INTRODUCTION — Despite the use of potent immunosuppressive agents both immediately after cardiac transplantation and during long-term maintenance, acute rejection remains an important problem. The incidence of any rejection between discharge and one year has decreased from 30 percent for primary transplants in 2004 to 2006 to 25 percent in 2010 to 2011 [1]. Acute cellular rejection is most likely to occur in the first three to six months, with the incidence declining significantly after this time [2].
The diagnosis of acute cardiac allograft rejection, including the role of endomyocardial biopsy performed either routinely or because of suggestive symptoms and the role of newer noninvasive methods of surveillance, is discussed separately. (See "Heart transplantation in adults: Diagnosis of allograft rejection".)
ISHLT grading system — The endomyocardial biopsy is graded using the International Society for Heart and Lung Transplantation (ISHLT) nomenclature adopted in 1990 and revised in 2004 [3-5]. For acute cellular rejection [5]:
●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
Grade 1 R includes grades 1A, 1B, and 2 in the 1990 system; grade 2 R was grade 3A; and grade 3 R was grades 3B and 4. (See "Heart transplantation in adults: Diagnosis of allograft rejection", section on 'Acute cellular rejection'.)
DRUGS USED TO TREAT ACUTE CELLULAR REJECTION — The major treatment modalities for acute cellular (T cell-mediated) rejection are oral or intravenous corticosteroids, or antithymocyte globulin. The dose and duration of therapy are discussed below for the different types of rejection.
OKT3 (muromonab-CD3) was the first monoclonal antibody approved as a drug in humans, but it is no longer available for use internationally. Its manufacturer voluntarily withdrew it from the market in 2010, as use had markedly declined as a consequence of its numerous side effects with less toxic alternatives available.
Corticosteroids — The mechanism of action of steroids in reversing acute rejection is incompletely understood. The major immunosuppressive action of corticosteroids is to inhibit the synthesis of almost all known cytokines. Steroids appear to act by inducing the synthesis of IkBa, a protein that traps free nuclear factor kappa B, an activator of cytokine genes and mediator of the proinflammatory action of tumor necrosis factor [6,7]. High-dose “pulse” corticosteroids may more effectively impair cytokine generation.
In transplant rejection, steroids act in part by suppressing the production of interleukin-1 (IL-1) by macrophages. This in turn leads to diminished production of IL-2 by activated T cells, thereby lessening the entire cellular immune response [8-10]. Inhibition of IL-6, tumor necrosis factor alpha, and interferon gamma may also be important [11]. In addition, they induce lymphocytolysis in some animal species; it is not known if this occurs in humans.
Antithymocyte globulin — Antithymocyte globulin is prepared by immunizing rabbits (Thymoglobulin) or horses (ATGAM) with human lymphoid cells derived from the thymus or cultured B cell lines. Antithymocyte globulins reverse rejection through a variety of effects. Most important is cell death by complement-dependent lysis or Fc receptor-mediated lysis and opsonization [12,13].
Disadvantages of using such polyclonal antilymphocyte preparations include lot-to-lot variability, cumbersome production and purification, nonselective targeting of all lymphocytes, and the need to administer the medication via central venous access.
There are no comparative data of Thymoglobulin and ATGAM in heart transplant recipients. However, trials in renal transplant recipients suggest that Thymoglobulin is preferred because of a significant reduction in the rate of acute rejection and a significant increase in allograft survival. (See "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Patients at high risk of rejection'.)
CD3 count monitoring as a means to adjust antithymocyte globulin dose has been found to result in lower doses and reduced costs in renal transplantation patients [14] and limited data suggest this approach is also helpful in cardiac transplant patients [15].
Side effects — The side effects of both Thymoglobulin and ATGAM include allergic and immune reactions and increased susceptibility to infection, especially with cytomegalovirus (CMV) [16]:
●A serum sickness reaction, characterized by fever, chills, arthralgias, and, on occasion, frank arthritis, occurs in many patients during the initial infusion. However, anaphylactic reactions, including respiratory distress and hypotension, are exceedingly rare.
