Recognizing and Treating Rejection

I. Transplant Heart rejection: What every physician needs to know.

As is the case with all transplanted solid organs, the cardiac allograft is subject to immune-mediated rejection since the recipient's immune system recognizes the donor heart as foreign tissue. There are two generic types of rejection: cellular rejection (the most common type) and antibody mediated rejection.

Cellular rejection occurs in 20% to 40% of patients during the first six posttransplant months and sporadically thereafter. It is the type of late rejection often seen accompanying advertently low immunosuppressant drug levels or after periods of patient noncompliance with medication regimens, the latter a situation which can be seen in association with depression, often in adolescent patients.

It is a predominantly T-cell mediated process and is associated with mononuclear cell infiltration and cardiac myocyte necrosis on endomyocardial biopsy, which is the "gold standard" for diagnosis of cellular rejection. It can be associated with left ventricular dysfunction either in the form of diastolic stiffness or of systolic failure with a drop in LV ejection fraction and consequent development of typical signs and symptoms of heart failure.

Acute antibody mediated rejection has been recognized as a real entity in recent years. It is mediated by the recipient's development of antibodies, often directed at the donor HLA antigens, and often leads to the same clinical consequences as cellular rejection. It is also associated with later development of cardiac allograft vasculopathy (CAV).

II. Diagnostic Confirmation: Are you sure your patient has Transplant Heart rejection?

There are no infallible clinical criteria for confirming this diagnosis. A patient with a heart transplant who presents with signs and symptoms of heart failure should be considered to have acute rejection until proven otherwise.

A. History Part I: Pattern Recognition:

In the early phases of cardiac rejection, symptoms may be vague and nonspecific, and include fatigue and malaise or nausea. Later, the heart transplant patient with acute rejection will usually have symptoms referable to and typical of the development of heart failure, including dyspnea with exertion, orthopnea, paroxysmal nocturnal dyspnea, and edema.

Symptoms can prominently include right upper quadrant abdominal discomfort, this due to stretching of the liver capsule consequent to elevated central venous pressure. A patient will often state that he's getting to feel similar to the way he did prior to his transplant.

Rejection is occasionally associated with atrial arrhythmias and patients should be questioned regarding the occurrence of palpitations or dizzy spells and should be admitted to a monitored bed if they are admitted to the hospital. Arrhythmias are not diagnostic of rejection, but should increase suspicion that it is occurring.

Physical signs are usually those compatible with heart failure in any patient (i.e., pulmonary rales, distended neck veins, enlarged/tender liver, peripheral edema). The development of blood pressure lower than normal for the patient (without an obvious cause such as dehydration) is a particularly ominous sign. Resting tachycardia, usually in the 90 to 110 range, is normal for the transplanted heart, but marked increases from baseline carry the same ominous significance as lower blood pressure.

B. History Part 2: Prevalence:

As noted above, acute cellular rejection occurs in 20% to 40% of heart transplant recipients during the first six posttransplant months. It is somewhat more frequent in female recipients and accounts for approximately 12% of deaths during the first postoperative year. Cellular rejection can be consequent to nonadherence to medications, a situation most prevalent in the adolescent population.

The prevalence of acute antibody mediated rejection is less clear, but it is much more common in patients who were "sensitized" to HLA antigens pre-transplant. Such patients include those who had been exposed to transfusions, often in the setting of prior heart surgery, and also multiparous females. There is some evidence that it may occur after posttransplant sensitization events, such as transfusions or even vaccinations.

C. History Part 3: Competing diagnoses that can mimic Transplant Heart rejection.

Other causes of heart failure must be considered in the posttransplant patient. The presence of a pericardial effusion, especially common early postoperatively, can lead to pericardial tamponade and most of the signs and symptoms noted above.

Later posttransplant, the development of allograft vasculopathy can lead to systolic or diastolic left ventricular (LV) and/or right ventricular (RV) dysfunction. Because of the denervated status of the heart, transplant patients are unable to experience the subjective sensation of angina pectoris, so lack of chest pain does not exclude this diagnosis. Occasionally, infectious complications, such as cytomegalovirus (CMV) and bacterial sepsis can lead to myocardial inflammation and dysfunction, and are another diagnostic consideration.

