Pediatric emergency medicine trisk 1034

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