rare complication but can mimic GVHD by presenting with fever and refractory diarrhea Laboratory findings include elevated lactic acid dehydrogenase (LDH) and fragmented erythrocytes on a peripheral blood smear The treatment is challenging and often requires removal of the possible offending immunosuppressant medication Jodele et al reported that early identification of TMA using a revised criterion and complementblocking therapy such as eculizumab may improve outcomes.196 Pancreatitis may also occur in HCT patients Barker et al reported a 4.9% incidence of pancreatitis that was not associated with any specific induction chemotherapy regimen.189 Werlin et al also reported a similar 3.5% incidence of pancreatitis and recommended testing for pancreatitis prior to attributing GI symptoms to mucositis.197 Myelosuppression and Hematologic Complications Myelosuppression and Immune Dysregulation Stem cell transplant conditioning results in an extended period of neutropenia, anemia, and thrombocytopenia Neutrophil engraftment is defined as an absolute neutrophil count (ANC) of 0.5 103/mL on consecutive days following the postconditioning nadir Neutrophil engraftment typically occurs to weeks following stem cell infusion The duration of time from stem cell infusion to engraftment depends on numerous transplant-related factors.198 When peripheral blood progenitor cells are used, engraftment typically occurs to days sooner than when bone marrow is used as the stem cell source.199 Engraftment occurs slower when umbilical cord blood is used compared with PBSCs and bone marrow.200 Granulocyte-stimulating factors are commonly used following autologous HCT and umbilical cord blood transplant 1123 to reduce the time to neutrophil engraftment.201 Platelet engraftment generally occurs to weeks following neutrophil engraftment but can take weeks to months A platelet count less than 100,000 on day 100 following transplantation is associated with poor outcome.201 Neutrophil engraftment does not signify the reconstitution of a fully functional immune system It is crucial to remember that engrafted post-HCT patients remain significantly immunocompromised and are at risk for life-threatening opportunistic infections The restoration of normal immune function can take as long as year in patients without significant post-HCT complications and longer in patients with chronic GVHD.202 Typically, natural killer cell recovery takes approximately month, and T-lymphocyte recovery takes to 12 months.203 Restoration of normal B-cell function takes approximately to months in the absence of GVHD.204 Infectious Complications Patients undergoing HCT have increased susceptibility to infection because of a combination of (1) neutropenia, (2) breakdown of physical barriers (mucositis, indwelling venous catheters, skin lesions), and (3) defects in cellular and humoral immunity as a result of the conditioning regimen and immunosuppressive therapy given The susceptibility to any particular organism varies according to the stem cell source (e.g., umbilical cord blood recipients are at increased risk for viral infection) and over the course of the transplant period During the first to weeks of the posttransplant period, while the patient is neutropenic, bacterial infections account for approximately 90% of the infections Enteric gram-negative bacilli (e.g., Escherichia coli, Klebsiella, Enterobacter, and Pseudomonas aeruginosa) can cause rapid hemodynamic instability The gram-positive infections (Staphylococcus and Streptococcus) are frequent causes of infections when central venous catheters are present Therefore, empiric antibiotic coverage for fevers during this time must be broad spectrum and provide adequate coverage for these organisms.205–207 Fungal infections are increasing in frequency with better treatment and prophylaxis of bacterial and viral infections, particularly after allogeneic transplantation Fungal pathogens in HCT patients include the yeasts (e.g., Candida spp and Cryptococcus neoformans), molds (e.g., Aspergillus, Fusarium, and Mucormycosis), and dimorphic fungi (e.g., Coccidioides, Histoplasma, and Blastomyces) Of these, Candida and Aspergillus are the most common Candida spp colonize the gastrointestinal tract in more than half of healthy people,208 but they become opportunistic infections in HCT patients Candidal infections can occur as superficial mucosal infections (e.g., thrush) or deeply invasive processes (hepatosplenic candidiasis) Esophageal candidiasis is associated with dysphagia and retrosternal pain This may be difficult to distinguish from chemotherapy or radiation-induced mucositis or herpetic mucositis Endoscopy may be necessary to diagnose and appropriately treat Candidemia may present with fever and systemic symptoms and is frequently not associated with tissue involvement Because many HCT patients receive fluconazole prophylaxis, candidemia should be treated with amphotericin B Traditionally, patients with documented candidemia or persistent/recurrent fevers underwent evaluation for multiorgan involvement, including CT or magnetic resonance