Heart transplantation in adults: Diagnosis of allograft rejection

INTRODUCTION — Despite the use of potent immunosuppressive agents, acute cellular rejection (ACR) and antibody-mediated rejection (AMR) remain important problems in heart transplantation.

This topic discusses the clinical manifestations and diagnosis of acute cardiac allograft rejection. The treatment of ACR and AMR is discussed separately. (See "Heart transplantation in adults: Treatment of rejection".)

INCIDENCE — The incidence of rejection after transplantation influences the surveillance schedule for rejection. The incidence of each type of rejection after transplantation is as follows:

●Acute cellular rejection – ACR is a common problem after heart transplantation, particularly during the first three to six months after transplantation:

•In a study that examined the incidence of ACR after discharge from transplantation surgery to one year, the incidence of moderate to severe ACR was 12 percent [1]. However, by excluding mild rejection and AMR, this statistic underrepresents the totality of rejection.

•In another report that described the incidence of treated rejection in the first year after transplantation, the rate was 13 percent [2].

●Antibody-mediated rejection – AMR (noncellular, vascular, humoral) is a poorly understood and infrequently diagnosed process that nonetheless leads to morbidity and mortality [3,4]. There is wide variation in the reported incidence of AMR among centers; unlike ACR, testing for AMR is not routine in most transplant centers [5]. In a review of 587 patients who underwent testing for AMR and ACR at a single center, 19 percent of rejection episodes were due to AMR alone, 60 percent were due to ACR alone, and 23 percent had mixed AMR and ACR [6].

Non-human leukocyte antigen-mediated AMR is a rare form of AMR.

●Mixed rejection – Due to the incomplete detection of AMR, the incidence of mixed rejection is poorly understood. Mixed rejection is present in 23 percent of patients who have rejection [6].

RISK FACTORS — Although rejection can occur in any heart transplant recipient, the likelihood of a rejection episode is influenced by several donor and recipient factors:

●Younger recipient [7-9].

●Female recipient [7,9].

●Female donor [7-9].

●More human leukocyte antigen (HLA) mismatches between the donor and recipient [9-12].

●Recipient antibodies against donor antigens (ie, donor-specific antibodies) that develop prior to or after transplantation, which is the main risk factor for AMR.

●Recipient antibodies against non-HLA, such as minor histocompatibility antigen (MHC) class I (MICA) [13].

●Nonadherence to immunosuppressive therapy, which may be a factor contributing to high rates of rejection in adolescents and young adults [14,15].

CLINICAL MANIFESTATIONS — Acute rejection can be detected in otherwise asymptomatic patients who are undergoing routine surveillance testing, or it can manifest as signs and symptoms of cardiac dysfunction that range from mild heart failure (HF) and palpitations to cardiogenic shock and syncope. Infrequently, patients with ACR present with atrial arrhythmias [16,17]. Rarely, patients with rejection present with nonspecific extracardiac symptoms such as fever. The presentations of ACR and AMR are not distinct.

In otherwise asymptomatic patients who are undergoing biopsy with right heart catheterization, isolated hemodynamic abnormalities are an uncommon presentation of rejection.

TESTS FOR REJECTION

Endomyocardial biopsy — Endomyocardial biopsy is considered the gold-standard for the detection of rejection. However, the distribution of ACR in the allograft is thought to be heterogenous or multifocal, and thus, endomyocardial biopsy is subject to sampling error [18,19]. Though the distribution of AMR is likely more homogenous than the distribution in ACR, the detection of AMR requires specialized staining for complement deposition that is subject to variability. For both types of rejection, there is considerable variation in pathologists’ interpretation of the results. (See 'Pathologic diagnosis' below.)

●Biopsy procedure – Endomyocardial biopsies are generally performed in a specialized facility, either a cardiac catheterization laboratory or a dedicated biopsy suite. Vascular access is obtained through the right internal jugular vein or, less commonly, through a femoral vein. In many programs, a right heart catheterization is performed and intracardiac pressures are recorded. Following right heart catheterization, a specialized cardiac bioptome similar to a bronchoscopic bioptome is then guided from the superior vena cava to the right atrium and across the tricuspid valve into the right ventricle (using fluoroscopy or, occasionally, echocardiography). (See "Endomyocardial biopsy".)

