Conditioning regimen

Patients undergoing HCT are subjected to a treatment regimen referred to as a conditioning regimen or preparative regimen prior to infusion of the hematopoietic progenitor cells. The purpose of this preparative regimen is multifold. In cases of malignant disorders, it provides eradication of disease. In addition, the preparative regimen must be immunosuppressive in allogeneic transplantation to allow the donor cells infused to establish themselves in the marrow cavity and overcome host rejection. The precise conditioning regimens can include chemotherapy alone or in combination with radiation. Numerous regimens have been explored and are dependent on the disease for which the transplant is required and the research interests of the institution performing the transplant.

Stem cell harvesting/collection/cryopreservation

Stem cells can be collected or harvested from either bone marrow or peripheral blood. For patients or donors undergoing bone marrow harvest, general anesthesia or regional anesthesia is given. Bone marrow is generally aspirated using special bone marrow harvest needles percutaneously from the posterior iliac crests through numerous passes. The amount of marrow taken is based on the size of the recipient. If there is a significant size discrepancy between the donor and recipient (recipient larger than donor), the donor may lose a significant amount of blood. Donors can be placed on iron therapy after harvest or they can electively store autologous blood ahead of time. A newer technique allows for the collected marrow to be processed with removal of red blood cells (RBCs; particularly necessary in cases of major ABO incompatibility between donor and recipient). These RBCs can be transfused to the donor postoperatively.

PBSCs can be mobilized in patients recovering from chemotherapy (autologous) or by giving allogeneic donors cytokines, such as granulocyte colony-stimulating factor (G-CSF). Their stem cells then can be collected using an apheresis machine in an outpatient setting. Collection of sufficient cells for transplantation may require several apheresis procedures. Stem cells for allogeneic transplantation usually are collected on the day they are anticipated to be reinfused into the patient. Autologous collection of stem cells requires cryopreservation of the cells until the day of reinfusion. Dimethyl sulfoxide (DMSO) is added to the collection product to ensure cell viability, and the cells are frozen in liquid nitrogen until needed.

Stem cells can be collected from umbilical cord blood. After delivery of the infant, sterile umbilical venous access is obtained, and the blood is collected into anticoagulated tubes. This can be done either before or after delivery of the placenta. A sample of this cord blood is used for HLA typing and infectious disease testing; the remainder is cryopreserved.

Reinfusion

The day of stem cell reinfusion is referred to as day 0 for the transplant period. Cryopreserved stem cells are thawed in a water bath under sterile conditions and may be washed to remove the DMSO cryopreservant. Stem cells are then infused into the patient though the indwelling central venous catheter. These cells can migrate into the bone marrow on their own. Blood transfusion–like complications can occur with reinfusion of stem cells; patients are generally placed on cardiac monitors with emergency medications available at the bedside during the infusion. The infusion procedure is generally short, lasting anywhere from approximately 10 minutes to 4 hours, depending on the volume of cells infusing.

Recovery period

After the reinfusion of stem cells, patients wait for count recovery to occur and receive treatment for any toxicities. Allogeneic transplant patients receive immunosuppressive medicines to prevent GVHD. Most patients are hospitalized for the entire transplant procedure, starting with the conditioning regimen. However, there is a trend toward outpatient HCT, particularly in the autologous setting. A typical hospitalization for HCT is 4 to 6 weeks, but it may be prolonged if umbilical cord blood is used or shortened for autologous transplants.

Complications

Patients undergoing HCT are at high risk for complications that may require a stay in the pediatric intensive care unit (PICU). In one series, 19% of pediatric HCT patients required a PICU admission. In other published series, 6% to 25% of pediatric HCT patients required mechanical ventilation. ^, Because of the high use of critical care services by HCT patients, it is beneficial for the pediatric intensivist to be familiar with their complications.

