infiltration of the portal triad is characteristic of acute cellular rejection Treatment of acute cellular rejection is typically with high-dose corticosteroids followed by a taper, with good response reported in up to 80% of patients In addition to corticosteroids, other treatment options include increasing CNI levels or addition of immunosuppressant agents such as mycophenolate For rejection that is refractory to these treatments, sirolimus or monoclonal antibodies such as rituximab can be tried In select cases, retransplantation may be necessary Chronic rejection can reflect long-term graft dysfunction and occurs in up to 10% of patients The etiology of chronic rejection remains unknown, but the major histologic feature of chronic rejection is loss of bile ducts that may or may not be associated with ischemic injury Over 50% of bile ducts may be lost and this ductopenia is associated with a progressive cholestasis and consequent rise in biliary enzymes In the absence of ischemic injury, chronic rejection may spontaneously resolve in approximately half of patients However, ductopenia associated with obliterative arteriopathy and subsequent ischemic necrosis represents a more relentless process with many children ultimately requiring retransplantation Other Solid Organ Transplantation In renal transplant patients, acute rejection is a frequent complication, defined as deterioration in graft function (increasing creatinine) Fever and graft tenderness are less common with current immunosuppressant regimens For intestinal transplant patients, the incidence of acute exfoliative rejection is high compared to other solid organ transplant patients Graft loss occurs in virtually all patients with severe rejection despite aggressive medical therapy TABLE 125.2 SPECIFIC SIGNS AND SYMPTOMS OF GRAFT REJECTION BY SOLID ORGAN TRANSPLANTED Goals of Treatment The goals of emergency department (ED) management of acute rejection include identifying that rejection is the most likely diagnosis, hemodynamic stabilization of the child’s condition, and potential initiation of rejection therapy When there is a concern for rejection, transplant recipients should be promptly evaluated in a transplant center where they may have screening labs, immunosuppressive drug levels, and graft-specific imaging studies performed ( Table 125.2 ) Clinical Considerations Clinical Recognition Cardiac Transplantation Cardiac transplant patients may present to the ED with early or fulminant signs and symptoms of rejection Mild, or early, clinical signs and symptoms of rejection are often nonspecific One presentation may include fever, abdominal pain, nausea, and vomiting, mimicking a gastrointestinal infection Another typical, nonspecific presentation may include respiratory symptoms such as tachypnea, pulmonary congestion, and cough In moderate to severe graft rejection, the clinical signs and symptoms mimic heart failure The decisive findings that lead to a rejection diagnosis are tachycardia out of proportion to fever or hydration status and an S3 gallop rhythm Hepatomegaly, ascites, facial and peripheral edema, jugular venous distention, and inability to lie flat may all be seen on examination of a child in moderate to severe rejection These findings are usually sufficient to initiate therapy Liver Transplantation Rejection of the hepatic allograft should be considered in the setting of elevated liver enzymes (ALT, AST, bilirubin, GGT) with or without fever Other subtle symptoms such as increased fatigue, pruritus, jaundice, or low-grade fevers also warrant screening laboratory studies to evaluate for rejection One challenge is that many of these symptoms can also be seen with infectious etiologies Elevation of these liver enzymes should prompt the clinician to ensure that the patient is receiving therapeutic immunosuppression as well as to consider rejection Triage Considerations Triage of transplant patients at risk of rejection requires knowledge of the solid organ involved as well as the risk of impending cardiovascular collapse For cardiac transplant patients, the presence of tachycardia, gallop rhythm, and low blood pressure should be recognized as potential signs of rejection requiring immediate critical care management and contacting the transplant team Liver transplant patients, however, typically present to triage in a more stable fashion Clinical Assessment History should be focused on assessment of medical adherence as well as a complete review of systems Physical examination is mainstay of diagnosis at this stage For cardiac transplant patients, tachycardia, gallop rhythm, orthopnea, tachypnea, congested breath sounds and