The bioptome is then used to obtain a minimum of three, and preferably four or more, evaluable specimens from the right ventricular septum [20]. Some samples may not be evaluable due to the presence of scar caused by previous biopsies. Most of the biopsy specimens are fixed immediately in 10 percent buffered formalin for light microscopy; tissue can also be frozen for immunohistochemical studies. Further details on specific tissue preparation are discussed elsewhere in this topic. (See 'Pathologic diagnosis' below.)

●Complications – The common complications of endomyocardial biopsy are discussed separately. (See "Endomyocardial biopsy", section on 'Complications'.)

Tricuspid regurgitation (TR) is a complication that can occur in cardiac transplant recipients, and its most likely cause is repeated passes of the bioptome across the tricuspid valve during surveillance and other biopsy procedures [21], though other causes of TR in patients after transplantation include right ventricular dilation, distortion of the tricuspid valve ring due to size mismatch between the donor and recipient, and pulmonary hypertension after transplantation. The reported prevalence of TR ranges from 47 to 98 percent and is moderate to severe in up to one-third of patients [21,22].

The evaluation and management of TR are discussed separately. (See "Etiology, clinical features, and evaluation of tricuspid regurgitation" and "Management and prognosis of tricuspid regurgitation".)

Gene expression profiling — Gene expression profiling (GEP) is a test designed to noninvasively detect ACR by quantifying the expression of genes from circulating mononuclear cells obtained from peripheral blood. The most common GEP test records the expression of eleven genes and reports a score between 0 to 40 points; grade 2 R rejection is more likely at higher scores. Three of the genes in this GEP test are sensitive to the dose of steroids; high-dose steroids may result in a false negative result [23]. GEP tests were designed to detect ACR but may have some ability to detect AMR. The clinical use of GEP is described elsewhere in this topic. (See 'Approaches to evaluating for rejection' below.)

The diagnostic characteristics of GEP testing for ACR and AMR include the following:

●Identifying acute cellular rejection – GEP testing was designed to detect ACR. In general, the most common GEP test has a high negative predictive value and specificity but a low positive predictive value and sensitivity:

•In a study including 107 patients who were at least six months posttransplantation, genes for the detection of ACR were selected and validated [23]. The outcome of the study was the ability of GEP to distinguish between grade 0 (termed "quiescence") and moderate to severe rejection (grade ≥3A in the 1990 system; classified as ≥2 R in the 2004 system). In the validation sample of patients who were more than one year after transplantation, a GEP score threshold of <30 points had a negative predictive value of 99.6 percent and a positive predictive value of 6.8 percent for moderate to severe ACR.

•In a subsequent study of the same GEP test described above but with a cutoff GEP score of ≥35 points to identify grade 2 R ACR, the sensitivity and specificity were 10 percent and 96 percent, respectively, while the negative predictive and positive predictive values were 98 and 3 percent, respectively [24].

●Identifying antibody-mediated rejection – The ability of GEP to detect AMR is not as well-studied compared with its ability to detect ACR. In a derivation study that included 55 patients with AMR and 55 patients without AMR, a panel of genes was selected to optimize detection of AMR from tissue obtained from endomyocardial biopsy. In the validation cohort of 27 cases of AMR and 71 controls, the diagnostic accuracy for each of the candidate transcripts ranged from an area under the curve of 0.80 to 0.86 [25]. Patients with AMR had evidence of endothelial activation, microcirculatory inflammation, and higher natural killer cell activity. These gene transcripts could identify the presence of AMR in endomyocardial biopsies and suggest the pathogenesis of AMR.

Donor-derived cell-free DNA — Donor-derived cell-free deoxyribonucleic acid (dd-CF DNA) is released from damaged donor heart cells and can be quantified relative to the amount of background circulating recipient cell-free DNA [25-27]. An increase in the percentage of dd-CF DNA in the blood indicates injury to the transplanted (ie, donor) heart that may be caused by ACR or AMR, as well as other forms of injury, such as cardiac allograft vasculopathy. The role of dd-CF DNA is described elsewhere in this topic. (See 'Approaches to evaluating for rejection' below.)