The reasons for these patients being at high risk for critical illness are multifactorial. Many of these patients are undergoing HCT for an underlying disease that places them at risk for critical illness, such as malignancies, severe immunodeficiencies, and metabolic disorders. To make room for the new hematopoietic progenitor cells, patients are given conditioning regimens with high doses of toxic chemotherapy and/or radiation. This makes them severely immunocompromised, placing them at high risk for opportunistic infections. The conditioning agents themselves cause significant oxidative stress and may be the common denominator behind many of these complications.

While mortality rates for HCT patients requiring ICU care are quite high in comparison with the general ICU population, they appear to be improving. Data from the 1980s showed mortality rates for mechanically ventilated pediatric HCT patients to be near 90%. ^, However, more recent data indicate that the mortality rates continue to improve, with a report using the Virtual PICU Systems Database demonstrating a mortality rate of 42.5% for HCT patients requiring invasive positive-pressure ventilation. Some of the improvements seen in outcomes over the years may be due to differing characteristics of the patients, as very few studies reported severity of illness scores. In any case, no series reporting on mortality of pediatric HCT patients was able to predict with 100% certainty that a given patient would not survive. Therefore, the critical care and transplant teams must work together and use their best judgment when making recommendations to families regarding appropriateness and duration of critical care services for this complex patient population.

Cardiac complications

Cardiac complications following HCT can occur during the immediate transplant period or can be late sequelae in survivors. The heart may be injured during the transplant process from a variety of pathophysiologic etiologies. First, previous cardiotoxic treatments and therapies, such as anthracyclines and iron overload from frequent RBC transfusions, may predispose the heart to subsequent injury during transplantation. In addition, cardiotoxic therapies, such as cyclophosphamide and irradiation used as part of the preparative regimen, may further injure the recipient heart. Moreover, hyperhydration therapies, blood product transfusions, and impaired renal function may place further stress on the heart. Sepsis, which commonly affects the HCT patient, has also been found to decrease cardiac contractility. More specific to the HCT patient, there are rare reports of acute GVHD affecting the heart and cardiovascular system. Further, transplant-associated thrombotic microangiopathy has been associated with cardiovascular complications such as pericardial effusions and pulmonary arterial hypertension. ^, Additionally, in a small series of children treated for a primary immunodeficiency with HCT (n = 10), cardiac chamber hypertrophy was reported to occur in those transplanted at less than 1 year of age and who received high-dose corticosteroids for acute GVHD. Finally, there is evidence to suggest that genetic susceptibility may also play a role in HCT-related heart failure. For example, using a nested case-control study design, it was noted that polymorphisms in the NAD(P)H oxidase subunit RAC2 as well as carbonyl reductase CBR1 were associated with a significant increase in the risk of acute heart failure among HCT recipients. These findings suggest that acute heart failure occurs as a result of oxidative stress or metabolic derangements induced by cardiotoxic alcohol metabolites of anthracyclines and that variants of RAC2 and CBR1 modulate this risk.

An analysis of 2821 adult and pediatric patients found that only 26 (0.9%) experienced a major or fatal cardiac complication in the first 100 days after transplant. Seven of the 26 cardiac complications occurred in children. Among the 26 patients with significant cardiac complications, 11 had evidence of heart failure, 5 had pericardial tamponade, and 10 had dysrhythmias. All 11 patients with heart failure died compared with only one each with tamponade or a dysrhythmia. All cases of heart failure occurred between day −6 and day +35. Four of the seven pediatric patients had heart failure. Electrocardiographic abnormalities have been reported in as many as 11% of pediatric HCT recipients.