To minimize the allergic manifestations, patients are usually pretreated with a cocktail of corticosteroids, antihistamines, and antipyretics. In addition, some centers routinely screen for an allergic response to either drug by administering a skin test one hour prior to administering the full dose if the test is negative. Patients with known allergies to rabbits or horses should not receive Thymoglobulin or ATGAM, respectively.
●A pruritic skin rash (20 percent) and presumed antiplatelet antibody-induced thrombocytopenia of varying severity (50 percent) can occur late in the course [11,17]. An antibody-mediated leukopenia may also be seen.
●Antithymocyte globulins can induce both CMV and herpes infections. These infections are rarely life threatening, and can usually be avoided with prophylactic antiviral therapy [11]. (See "Prophylaxis of infections in solid organ transplantation", section on 'Cytomegalovirus'.)
Antithymocyte globulins do not generally induce a host antibody response to the rabbit or horse serum (in contrast to the response to the murine monoclonal antibody OKT3). As a result, there is a greater opportunity for successful readministration if necessary.
TREATMENT OPTIONS FOR ACUTE REJECTION — The type of therapy used to treat an acute rejection episode depends upon the histologic severity, the degree of hemodynamic compromise and/or symptoms, and the number of rejections immediately preceding the rejection to be treated.
Hemodynamic compromise — Hemodynamic compromise is defined as one or more of the following:
●A reduction in cardiac output (<4.0 L/min) or cardiac index (<2.0 L/min per m2).
●A decrease in pulmonary artery saturation (<50 percent).
●An elevation in pulmonary artery or pulmonary capillary wedge pressure.
In addition, the presence of new symptoms of profound fatigue or dyspnea (ie, heart failure symptoms) in association with cellular rejection has often been interpreted to represent hemodynamic compromise as well.
Therapy varies with the pathologic grade and the presence or absence of hemodynamic compromise. According to the revised 2004 International Society for Heart and Lung Transplantation (ISHLT) grading system, grade 1 R includes grades 1A, 1B, and 2 in the 1990 system; grade 2 R was grade 3A; and grade 3 R was grades 3B and 4 [5]. (See 'ISHLT grading system' above.)
Grade 1 R — Grade 1 R rejection (grades 1A, 1B, and 2 in the 1990 system) is generally not treated unless there is concomitant hemodynamic dysfunction since corticosteroid therapy does not increase the likelihood of resolution [18,19]. In one study of patients with focal moderate (grade 2 in the 1990 system) rejection, for example, resolution occurred in 85 percent of patients treated with corticosteroids compared to 87 percent of those who were not treated [19].
However, another report suggested that the outcome of grade 2 rejection, even late after transplantation, was not necessarily benign [20]. Grade 2 rejection was the strongest predictor of the development grade 3A (now grade 2 R) or higher rejection on a subsequent biopsy, with an odds ratio of 2.4 [20].
Therapy for mild or focal moderate rejection associated with hemodynamic compromise includes high-dose corticosteroids or antibody therapy, depending upon the severity of hemodynamic compromise. A typical regimen is to administer oral pulse prednisone (3 to 5 mg/kg for three to five days) in this setting [21]; an alternative is intravenous pulse methylprednisolone (500 to 1000 mg/day for three days) [22]. (See 'Grade 2 R without hemodynamic compromise' below.)
Grade 2 R without hemodynamic compromise — The primary therapy for grade 2 R rejection (grade 3A in the 1990 system (table 1)) not associated with hemodynamic dysfunction consists of a transient increase in the corticosteroid dose. A typical regimen is to administer oral pulse prednisone (3 to 5 mg/kg for three to five days) in this setting [21]; an alternative is intravenous pulse methylprednisolone (500 to 1000 mg/day for three days) [22].
The patient is generally returned to the oral steroid dose he or she was taking after the high-dose regimen is completed. Gradual steroid tapering has been recommended in the past but offers no clinical advantage. Cyclosporine or tacrolimus doses are only changed if the blood levels are subtherapeutic.