The accuracy of dd-CF DNA for the detection of ACR and AMR was reported in a large prospective study of 171 patients who had undergone transplantation at least seven days prior [28]. The study assessed the ability of dd-CF DNA to detect grade 2 R ACR or grade 1 AMR. The study reported the following:

●For the detection of ACR in patients who were at least 14 days posttransplantation, the sensitivity and specificity of dd-CF DNA were 83 and 82 percent, respectively, for the cutoff value of 0.25 percent dd-CF DNA.

●For the detection of AMR in similar patients, the sensitivity and specificity of dd-CF DNA were 88 and 82 percent, respectively, for the cutoff value of 0.25 percent dd-CF DNA. For either AMR or ACR and at the 0.25 percent cutoff, the sensitivity and specificity were 88 and 82 percent, respectively.

●Given the limitations of endomyocardial biopsy to detect ACR and AMR, the study also evaluated dd-CF DNA as the reference standard to assess the accuracy of endomyocardial biopsy. When dd-CF DNA ≥0.25 percent was used as the reference standard, the study found that endomyocardial biopsy had a sensitivity of 20 percent and specificity of 99 percent.

APPROACHES TO EVALUATING FOR REJECTION

Surveillance in asymptomatic patients — In asymptomatic patients who underwent cardiac transplantation in the last year, our approach to surveillance testing with endomyocardial biopsy and serologic testing is described in a table (table 1). This schedule may be modified to wean a patient from steroids more rapidly or in response to other significant changes in maintenance immunosuppression (eg, reduction of tacrolimus levels to prevent kidney injury).

Some programs continue routine surveillance testing (eg, biopsies or serologic testing) every three to four months in the second year. Surveillance biopsies are rarely conducted beyond two years, though surveillance in this period for some patients with significant risk factors for rejection may be reasonable. (See 'Risk factors' above.)

●Specifics of testing and interpretation – The details of testing and our approach to interpretation of test results are as follows:

•Endomyocardial biopsy – During each endomyocardial biopsy, we obtain samples to assess for ACR. In select patients (eg, history of donor-specific antibodies, past history of AMR), we assess for signs of AMR, though some programs routinely test for AMR. The diagnostic criteria for ACR and AMR are discussed elsewhere in this topic. (See 'Diagnosis' below.)

The description of the endomyocardial biopsy procedure is described elsewhere. (See "Endomyocardial biopsy", section on 'Technique'.)

•Serologic testing – The preferred test for surveillance of asymptomatic patients is determined by the time after transplantation (table 1):

-Two weeks to two months after transplantation – For asymptomatic patients between two weeks and two months after transplantation, we perform a donor-derived cell-free (dd-CF) DNA test. dd-CF DNA cannot be used earlier after transplantation due to the high levels of circulating donor DNA caused by the stresses of procurement and implantation. In contrast with gene expression profiling (GEP), dd-CF DNA test results are not influenced by high-dose steroids used in the months following transplantation. (See 'Donor-derived cell-free DNA' above and 'Gene expression profiling' above.)

-Between two months and twelve months after transplantation – For asymptomatic patients who require surveillance testing within 2 to 12 months after transplantation, we use a GEP test and a dd-CF DNA test.

-Beyond one year after transplantation – For asymptomatic patients who require surveillance testing 12 or more months after transplantation, we typically perform dd-CF DNA testing. ACR in this interval is rare, and dd-CF DNA testing can detect both ACR and AMR, while GEP can only detect ACR.

After obtaining serologic tests for rejection, we perform confirmatory biopsies based on the test results as follows:

-Simultaneous gene expression and cell free DNA test results – If a GEP test and dd-CF DNA are obtained simultaneously, the result of each test must be considered. If the dd-CF DNA result is positive, we obtain a biopsy regardless of the GEP result. If the dd-CF DNA result is negative and the GEP result is positive, the approach to performance of a biopsy is individualized and may be influenced by such factors as the severity and frequency of past episodes of rejection. If both tests are negative, we do not perform a biopsy. This approach is based on the diagnostic characteristics of these tests, as described elsewhere in this topic. (See 'Gene expression profiling' above and 'Donor-derived cell-free DNA' above.)

-Isolated gene expression profiling – If an isolated GEP test is negative, we do not perform an endomyocardial biopsy. If an isolated GEP test is positive, we typically obtain a biopsy. In patients who have two negative biopsies following elevated GEP test results, we do not obtain further biopsies based on GEP results and cease GEP testing. This approach is motivated by the high negative predictive value and low positive predictive value of GEP testing, which is discussed elsewhere in this topic. (See 'Gene expression profiling' above.)