D. Physical Examination Findings.

The physical examination findings of cardiac allograft rejection are those of heart failure. The blood pressure may be lower than normal and the pulse rate higher than normal for the patient. Fever is unusual. In severe cases, there can be signs of low cardiac output such as mental obtundation and cool, clammy extremities.

E. What diagnostic tests should be performed?

Several laboratory studies and an imaging studies should be considered to help confirm the diagnosis.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

1a. "Gold Standard"

The "gold standard" diagnostic test for cardiac allograft rejection is the endomyocardial biopsy. This invasive procedure is usually performed in an experienced cardiac catheterization lab and usually employs fluoroscopy and uses the right internal jugular approach with a specialized bioptome instrument to retrieve three or four samples of myocardium from the right ventricular septum.

This procedure is quite safe in experienced hands and is associated with only rare complications. There exists an internationally standardized pathology grading scale for the histologic severity of acute cardiac rejection.

Specimens should be interpreted by an experienced cardiac pathologist who is familiar with using this grading scale. If antibody mediated rejection is suspected, immunohistochemistry and serologic assay for the existence of and titers of donor specific antibodies should be obtained.

1b. Possible alternatives.

In recent years a possible non-invasive alternative to the endomyocardial biopsy with the potential to screen low risk patients who are free of rejection has been developed. It is based on a blood test (termed Allomap) assaying peripheral blood leukocytes and has a reasonable negative predictive value. However, it has not been correlated with antibody mediated rejection and is as expensive as a biopsy. Newer and encouraging modalities under investigation include blood assays for circulating donor DNA.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There are no radiographic studies that are helpful in establishing the diagnosis of cardiac rejection. The transthoracic echocardiogram is most useful to exclude pericardial effusion and to assess systolic function, and is usually the first diagnostic test performed.

The amount of decrease in systolic function is correlated with the urgency of the situation and drops of >10% in ejection fraction should lead to performance of an endomyocardial biopsy in the absence of other obvious causes, such as ischemia or sepsis.

A 12-lead electrocardiogram is also important to assess for changes suggestive of alternative diagnoses, such as ischemia or infarction. Rejection can be associated with a generalized drop in EKG voltage in the absence of a pericardial effusion, but there are really no pathognomic EKG signs of rejection otherwise. Rejection is occasionally accompanied by atrial arrhythmias, especially in the early postoperative period, but they are not reliable indicators.

III. Management.

The treatment of acute cardiac allograft rejection generically involves augmentation of immunosuppression; the intensity of the augmentation employed is chosen based on the clinical or histological severity of the rejection episode. Both cellular and antibody-mediated rejection are treated with high-dose corticosteroids, usually 500 to 1,000 mg of methylprednisolone intravenously daily for 3 days. For mild episodes, especially in long-term patients, resumption of oral prednisone at 1 mg/kg/day for 3 days with a subsequent taper can be employed safely.

Acute cellular or antibody-mediated rejection associated with any evidence of hemodynamic compromise usually mandates further therapy beyond corticosteroids and this management should be employed whenever possible by physicians and in a center experienced with the care of transplant recipients. The most common next agent used is rabbit antithymocyte globulin (rATG), a polyclonal antibody preparation that targets all T cells. It is given as an intravenous infusion of 1.5 mg/kg (up to 125 mg) daily for 3 days.

Acute antibody-mediated rejection can be treated with corticosteroids alone when mild. ATG is usually employed, as above, when there is hemodynamic instability. Subsequently, it is recommended that the patient undergo plasmapheresis to remove the circulating antibodies that are mediating the rejection.

Plasmapheresis requires the insertion of a central venous catheter and one plasma volume exchange is performed daily or every other day for a minimum of five treatments. Patients with hemodynamic instability, severe graft dysfunction, or high titers of donor specific antibody may require more intense initial treatment (i.e., daily plasmapheresis) and longer duration of therapy.

