What are some of the signs and symptoms of rejection?

The clinical diagnosis of rejection is often difficult. Frequently, patients have rejection on biopsy without symptoms. Less often patients may have nonspecific complaints of fatigue or malaise as the original symptom. Left untreated, a patient may progress to having dyspnea on exertion, orthopnea, and paroxysmal nocturnal dyspnea consistent with overt heart failure. Signs on physical exam often alert a physician to the presence of rejection before a patient is critically ill. Elevated neck veins, tricuspid regurgitation, and a third heart sound are all very suggestive, although not diagnostic, of rejection. Fevers without a source, arrhythmias of any kind, and hypotension also may be presentations of cardiac rejection.

How is the diagnosis of rejection made?

Endomyocardial biopsy remains the gold standard for the diagnosis of rejection. It is extremely sensitive and specific. The International Society of Heart and Lung Transplantation developed a scale for grading the severity of cellular rejection that is now widely used and that is based on the amount of lymphocytic infiltrate and degree of myocyte damage. Humoral (vascular) rejection is much less common than cellular rejection, although it may occur in up to 20% of patients receiving antilymphocyte preparations. This antibody-mediated rejection is characterized by an increased incidence of fatal rejection, development of graft atherosclerosis, and a poorer long-term prognosis. The diagnosis of antibody-mediated rejection is based on endothelial cell swelling on microscopy along with immunofluorescent staining of complement and immunoglobin on the vascular endothelium. Hyperacute rejection is another form of rejection that is mediated by preformed antibodies in the recipient against antigens on the donor heart. This type of rejection is often characterized by immediate graft failure post transplantation and has an extremely poor prognosis.

Are noninvasive tests such as cardiac echocardiography useful in the diagnosis of rejection?

In general, cardiac imaging studies lack the sensitivity and specificity to be useful in diagnosing rejection. By the time left ventricular function deteriorates, the level of rejection is usually fairly advanced and more difficult to treat. Echocardiography, however, is not entirely useless in the management of heart transplant recipients. Doppler echocardiographic evaluation of patients to assess diastolic function is a fairly sensitive technique for following the changes that occur with rejection. Other echocardiographic findings such as increased wall thickness or edema may provide clues about humoral rejection that is not routinely detected by standard biopsy staining techniques. Echocardiography can also provide evidence of wall motion abnormalities, suggesting ischemic disease, and can assist in the evaluation of valvular dysfunction, which may explain worsening cardiac function.

What are the different kinds of rejection?

Rejection currently accounts for 17% of deaths in transplanted patients. Hyperacute, cellular, and humoral rejection are the major forms of rejection as we currently understand them.

Hyperacute rejection usually presents immediately after transplantation as severe graft dysfunction. It occurs when the recipient has preformed antibodies to HLA antigens on the donor heart. These antibodies can be formed when there is previous exposure to HLA antigens common to the donor, as may occur with blood transfusions, pregnancy, or previous organ transplantation. Most instances of hyperacute rejection can be prevented by screening recipients for anti-HLA antibodies prior to transplantation. Patients who have a broad spectrum of anti-HLA antibodies are usually required to undergo crossmatching prior to transplantation.

Cellular rejection is the commonest form of rejection. T-lymphocytes mediate this process, which involves perivascular and perimyocytic lymphocytic infiltrates. This form of rejection is diagnosed by H&E staining of biopsy specimens and usually responds very well to increased levels of immunosuppression. Cellular rejection occurs most frequently and most aggressively in the first few months following transplantation. It is uncommon after the first 6 months unless the recipient has a concurrent infection, a recent reduction in immunosuppression, or has had frequent previous episodes of rejection.

Humoral (vascular) rejection is much less common than cellular rejection but carries a much worse prognosis. Patients with this type of rejection characteristically have deposition of immunoglobin and complement in a vascular pattern by immunofluorescent staining. They also have generalized endothelial cell swelling by light microscopy. Vascular rejection is seen more commonly in patients with sensitization to OKT3.

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