-Isolated donor-derived cell-free DNA – In the presence of an isolated positive dd-CF DNA test, we obtain an endomyocardial biopsy, while a negative dd-CF DNA result does not require a follow-up biopsy. This approach is motived by the high diagnostic accuracy of the dd-CF DNA test, which is described elsewhere in this topic. (See 'Donor-derived cell-free DNA' above.)

●Evidence and rationale – The indication for rejection surveillance in the weeks and months early after transplantation is based on experience and potential for adverse outcomes caused by untreated allograft rejection. There is no true "gold standard" for the detection of ACR or AMR except pathologic examination. Endomyocardial biopsy is considered a standard for comparison but suffers from sampling variation and is invasive. (See 'Endomyocardial biopsy' above.)

The use of serologic tests as substitutes for endomyocardial biopsy is motivated by the noninvasive nature of these tests and reasonable correlation with endomyocardial biopsy results:

•Gene expression profiling – While GEP has been compared with endomyocardial biopsy in two noninferiority trials, these trials have methodologic flaws, and it is unclear how to interpret a noninferiority trial in which the diagnostic accuracy of the reference test (ie, endomyocardial biopsy) is not well-established:

-The Invasive Monitoring Attenuation through Gene Expression (IMAGE) trial was performed as a noninferiority comparison between a GEP test and routine biopsies for a composite primary outcome of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or retransplantation [29]. The 602 patients were enrolled six months to five years following transplantation (85 percent received transplantation more than one year prior to enrollment). A mandatory biopsy was performed for a GEP test score of 30 (increased to a threshold of 34 midtrial). There was no significant difference in two-year cumulative rates of the composite outcome between the GEP and routine biopsy groups (14.5 and 15.3 percent; hazard ratio 1.04, 95% CI 0.67-1.68). However, this result is consistent with as high as a 68 percent increase in risk using the GEP strategy. More broadly, the results of the trial highlight the uncertainty around the efficacy of rejection surveillance of any type.

-Early IMAGE was a single-center study that randomized 60 transplant patients from two to six months after transplant to either GEP or biopsy-guided therapy (30 patients in each group) [30,31]. It too was designed as a noninferiority comparison with the same primary composite endpoint as the original IMAGE trial. Early IMAGE also showed similar rates of the composite endpoint, though the study was not adequately powered to establish the noninferiority of GEP testing. The Early IMAGE study also showed that corticosteroids could be weaned during months 2 to 6 as effectively when guided by GEP as by biopsy.

•dd-CF DNA – dd-CF DNA has higher sensitivity and specificity compared with GEP but has not been studied as extensively as GEP. (See 'Gene expression profiling' above and 'Donor-derived cell-free DNA' above.)

•Other tests – Alternatives to testing for rejection with endomyocardial biopsy, GEP, and dd-CF DNA include high-sensitivity troponin, B-type natriuretic peptide, echocardiography, cardiovascular magnetic resonance imaging, and imaging of radiolabeled tracers (eg, lymphocytes, antimyosin antibodies, annexin-V) [32-42]. While such tests correlate with histologic evidence of rejection, they are not used for surveillance of rejection or to confirm the diagnosis of rejection.

Tests such as echocardiography and cardiac biomarkers are frequently used in the initial evaluation of patients with signs or symptoms of rejection to identify cardiac abnormalities that require further evaluation. The use of these tests in symptomatic patients is described elsewhere in this topic. (See 'Symptomatic patients' below.)

The schedule for surveillance testing is based on the higher incidence of ACR in the months following transplantation surgery. After the incidence of ACR declines, surveillance for rejection is less likely to identify significant rejection, and the practice of surveillance biopsies in asymptomatic patients beyond the first year is controversial (see 'Incidence' above):

•A study of the Cardiac Transplant Research Database found no benefits from surveillance biopsy beyond five years posttransplant [43].

•Evidence from the IMAGE study of subjects six months to five years posttransplant indicates that intermediate-term outcomes are similar between patients with asymptomatic and symptomatic rejection [29].