A course of plasmapheresis should be followed immediately by infusion of intravenous immunoglobulin (IVIG) to avoid rebound of antibody levels. This is given as an infusion of 2 g/kg (not to exceed 140 g), divided over 2 consecutive days, with the first dose started within 4 hours of the last plasmapheresis treatment. Rituximab (monoclonal anti-CD20 antibody) is sometimes given subsequently to prolong the decrease in antibody production.

Protocols vary at different transplant centers, but usually include these components

A. Immediate management.

Immediate management of acute rejection should involve administration of high-dose corticosteroids, as noted above. Careful assessment of the patient may reveal the need for diuretic therapy or even inotropic support in severe cases. In most cases, the need for inotropic support should involve intensive care unit (ICU) admission with hemodynamic monitoring.

B. Physical Examination Tips to Guide Management.

Heart rates significantly in excess of and blood pressure significantly lower than the patients usual baseline are ominous signs, as are signs of heart failure and a third heart sound in a patient with a rejection episode. Resolution of these signs will signal successful therapy. Lack of such clinical improvement or worsening of any of these findings suggests lack of response to management.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

There are few, if any, laboratory tests to monitor the success of rejection therapy aside from a follow-up endomyocardial biopsy. A global assessment of the patient's level of clinical stability and improvement in hemodynamic status (if they have been compromised) is most important.

A follow-up echocardiogram to assess for recovery of systolic function (if it has been compromised) is important; function may be permanently impaired, but usually improves with effective therapy.

Continuing evidence of hemodynamic instability, especially inotrope requirement, is an ominous phenomenon and can require mechanical circulatory support and/or empiric further rejection therapy. Followup endomyocardial biopsy is generally recommended about two weeks following the course of rejection therapy.

D. Long-term management.

Long-term management after treatment for an acute rejection episode in a heart transplant recipient involves careful follow-up of immunosuppressant drug levels to ensure that they remain in the therapeutic ranges and also careful surveillance for infectious complications, which can supervene during periods of intensified immunosuppression.

If systolic function remains compromised, then standard therapy for systolic dysfunction should be employed and doses of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors initiated and titrated as tolerated.

E. Common Pitfalls and Side-Effects of Management

The most common unintended side effects or sequelae of rejection therapy are the development of opportunistic infections and the development of malignancy. Susceptibility to infectious complications is routinely expected in any patient having chronic immunosuppression; the level of susceptibility is much increased during periods of intensified immunosuppression, as is given with rejection therapy. Recognizing that this high susceptibility exists during the window of rejection therapy should lead to a low threshold to evaluate any complaints, such as fever or cough, which could signify a serious infection.

All patients requiring chronic immunosuppression have a higher than average prevalence of malignancy, most frequently those malignancies involving the skin and the lymphatic system. It is rare to see a cancer following a single rejection episode, but patients unfortunate enough to have multiple episodes requiring augmentation of immunosuppression should be monitored carefully.

IV. Management with Co-Morbidities

The use of high-dose corticosteroids for rejection therapy in patients with glucose intolerance or frank diabetes usually causes glucose control to deteriorate temporarily and doses of diabetic medication often need to be modified accordingly.

Patient counseling is extremely important in cases where the rejection episode is consequent to patient nonadherence with the immunosuppressive regimen. Patients need to know that they can die or be disabled as a consequence of a severe rejection episode and that regular medication adherence is of prime importance. Other than this, patient recognition of the signs and symptoms of heart failure (usually not a problem in patients who have all had advanced heart failure before transplant) and of possible infectious complications is important to stress.

V. Patient Safety and Quality Measures

A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

It is appropriate to follow immunosuppressive drug levels very carefully for a time after a rejection episode and not let them drop to even near subtherapeutic ranges.

VI. What's the Evidence for Specific Management and Treatment Recommendations?

"The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. Task force 2: Immunosuppression and rejection". J Heart Lung Transplant. vol. 29. 2010. pp. 914-956.

Pham, MX, Teuteberg, JJ, Kfoury, AG. "Gene-expression profiling for rejection surveillance after cardiac transplantation". New Engl J Med. vol. 362. 2010. pp. 1890-1900.

DeVlaminck, I, Valantine, HA, Snyder, TM. "Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection". Sci Transl Med. vol. 6. 2014. pp. 241-8.

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