In another report, the Associazione Italiana Ematologia Oncologia Pediatrica-BMT Group described their transplant-related toxicities in 636 pediatric patients transplanted for acute leukemia. In their experience, the incidence of moderate or severe cardiac toxicity in the first 90 days posttransplant varied by the type of transplant, with autologous recipients experiencing an incidence of 1.9% (4 in 216, 2 deaths) and allogeneic recipients of a compatible related donor experiencing a comparable incidence of 2.4% (7 in 294, 4 deaths). However, recipients of an allogeneic alternative donor experienced a 6.4% rate of these cardiac complications (8 in 126) with all 8 experiencing an early death. In that study, the presence of moderate or severe cardiac toxicity increased the relative risk of an early posttransplant death more than ninefold (relative risk [RR], 9.1; 95% confidence interval [CI], 2.8–29.6) and more so than toxicity to any other organ system. The manifestations of the cardiac disease are varied; they include myocardial ischemia and pericarditis in addition to dysrhythmias, pericardial effusion, and progressive congestive heart failure. One further cardiovascular complication that merits special attention in the pediatric HCT patient is the occurrence of pulmonary hypertension.

Pulmonary arterial hypertension in the setting of pediatric HCT has been reported with increased frequency once it was identified as a potential concern and assessed for with routine screening. In one report, a routine day +7 echocardiogram detected elevated right ventricular pressures in 13% of the patients. In that report and others, pulmonary arterial hypertension was found to be associated with transplant-associated thrombotic microangiopathy. ^, Additionally, pulmonary arterial hypertension is reported to occur in the setting of patients undergoing transplant for malignant infantile osteopetrosis. Pulmonary venoocclusive disease may also account for episodes of pulmonary arterial hypertension. The incidence of pulmonary venoocclusive disease in HCT patients is speculative given the limited available data. Pulmonary arterial hypertension is reported to be the proximate cause of death in pediatric patients undergoing HCT for hemophagocytic lymphohistiocytosis and idiopathic myelofibrosis. ^, Independent of the cause, pulmonary arterial hypertension should always be suspected in the pediatric HCT patient with unexplained cardiopulmonary dysfunction, as emergent therapy may be life-saving.

Late cardiovascular toxicity occurring a year or more after HCT has also been reported. Late cardiovascular complications following HCT include heart failure, dysrhythmias, hypertension, and cerebrovascular accidents. Duncan et al. recently reported on late cardiovascular complications among 661 pediatric allogeneic HCT patients. Cardiovascular complications assessed accounted for approximately 4% of survivors, including cardiomyopathy (3%), cerebrovascular accident (0.6%), coronary artery disease (0.2%), and cardiac-related death (0.5%). Several pathologic mechanisms of late congestive heart failure have been offered, including the same mechanisms causing acute heart failure, such as previous cardiotoxic agents (anthracyclines, alkylating agents, thoracic irradiation) in conjunction with cyclophosphamide and total body irradiation during conditioning regimens.

Despite the relatively low incidence of overt cardiac dysfunction, subclinical cardiac dysfunction appears relatively common in pediatric HCT recipients and may portend a poor outcome. For example, in a case control study of 40 consecutive pediatric HCT patients, HCT patients were found to have similar left ventricular ejection fractions as controls. However, the HCT recipients were found to have significantly decreased rate-corrected velocity of circumferential fiber shortening, mitral inflow E velocity, and mitral septal annular E′ velocity. Using speckle tracking echocardiography, HCT patients were also noted to have decreased left ventricular global circumferential systolic strain, circumferential systolic strain rate, circumferential diastolic strain rate, and longitudinal diastolic strain rate. Strain echocardiography has also been used to assess changes in cardiac function among pediatric patients undergoing HCT for sickle cell disease and severe aplastic anemia. This technology has demonstrated initial decrease in function following transplant and subsequent improvement over time.