Symptomatic patients — In patients with any of the clinical manifestations of acute rejection, an initial evaluation is performed to assess the severity of suspected rejection (see 'Clinical manifestations' above). The initial evaluation typically includes:

●History and physical examination – The history and physical examination are focused on identifying any alterations to the immunosuppressive regimen, recent use of medications that may interact with immunosuppression, and the time course and nature of any HF, chest pain, or palpitations. Additionally, the examination should include an assessment for venous congestion (eg, elevated jugular venous pressure, leg edema), third heart sound, and signs of inadequate perfusion (eg, cool extremities).

●Laboratory tests – Patients suspected of having rejection should have an assessment of electrolytes, kidney function, liver function, cell counts, and coagulation studies. In most patients, we obtain high-sensitivity troponin and B-type natriuretic peptide levels to evaluate for signs of myocardial injury and as a noninvasive measure of cardiac filling pressures, respectively.

●Electrocardiogram – All patients suspected of rejection should have an electrocardiogram performed to evaluate for a change in rhythm or other signs of rejection (eg, loss of voltage).

●Echocardiography – Echocardiography is typically obtained to assess for significant changes in ventricular function and elevated filling pressures.

Based on the initial evaluation, we take the following steps:

●Patients with risk factors or evidence of cardiac abnormalities – In symptomatic patients with a history of alterations to immunosuppression, evidence of new cardiac abnormalities on initial testing, or whose symptoms are unexplained and suspicious for rejection, we typically perform an endomyocardial biopsy to assess for rejection. In these patients, a GEP test or a dd-CF DNA test are not substitutes for an endomyocardial biopsy.

In such patients, endomyocardial biopsy should be performed to assess for ACR and AMR.

●Patients without risk factors or signs of new cardiac abnormalities – In patients in whom the initial evaluation does not reveal a history of disrupted immunosuppression (eg, cessation, interaction with drugs that decrease immunosuppression levels), new signs of cardiac dysfunction, or reveals a noncardiac cause for symptoms (eg, pneumonia), further testing is individualized.

Other indications for testing — In patients who have changes to their immunosuppressive regimen (eg, dose reduction in tacrolimus or glucocorticoids, change from tacrolimus to sirolimus) or who have recovered from an episode of acute rejection, we typically perform an endomyocardial biopsy one to two weeks after the change in therapy or after the rejection event to assess for rejection [43]. In some patients with small changes in therapy or low-grade rejection, either a GEP test or a dd-CF DNA test is a reasonable alternative to endomyocardial biopsy.

Surveillance during the COVID-19 pandemic — As recommended by the International Society for Heart and Lung Transplantation, during the coronavirus disease 2019 (COVID-19) pandemic, for patients with stable allograft function and low risk of rejection (such as patients >3 months from transplant with no recent history of rejection, who are not sensitized and lack a positive cross match), routine surveillance biopsies are deferred as clinically appropriate until local resources and capacity allow [44]. For patients with moderate or high risk of rejection, the benefits of surveillance biopsies are weighed against the risks of exposure to the patient and health personnel and limitations of available resources.

DIAGNOSIS

Clinical diagnosis — In patients who have undergone heart transplantation, the presence of new HF symptoms, unexplained arrhythmias, objective decline in cardiac function, or hemodynamic signs of acute rejection (eg, elevated filling pressures) suggests the presence of acute rejection. In patients with any of these findings, an initial evaluation and endomyocardial biopsy are typically required to confirm the diagnosis; though empiric treatment (eg, intravenous solumedrol 500 to 1000 mg per day) is often initiated before confirmation with an endomyocardial biopsy.

Pathologic diagnosis — The diagnosis of rejection is confirmed by pathologic examination of myocardium sampled from an endomyocardial biopsy. The approach to testing for rejection is described elsewhere in this topic. (See 'Approaches to evaluating for rejection' above.)

The types of rejection that can be diagnosed and their criteria include:

Acute cellular rejection — ACR is formally diagnosed by light microscopy of hematoxylin- and eosin-stained specimens on endomyocardial tissue. Morphologically, ACR manifests as a mononuclear inflammatory response, predominantly lymphocytic, that infiltrates the myocardium. In more severe cases, granulocytes are also seen [20]. Severe rejection is typically accompanied by evidence of cardiac myocyte injury or necrosis.