imaging (MRI) of the brain, chest, and abdomen, and an ophthalmologic examination However, given that more attention is being focused on the radiation risk of CT for 1124 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology the development of future cancers and the improvement in antifungal prophylaxis, the use of abdominal and pelvic CT scans as screening tools (not in cases of documented fungemia) for invasive fungal disease is now being questioned A recent quality improvement project from St Jude Children’s Research Hospital found a very low yield of abdominal CT in detecting undiagnosed fungal infections in patients with prolonged fever and neutropenia.209 The authors recommend that routine abdominal CT as a screening tool for invasive fungal disease no longer be performed Instead, they recommend ultrasound or limited MRI in patients with clinical suspicion for invasive fungal disease in the abdomen Aspergillus spores are routinely inhaled; in immunocompromised or HCT patients, they can cause invasive infections Neutropenia and GVHD with immunosuppressive treatment are risk factors for these infections Outbreaks of aspergillus can occur in areas of construction or with contaminated ventilation Invasive aspergillosis occurs most commonly in the lungs, with fever, cough, dyspnea, and, ultimately, hemoptysis as the disease progresses The characteristic radiographic appearance is a cavitary lesion, but nodular infiltrates and bronchopneumonia are also reported.210 BAL should be performed initially However, up to 50% of patients have a negative BAL Open-lung biopsy should be considered if suspicion remains after a negative BAL.211 CMV is one of the most problematic viral infections for HCT patients CMV may emerge in the allogeneic patient between to months posttransplantation if either the patient or donor was CMV positive before transplant CMV lies dormant after the initial clinical infection However, in immunosuppressed patients, this virus can reactivate and result in interstitial pneumonitis, enteritis, encephalitis, retinitis, or bone marrow suppression CMV infection is defined as the identification of CMV from any site or the seroconversion to CMV positivity on polymerase chain reaction (PCR) or antigenemia testing CMV disease is defined as the clinical manifestations seen in the presence of CMV infection The use of CMV-negative blood products and leukofiltration of blood products along with routine screening during the first 100 days posttransplant with PCR or antigen testing has helped reduce the risk of CMV infections in patients undergoing transplant Monitoring of CMV with antigenemia and/or PCR testing is the standard of care for 100 days posttransplant and allows for preemptive therapy if results of these tests become positive (even before the onset of clinically apparent disease) Ganciclovir, valganciclovir, or foscarnet treatment is then given for to 14 days followed by prophylaxis and/or screening through 100 days posttransplantation.212 Interstitial pneumonitis from CMV presents with hypoxia and fever and an interstitial pattern on chest radiograph Untreated, there is an 80% mortality rate.213 Ganciclovir and intravenous (IV) immunoglobin is the recommended treatment for CMV interstitial pneumonitis.214 For patients resistant to ganciclovir or with unacceptable medication toxicity, foscarnet may be used.215,216 Ganciclovir can cause neutropenia, and administration of growth factor (e.g., G-CSF, granulocyte macrophage– CSF) should be considered if the ANC falls below 1000/mL If the ANC falls below 500/mL, holding the drug should be considered In addition, renal adjustment may be necessary as both ganciclovir and foscarnet can be nephrotoxic CMV prophylaxis with ganciclovir is prohibited by its marrow-suppressive effects CMV enteropathy presents with dysphagia, abdominal pain, nausea, vomiting, diarrhea, and/or gastrointestinal bleeding These symptoms can be seen with GVHD as well; endoscopy should be performed to aid in the diagnosis Treatment is similar to that of CMV pneumonia EBV, human herpesvirus 6, HSV, adenovirus, VZV, human metapneumovirus, and BK virus infections are all common posttransplantation that cause a range of clinic findings, including hemorrhagic cystitis, colitis, retinitis, encephalitis, and pneumonitis The diagnostic and treatment options for each of these viruses and clinical presentations is beyond the scope of this chapter The reader is referred to multiple published reviews of this topic.217–221 Recent study has focused on the role of adoptive transfer of virus-specific T cells from seropositive donors Translational and clinical research has focused on the role of this immunotherapeutic approach to the treatment of CMV, EBV, and adenovirus Broad application of this biotechnology is evolving.222–224 Graft Failure Graft failure is an uncommon, potentially lethal complication of HCT Primary graft failure is defined as failure of the stem cell graft to recover hematopoietic function by day 30, although some patients successfully engraft later than day 30 Secondary graft failure is the