In another report, 100 pediatric HCT patients underwent a routine scheduled echocardiogram at day +7. At least one abnormality was noted in 30% of the children—most commonly, a pericardial effusion or an elevated estimated right ventricular pressure. Survival was decreased in those children with any abnormality detected. Pericardial effusion has been reported to occur in approximately 17% of pediatric HCT recipients. It is asymptomatic in approximately half of the cases and is rarely the proximal cause of death. Despite that observation, HCT patients with a pericardial effusion have a significantly increased risk of mortality. Additionally, a pericardial effusion may be anticipated in patients with a pretransplant prolonged corrected QT dispersion. ^{, ,}

In another assessment, the group at Cincinnati Children’s Hospital began performing screening echocardiograms on all HCT patients admitted to the PICU. They observed abnormalities that required follow-up or intervention in 50% of patients. The most common abnormalities noted were elevated right ventricular pressures, left ventricular systolic dysfunction, pulmonary hypertension, and pericardial effusions. Two-thirds of the pericardial effusions found required pericardiocentesis, and all patients with pulmonary hypertension required treatment with pulmonary vasodilators. In addition to echocardiography and electrocardiography, biomarkers may also identify patients at risk for cardiac dysfunction. Elevations in N-terminal pro B-type natriuretic peptide concentrations at day 14 after stem cell transplant can identify patients at risk of developing cardiac events during the first 6 months after HCT. ^,

In summary, cardiac toxicity may present as an acute finding in the immediate posttransplant period with evidence of progressive heart failure, dysrhythmias, and pericardial effusions with tamponade. Late cardiovascular complications are also being studied. Although clinically evident late cardiac complications are being reported, there appear to be several subclinical findings detected by use of more involved testing. The importance of these subclinical findings requires more study and is likely to be better understood as these children age further.

Pulmonary complications

The incidence of HCT-related pulmonary complications in children is reported to be between 12% and 25%. ^, The need for mechanical ventilation support is the most frequent reason for admission of HCT patients to the PICU. ^{, ,} Pulmonary complications can be divided into early and late complications ( Table 93.1 ). Early complications occur within the first 100 days after transplant. The division into early and late complications is not absolute but may help the clinician in developing a differential diagnosis. Early complications include infection, periengraftment respiratory distress syndrome (PERDS), pulmonary cytolytic thrombi (PCT), diffuse alveolar hemorrhage (DAH), and idiopathic pneumonia syndrome (IPS). Late-onset complications occur beyond 3 months after HCT and include bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and IPS.

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. BAL identified the cause of respiratory symptoms in 53 (67.9%) of 78 of their allogeneic HCT recipients and 7 (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 2 of 7 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. 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 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. 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. ^,

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.

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). ^, If there is a suspicion of active infection in the liver, liposomal amphotericin, voriconazole, or caspofungin should be given until engraftment is established. ^, 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. ^, Sepsis can also lead to cholestasis and hyperbilirubinemia. This is mediated by endotoxins, interleukin-6 (IL-6), and TNF-α. ^, 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. ^, 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. The disease process begins in the sinusoids due to endothelial injury and affects venules only late in the course of the disease. The pathogenesis is believed to result from hepatic venule and sinusoidal endothelial injury. Histologically, subendothelial edema, endothelial cell damage with microthrombosis, fibrin deposition, and expression of factor VIII and von Willebrand factor within venular walls is observed. 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. Risk factors may include elevated transaminases before the conditioning regimen, ^, age younger than 6 to 7 years, use of methotrexate for GVHD prophylaxis, presence of oral mucositis, interstitial pneumonitis, and/or RBC transfusion iron overload. 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. ^{, , ,} 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. 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%, with mortality rates ranging from 3% to 67%. 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. first described VOD and modified this criterion as hyperbilirubinemia greater than 2 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. in Seattle defined VOD in their series as two of the following criteria occurring within 20 days of transplantation: hyperbilirubinemia greater than 2 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 6 and 7 after transplantation, peaking around 10 days after onset, and returning to baseline 10 days later if they are going to recover. Multiorgan failure is seen frequently in patients with VOD. ^, Severe VOD (S-VOD) is associated with the development of multiorgan failure, including renal failure, pulmonary insufficiency, cardiac failure, and changes in mental status. Liver ultrasound with Doppler study demonstrating reversal of portal flow is a late finding in VOD 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. Transvenous liver biopsy and hepatic venous pressure gradient measurements can be performed safely 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. Hepatic venous pressure gradient levels greater than 10 mm Hg have been found to be highly specific for diagnosis of VOD. ^,

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. ^{, ,} Ursodeoxycholic acid is recommended for prophylaxis in patients at risk for VOD. ^, Defibrotide is not approved for prophylaxis for VOD. 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. 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. ^, 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. 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. 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. Screening and empiric management for fevers or clinical instability should follow the standard of care HCT guidelines.