Cardiac transplant biopsies have been graded for ACR according to the standardized International Society for Heart and Lung Transplantation (ISHLT) nomenclature, which was introduced in 1990 [45,46] and revised in 2004 [20]. We prefer to use the 2004 system:

●Grade 0 – No rejection

●Grade 1 R, mild – Interstitial and/or perivascular infiltrate with up to one focus of myocyte damage

●Grade 2 R, moderate – Two or more foci of infiltrate with associated myocyte damage

●Grade 3 R, severe – Diffuse infiltrate with multifocal myocyte damage, with or without edema, hemorrhage, or vasculitis

The 2004 nomenclature can be mapped to the 1990 nomenclature, which is in use at most centers (table 2).

Acute antibody-mediated (humoral) rejection — The diagnosis of AMR is based upon the following histologic features [5,20,47]:

●Light microscopy demonstrates myocardial capillary injury with intravascular macrophage accumulation. Other findings may include intravascular thrombi and interstitial edema, hemorrhage, and neutrophilic infiltration in and around the capillaries.

●Positive immunofluorescence or immunoperoxidase staining within the capillaries for immunoglobulins (eg, IgG, IgM, IgA), complement (C4d, C3d, and/or C1q), or CD68 staining of macrophages.

●The histologic findings are commonly accompanied by serum antibodies directed against the donor’s human leukocyte antigen (HLA) class I and II antigens (ie, donor-specific antibodies). Such antibodies may arise de novo after transplantation or be preformed due to other exposures that include transfusion, pregnancy, and previous transplantation [5,48].

If all three of these features are present, the patient is diagnosed with AMR.

In patients who have evidence of capillary injury and complement deposition by immunofluorescence but who do not have measurable HLA antibodies to the donor, rejection may be caused by non-HLA antibodies [5]. In such patients, repeating the donor-specific antibody assay may be helpful to identify donor-specific antibodies. Antibodies also may be formed against a variety of non-HLA, although the role of these antibodies in AMR is not well defined, and they are not routinely measured in the clinical setting [49,50].

A nomenclature for the severity of pathologic AMR (pAMR) was developed in 2013 by the ISHLT [51]:

●pAMR 0: Negative for pathologic AMR – Both histologic and immunopathologic studies are negative.

●pAMR 1: Histopathologic AMR alone – Histologic findings present and immunopathologic findings negative.

●pAMR 1: Immunopathologic AMR alone – Histologic findings negative and immunopathologic findings positive.

●pAMR 2: Pathologic AMR – Both histologic and immunopathologic findings are present.

●pAMR 3: Severe pathologic AMR – This category recognizes the rare cases of severe AMR with histopathologic findings of interstitial hemorrhage, capillary fragmentation, mixed inflammatory infiltrates, endothelial cell pyknosis, and/or karyorrhexis and marked edema. The experience of the group was that these cases are associated with profound hemodynamic dysfunction and poor clinical outcomes.

The treatment of AMR is discussed elsewhere. (See "Heart transplantation in adults: Treatment of rejection", section on 'Antibody-mediated rejection'.)

Nonrejection findings — There are several processes that can produce cellular infiltration in the cardiac allograft and must be distinguished from acute rejection. The 2004 ISHLT revision included the following biopsy descriptions of nonrejection findings [20]:

●Ischemic injury – Ischemic injury can be seen soon after transplantation (up to six weeks posttransplant) and in patients with graft injury after (related to allograft coronary disease). Perioperative ischemic damage can cause myocardial necrosis as a result of donor trauma with catecholamine excess, pressor therapy during acute care, ex vivo organ ischemia, or reperfusion injury. The histologic appearance of ischemic damage early after transplant usually includes myocyte necrosis out of proportion to the cellular infiltrate, which is predominantly polymorphonuclear rather than mononuclear [52]. Later ischemic injury is related to allograft coronary disease, which is also called transplant vasculopathy. (See "Heart transplantation: Clinical manifestations, diagnosis, and prognosis of cardiac allograft vasculopathy".)

●Quilty effect – The Quilty effect describes the presence of one or more dense subendocardial monomorphic lymphocytic infiltrates, so called because they were first seen in a patient of that name [53]. Quilty lesions differ from rejection in two respects: They extend to the endocardial surface of the heart, and they include a substantial proportion of B lymphocytes. Quilty lesions are felt to have no clinical significance.