loss of the donor stem cell graft after initial engraftment The risk of graft failure is increased with HLA disparity between donor and host, when reduced intensity conditioning regimens are used, with the use of umbilical cord blood stem cells, and when transplant is performed for a nonmalignant hematologic condition.225 It is rare in HLA-matched sibling donor transplants Graft failure is treated with the infusion of hematopoietic cells either alone or in combination with growth factors, chemotherapy, or immunosuppression.226,227 Graft failure is an emergency, as the risk of death increases with the duration of neutropenia and because there are few effective therapies Hematologic Complications HCT recipients commonly require blood product transfusions during the acute transplant phase due to conditioning-associated myeloablation and potentially increased consumption of platelets and RBCs For most patients, the need for blood product transfusions declines rapidly following engraftment and hospital discharge However, patients may require transfusion support for months after transplant All blood products should be gammairradiated to rid the product of competent donor T cells that can cause transfusion associated-GVHD.228 Additionally, blood products must be CMV negative to prevent transmission of the virus to nonimmune patients This can be achieved by using blood from CMV-seronegative donors or with leukofiltration.229 Donors and recipients who are HLA matched are not necessarily ABO matched ABO matching is not required for successful transplant and is a secondary consideration when choosing a donor However, ABO mismatching puts the recipient at risk for immune-mediated hemolytic anemia The risk for, and severity of, potential hemolytic anemia depends on the degree of compatibility and is divided into four groups: (1) ABO matched; (2) minor ABO mismatch, in which there is potential for hemolysis of the recipient RBCs by donor isoagglutinins (e.g., donor blood type O1 and recipient A1); (3) major ABO mismatch, in which case the recipient isoagglutinins are directed against donor RBCs after engraftment (e.g., donor blood type A1 and recipient O1); and (4) bidirectional mismatch, which combines minor and major ABO mismatch (e.g., donor blood type A1 and recipient blood type B1).230 When there is a major or bidirectional mismatch, the stem cell product must be RBC depleted or the patient must CHAPTER 93 Critical Illness in Children Undergoing Hematopoietic Progenitor Cell Transplantation have the offending isoagglutinins removed by pheresis prior to infusion to prevent a hemolytic reaction Minor incompatibility, in which the recipient’s RBCs are incompatible with components of the donor’s plasma, puts the recipient at risk for an immunemediated transfusion reaction Plasma depletion of the product prior to infusion reduces the risk Even when plasma depletion is used, mild hemolysis can exist for weeks to months due to antibody production from the newly produced B lymphocytes against residual recipient RBCs There are many described late hemolytic complications of transplant, most of which are uncommon Autoimmune hemolytic anemias, thrombocytopenia, and neutropenias from postHCT immune dysregulation can occur months to years after transplantation and are typically managed with immunosuppression, immunomodulation, or IV immunoglobin Transplant-associated thrombotic microangiopathy (TATMA) is increasingly recognized as an important complication of HCT.231 The diagnosis should be suspected in patients who present with hypertension, evidence of hemolytic anemia, thrombocytopenia, proteinuria, and multisystem involvement, such as renal failure, pleural effusions, neurologic changes, ascites, and/or pericardial effusions The diagnosis is made by biopsy with evidence of microangiopathy on the specimen or by meeting clinical criteria, including elevated LDH, proteinuria, thrombocytopenia, anemia, microangiopathy, and/or elevated sC5b-9 levels.232,233 Patients at particularly high risk for severe disease are those with proteinuria and elevated sC5b-9 levels The underlying pathophysiology is thought to involve abnormalities in complement activation.234 Treatment with eculizumab, a monoclonal antibody that prevents the formation of sC5b-9, is promising.235 Hemolytic uremic syndrome (HUS) is a potentially life-threatening, uncommon post-HCT complication It presents with hemolysis and mild to moderate renal dysfunction at a median time of months post-HCT.236 Patients may also have seizures and hypertension Many cases of post-HCT HUS gradually self-resolve, although patients may be left with residual renal dysfunction Post-HCT thrombotic thrombocytopenic purpura (TTP) classically presents earlier than HUS with thrombocytopenia, schistocytes on the peripheral blood smear, and elevated LDH Endothelial damage from transplant conditioning, GVHD, and calcineurin inhibitors are believed to contribute to the development of post-HCT TTP.237 It differs from classic TTP of childhood in that ADAMTS13 deficiency is not present.237,238 Additionally, standard therapies