rales, pallor, low blood pressure, jugular venous distention, abdominal ascites, and hepatomegaly may all be seen Chest radiograph may reveal cardiomegaly and pulmonary congestion ECG may show low voltage, strain pattern, and even ischemia An echocardiogram obtained in the ED is helpful to determine ventricular function and the presence of a pericardial effusion or valvar insufficiency, which are common in rejection Laboratory findings compatible with rejection include elevated BNP (as a marker of cardiac failure); immunosuppression drug levels that are very low (as in noncompliance) or very elevated (as in diminished metabolism due to decreased cardiac output); elevated LFTs and renal indices, as the result of low cardiac output Liver transplant patients develop fever from bile duct inflammation and cholangitis This may be accompanied by graft-site tenderness Other possible physical examination findings include encephalopathy, jaundice, bruising, and a tendency for bleeding Initial assessment for concern of rejection should include LFTs (AST, ALT, bilirubin, GGT) as well as measures of synthetic liver function values such as INR, prothrombin time, albumin, glucose, and ammonia level If there is a coagulopathy, vitamin K should be administered A Doppler ultrasound of the hepatic allograft is indicated in settings of fever Management First-line management for cardiac rejection is intravenous solumedrol, 10 mg/kg (max dose 500 mg) as a bolus If there is hemodynamic compromise, milrinone is an appropriate addition to therapy, as is intravenous furosemide for pulmonary congestion Therapy should be discussed with the transplant team For liver, intestinal, and renal transplant patients, if there is concern for rejection, a biopsy of the transplanted organ is indicated Assessment of patient safety for biopsy should include a hemoglobin level, a coagulation panel, and a type and screen POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER CLINICAL PEARLS AND PITFALLS PTLD is a spectrum of neoplastic diseases that can occur in children after solid organ transplant PTLD is often associated with EBV infection Children may be asymptomatic, or have nonspecific symptoms such as malaise and fever Diagnosis rarely occurs in the ED, yet clinicians must have a high level of suspicion Goals of Treatment PTLD represents a spectrum of lymphoproliferative diseases that occur in patients post transplant Diagnosis of PTLD in the ED is rare, but it is important for emergency clinicians to recognize the common symptoms, which include malaise, fever, chronic gastrointestinal symptoms, and/or pulmonary symptoms A high clinical suspicion of PTLD warrants admission for further diagnostic testing Current Evidence EBV is a ubiquitous virus and, similar to CMV, is associated with hepatitis as well as a more systemic illness EBV infection commonly occurs in the first year following transplantation when immunosuppression levels are higher, but can present anytime following transplantation EBV infection is more common in children and can reflect primary disease or reactivation of disease Between 60% and 80% of pediatric transplant recipients are EBV seronegative at the time of transplantation and high levels of immunosuppression increase the risk of developing symptomatic disease Acute EBV infection presents as a mononucleosis-like syndrome with diffuse B-cell hyperplasia Of particular concern with EBV infection is the risk of subsequent development of PTLD PTLD refers to a spectrum of lymphoproliferative disorders that ranges from Bcell hyperplasia to monoclonal lymphoma In many cases, development of PTLD results from EBV activation and mutation of lymphocytes in the immunosuppressed host PTLD is the most common neoplastic disorder in children following transplantation In addition to EBV infection post transplant, significant risk factors for development of PTLD include younger age at transplant and prolonged, intense immunosuppression, such as may occur post treatment of serial rejection episodes or after many years of chronic immunosuppression Serial monitoring of EBV viral load has allowed for earlier ...Goals of Treatment The goals of emergency department (ED) management of acute rejection include identifying that rejection is the... occur in patients post transplant Diagnosis of PTLD in the ED is rare, but it is important for emergency clinicians to recognize the common symptoms, which include malaise, fever, chronic gastrointestinal... common in children and can reflect primary disease or reactivation of disease Between 60% and 80% of pediatric transplant recipients are EBV seronegative at the time of transplantation and high levels