Repeat endomyocardial biopsies are typically obtained on a weekly basis for the subsequent two weeks after the high-dose steroids are given to verify histologic resolution of rejection. Approximately 80 to 85 percent of these rejection episodes respond to the initial corticosteroid regimen. Resolution of rejection was defined as a subsequent biopsy of grade 2 (single focus of dense mononuclear cell infiltrate with myocyte injury) or less in the 1990 system without hemodynamic compromise.
A second regimen of intravenous pulse methylprednisolone may be given for three days if the endomyocardial biopsy shows persistent rejection, but multiple other agents are being evaluated. These include antithymocyte globulin, photopheresis, switching from cyclosporine to tacrolimus, and addition of sirolimus. There is no consensus on the optimal approach.
The patient is returned to the usual regimen of routine surveillance biopsies once the rejection episode has resolved. Some centers use this opportunity to switch from cyclosporine to tacrolimus based immunosuppression (if the patient is not already on a tacrolimus maintenance regimen), while other centers consider the addition of sirolimus. There is no consensus on the optimal approach.
Severe or refractory rejection — Severe rejection is defined as grade 2 R rejection (grade 3A in the 1990 system) associated with hemodynamic compromise, grade 3 R rejection (grades 3B and 4 in the 1990 system), or rejection episodes that fail to respond to corticosteroids. Severe rejection is generally treated with antithymocyte globulin.
Calcineurin inhibitors and mycophenolate mofetil (or azathioprine) are continued at their pretreatment doses if therapeutic levels have been achieved. As an alternative, tacrolimus can be substituted for cyclosporine. Tacrolimus is increasingly used as the primary immunosuppressive. Intravenous methylprednisolone at a dose of 500 mg is given as premedication on day one in lieu of standard prednisone doses. Antihistamines and antipyretics are also given on day one.
This regimen reverses 80 to 95 percent of rejection episodes. Endomyocardial biopsies are usually obtained at the end of the course and then one week later to verify both resolution of rejection and the absence of recurrence. The patient is returned to the usual regimen of routine surveillance biopsies if these goals are achieved. The management of persistent rejection is discussed below. (See 'Resistant or recurrent rejection' below.)
Therapy for rejection should be modified or stopped prior to completion of the full course of antibody therapy if the patient has a documented infection with resolution of rejection on endomyocardial biopsy.
Antibiotic and antiviral prophylaxis — Antibiotic and antiviral prophylaxis should be given to any patient treated with high-dose steroids or antilymphocyte therapy. A typical regimen includes:
●Clotrimazole lozenges to prevent oral candidiasis.
●Acyclovir to prevent herpesvirus infections.
●Trimethoprim-sulfamethoxazole or, in patients allergic to sulfa drugs, aerosolized pentamidine to prevent Pneumocystis jirovecii (carinii) pneumonia.
Some centers also give ganciclovir as prophylaxis against CMV infection, particularly for treatment of rejection in the first year. (See "Prophylaxis of infections in solid organ transplantation".)
Acute antibody-mediated (humoral) rejection — In addition to a T cell-mediated cellular response, transplant rejection may be mediated by antibodies (eg, antiendothelial or anti-HLA antibodies). This form of rejection is also called humoral or vascular rejection. (See "Heart transplantation in adults: Diagnosis of allograft rejection", section on 'Acute antibody-mediated (humoral) rejection'.)
In the 2013 ISHLT working formulation, the criteria for pathologic diagnosis of acute antibody-mediated rejection (AMR) were updated [5,23,24]:
●On light microscopy, histologic criteria include intravascular-activated mononuclear cells described as macrophage accumulation that distends and fills vascular lumens as well as endothelial cells with large nuclei and expanded cytoplasmic projections that appear to narrow or occlude the lumens. Findings of severe antibody-mediated rejection include interstitial edema, hemorrhage, myocyte necrosis, capillary fragmentation, mixed inflammatory infiltrates, and endothelial cell pyknosis and/or karyorrhexis. Only intact myocardium should be evaluated.