for idiopathic TTP, such as plasma exchange, not appear to be effective for the treatment of postHCT TTP Iron Overload Iron overload has been recognized as an important transplant complication as well as a risk factor for the development of other transplant-related toxicities.239 HCT patients are at risk for increased iron burden due to repeated blood transfusions pre- and post-HCT and disturbed iron metabolism in the setting of chronic inflammation.239,240 Adverse effects from iron overload may include increased susceptibility to infection, VOD, chronic liver disease, endocrine abnormalities, and cardiac dysfunction.1,241,242 Studies suggest that iron overload has an adverse impact on survival in patients undergoing HCT for beta-thalassemia major and hematologic malignancies.240,243,244 However, the impact of iron overload on transplant-related toxicities in patients transplanted for other reasons is less well established.245 1125 There are multiple ways to diagnose iron overload Liver biopsy remains the gold standard, but frequently the diagnosis is made with imaging and laboratory studies Elevated ferritin is a nonspecific marker of inflammation, rendering this a sensitive— but not specific—indicator of iron overload Serum iron studies are useful adjuncts for diagnosis and are often used for monitoring the efficacy of therapy MRI can provide a quantification of organ-specific iron burden.246 Phlebotomy is a standard treatment for iron overload.247,248 However, it may have limited utility given that many patients may be anemic after HCT Iron chelation is effective but may be limited by the practical considerations in the case of deferoxamine infusion and potential toxicities of the treatments.249 Graft-Versus-Host Disease GVHD is the most common complication of allogeneic HCT GVHD develops when donor T lymphocytes respond to proteins on recipient cells.250 Activated donor T lymphocytes, monocytes, and macrophages trigger a self-propagating cycle of cytokine production and inflammation.250,251 GVHD was historically categorized by the time of occurrence following transplant, with acute GVHD diagnosed if symptoms developed before day 100 or chronic if the presentation was after day 100 The traditional definitions of acute and chronic GVHD not fully address the pathophysiology of the diseases and have evolved Consensus recommendations from the 2014 National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic GVHD advise classification based on the clinical features rather than the posttransplant day and provide revisions to 2005 recommendations.252 This classification recognizes two main categories of GVHD (acute and chronic), each with subcategories Acute GVHD includes classic acute GVHD that develops within 100 days after transplant and persistent, recurrent, or late-onset acute GVHD that clinically resembles acute GVHD but occurs greater than 100 days after transplantation Chronic GVHD includes classic chronic GVHD occurring more than 100 days after HCT with manifestations specific to chronic GVHD and an overlap syndrome, which has features of chronic GVHD and features typical of acute GVHD.252 The skin, gastrointestinal tract, and liver are the most common involved systems in acute GVHD The cutaneous presentation is typically an erythematous maculopapular rash, although there are a wide variety of possible skin findings Diffuse bullous lesions with skin sloughing are the most severe manifestation of cutaneous GVHD Acute gastrointestinal GVHD is characterized by diarrhea that is often bloody, may contain tissue, and is accompanied by severe abdominal pain and cramping Hepatic acute GVHD typically presents with a cholestatic pattern of elevated bilirubin and alkaline phosphatase Isolated transaminase elevation is uncommon Less common presentations of acute GVHD are oral inflammation with possible ulceration and ocular inflammation Acute GVHD is graded according to severity of the systems involved (eTable 93.2) Gastrointestinal tract chronic GVHD may present as anorexia, nausea, vomiting, diarrhea, malabsorption, or weight loss Other manifestations of chronic GVHD are sicca syndrome, oral scarring with salivary gland scarring, fasciitis, immune dysfunction, protein-losing renal disease, and genitourinary scarring Immune dysfunction independent of immunosuppressive medications is characteristic of chronic GVHD Patients with chronic GVHD have abnormal splenic function and often need prophylaxis against encapsulated bacteria.253 ... been used for VOD Jones et al.158 first described VOD and modified this criterion as hyperbilirubinemia greater than mg/dL within 21 days of transplantation with at least two of three other findings:... these viruses and clinical presentations is beyond the scope of this chapter The reader is referred to multiple published reviews of this topic.217–221 Recent study has focused on the role of adoptive... and clinical research has focused on the role of this immunotherapeutic approach to the treatment of CMV, EBV, and adenovirus Broad application of this biotechnology is evolving.222–224 Graft Failure