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. 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. Lower GI/intestinal acute complications include C. difficile colitis, viral and other gastroenteritis, typhlitis, intestinal GVHD, and intestinal thrombotic microangiopathy. 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%. The incidence of typhlitis in this series was much lower than the 32% incidence previously reported in the literature for AML patients.

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.

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. The incidence of typhlitis can vary depending on the aggressiveness of chemotherapy and prophylactic antibiotics used. The typical time frame to be diagnosed with typhlitis after HCT appears to be 15.5 ± 7 days. 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 demonstrate luminal narrowing and stranding in the pericecal fat. 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.

Pneumatosis intestinalis can be noted in typhlitis, in which case it implies imminent bowel perforation. 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. ^{, ,}

Intestinal acute GVHD usually develops after 3 to 5 weeks and can be accompanied by skin and hepatic GVHD. Chronic GVHD occurs several months after transplantation. ^, Symptoms include secretory diarrhea, fever, nausea, vomiting, abdominal pain, and intestinal hemorrhage. In addition to nonspecific findings, CT imaging may reveal bowel wall enhancement correlating with mucosal destruction and replacement with granulation tissue.

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 complement-blocking therapy such as eculizumab may improve outcomes.

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. Werlin et al. also reported a similar 3.5% incidence of pancreatitis and recommended testing for pancreatitis prior to attributing GI symptoms to mucositis.

Myelosuppression and hematologic complications

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 2 to 4 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.

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, 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 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. 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. 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.

CMV is one of the most problematic viral infections for HCT patients. CMV may emerge in the allogeneic patient between 1 to 3 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 7 to 14 days followed by prophylaxis and/or screening through 100 days posttransplantation. Interstitial pneumonitis from CMV presents with hypoxia and fever and an interstitial pattern on chest radiograph. Untreated, there is an 80% mortality rate. Ganciclovir and intravenous (IV) immunoglobin is the recommended treatment for CMV interstitial pneumonitis. For patients resistant to ganciclovir or with unacceptable medication toxicity, foscarnet may be used. ^, 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/μL. If the ANC falls below 500/μL, 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.

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.

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. 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. ^, 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 gamma-irradiated to rid the product of competent donor T cells that can cause transfusion associated-GVHD. 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.

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 O+ and recipient A+); (3) major ABO mismatch, in which case the recipient isoagglutinins are directed against donor RBCs after engraftment (e.g., donor blood type A+ and recipient O+); and (4) bidirectional mismatch, which combines minor and major ABO mismatch (e.g., donor blood type A+ and recipient blood type B+). When there is a major or bidirectional mismatch, the stem cell product must be RBC depleted or the patient must 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 immune-mediated 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 post-HCT immune dysregulation can occur months to years after transplantation and are typically managed with immunosuppression, immunomodulation, or IV immunoglobin.

Transplant-associated thrombotic microangiopathy (TA-TMA) is increasingly recognized as an important complication of HCT. 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. ^, 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 . Treatment with eculizumab, a monoclonal antibody that prevents the formation of sC5b-9, is promising.

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 5 months post-HCT. 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. It differs from classic TTP of childhood in that ADAMTS13 deficiency is not present. ^, Additionally, standard therapies for idiopathic TTP, such as plasma exchange, do not appear to be effective for the treatment of post-HCT TTP.

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. Activated donor T lymphocytes, monocytes, and macrophages trigger a self-propagating cycle of cytokine production and inflammation. ^, 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 do 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. 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.

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 ).

eTABLE 93.2

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