●Infection – Opportunistic infections such as cytomegalovirus (CMV) and toxoplasma myocarditis can produce lymphocytic infiltration in the allograft myocardium. These infections can be distinguished from rejection by the presence of characteristic CMV inclusion bodies in the lymphocytes or toxoplasma organisms in the myocardium [54]. (See "Infection in the solid organ transplant recipient".)

●Lymphoproliferative disorder – Rarely, posttransplant lymphoproliferative disorders (PTLDs) involve the heart, with myocardial infiltration of atypical lymphocytes [55]. Most PTLDs are due to malignant transformation of B lymphocytes; immunohistologic evaluation can distinguish such infiltrates from the predominantly T cell infiltrates of rejection. In addition, Epstein-Barr virus gene expression in these cells can often be detected using in situ hybridization. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Heart transplant (The Basics)")

●Beyond the Basics topics (see "Patient education: Heart transplantation (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Risk factors – Rejection is more common early after transplant, though it can occur at any time. (See 'Incidence' above.)

Although rejection can occur in any heart transplant recipient, the likelihood of a rejection episode is influenced by the time after transplantation as well as several donor and recipient factors (see 'Risk factors' above):

•Younger recipient, female recipient, female donor.

•More human leukocyte antigen (HLA) mismatches between the donor and recipient, recipient antibodies against donor antigens (ie, donor-specific antibodies).

•Recipient antibodies against non-HLA, such as minor histocompatibility antigen (MHC) class I (MICA).

•Nonadherence to immunosuppressive therapy.

●Clinical manifestations – Acute rejection can be detected in otherwise asymptomatic patients who are undergoing routine surveillance testing, or it can manifest as signs and symptoms of cardiac dysfunction that range from mild heart failure (HF) and palpitations to cardiogenic shock and syncope.

In otherwise asymptomatic patients who are undergoing biopsy with right heart catheterization, isolated hemodynamic abnormalities are an uncommon presentation of rejection. (See 'Clinical manifestations' above.)

●Surveillance for rejection in asymptomatic patients – In asymptomatic patients who underwent cardiac transplantation in the last year, our approach to surveillance testing with endomyocardial biopsy and serologic testing is described in a table (table 1). This schedule may be modified to wean a patient from steroids more rapidly or in response to other significant changes in maintenance immunosuppression (eg, reduction of tacrolimus levels to prevent kidney injury). (See 'Surveillance in asymptomatic patients' above.)

Some programs continue routine surveillance testing (eg, biopsies or serologic testing) every three to four months in the second year. Surveillance biopsies are rarely conducted beyond two years, though surveillance in this period for some patients with significant risk factors for rejection may be reasonable. (See 'Risk factors' above.)

●Testing for rejection in symptomatic patients – In symptomatic patients with a history of alterations to immunosuppression, evidence of new cardiac abnormalities on initial testing, or whose symptoms are unexplained and suspicious for rejection, we typically perform an endomyocardial biopsy to assess for rejection. In these patients, a gene expression profiling (GEP) test or a donor-derived cell-free (dd-CF) DNA test are not substitutes for an endomyocardial biopsy. (See 'Symptomatic patients' above.)

●Other indications for rejection testing – In patients who have changes to their immunosuppressive regimen (eg, dose reduction in tacrolimus or glucocorticoids, change from tacrolimus to sirolimus) or who have recovered from an episode of acute rejection, we typically perform an endomyocardial biopsy one to two weeks after the change in therapy or after the rejection event to assess for rejection [43].

In some patients with small changes in therapy or low-grade rejection, either a GEP test or a dd-CF DNA test is a reasonable alternative to endomyocardial biopsy. (See 'Other indications for testing' above.)

●Diagnosis

•Clinical diagnosis – In patients who have undergone heart transplantation, the presence of new HF symptoms, unexplained arrhythmias, objective decline in cardiac function, or hemodynamic signs of acute rejection (eg, elevated filling pressures) suggest the presence of acute rejection. (See 'Clinical diagnosis' above.)

•Pathologic diagnosis – The diagnosis of rejection is confirmed by pathologic examination of myocardium sampled from an endomyocardial biopsy. The examination may reveal acute cellular rejection (ACR) (table 2), antibody-mediated rejection (AMR), or both. (See 'Acute cellular rejection' above and 'Acute antibody-mediated (humoral) rejection' above.)