●Recommendations for immunopathologic assessment of AMR, including antibody selection and interpretation, are presented in the working formulation.
•For paraffin section immunohistochemistry, C4d and CD68 are included in the primary/mandatory panel. The secondary/optional panel includes pan-T-cell CD3, pan-B-cell CD20, complement C3d, endothelial cell CD31 or CD34, complement regulatory proteins, and others.
•For frozen section immunofluorescence, C4d, C3d, and Anti-HLA-DR (used by some centers to identify capillary structures) are included in the primary/mandatory panel. The secondary/optional panel includes fibrin, immunoglobulin G and M, and others.
●The grade of pathologic AMR (pAMR) is defined by combined histologic and immunopathologic findings. If both histologic and immunopathologic studies are negative, the pAMR grade is 0. If there is either histopathologic AMR alone or immunopathologic AMR alone, the grade is 1. If both histologic and immunopathologic findings are present (without histologic evidence of severe AMR), the grade is 2 (pathologic AMR). If there are histologic findings of severe AMR and immunopathologic findings, the grade is 3 (severe pathologic AMR).
AMR often occurs during the first month after transplantation, in association with antidonor antibodies, and can occur as early as two to seven days, if the recipient is presensitized to donor HLA antigens, or as late as months to years after transplantation [23,25].
AMR is typically more severe hemodynamically than the more common T-cell mediated cellular rejection. Graft dysfunction is present in approximately two-thirds of early AMR episodes, with hemodynamic compromise (shock, hypotension, decreased cardiac output, and/or a rise pulmonary capillary wedge pressure) in approximately one-half of AMR episodes [23,26]. In comparison, graft dysfunction is uncommon (10 to 15 percent) with late episodes [23].
AMR is associated with a worse prognosis than cellular rejection, as illustrated in a review of 587 patients at a single center: 19 percent of rejection episodes were due to humoral rejection alone, 60 percent to cellular rejection alone, and 23 percent to mixed cellular and vascular rejection [25]. The following findings were noted in the patients with AMR:
●A significantly higher rate of overall mortality (64 versus 30 and 39 percent with cellular and mixed rejection).
●A significantly higher rate of graft loss due to acute rejection (15 versus 2.5 and 2 percent).
●A significantly higher rate of graft loss due to transplant vasculopathy than cellular rejection (15.7 versus 5.7 percent); the rate was also increased (15 percent) in patients with mixed rejection.
The optimal therapy of AMR is not well defined, and it is not clear whether treatment should only be initiated in those patients with graft dysfunction and histologic features of AMR listed above. A small study suggested that the outcome in patients with antibody-mediated rejection severe enough to produce hemodynamic compromise may be improved by plasmapheresis in combination with corticosteroids and antilymphocyte antibodies (antithymocyte globulin or OKT3) [27]. In this study, the administration of cyclophosphamide rather than azathioprine for maintenance therapy did not prevent further episodes of humoral rejection. (See 'Photopheresis' below.) Rituximab, a chimeric monoclonal antibody against CD20 that is found on the surface of B cells, is increasingly used in addition to the above therapies, to treat AMR [28-31].
RESISTANT OR RECURRENT REJECTION — The approach to resistant or recurrent acute rejection depends upon the clinical setting. Rebound rejection can occur shortly after antithymocyte globulin; these episodes can be treated with corticosteroids. If the patient fails to respond, then another course of antibody therapy can be given.
Alternative approaches can be used in the patient who has received two or three courses of antithymocyte globulin. These include photopheresis, total lymphoid irradiation, and changes in the maintenance immunosuppressive regimen. Several reports have emphasized the utility of photopheresis for reversal of recalcitrant rejection or reduction of the frequency of rejection, because it is often effective and has few side effects.
Photopheresis — Photopheresis, also called photochemotherapy, was first developed as immunotherapy for cutaneous T-cell lymphoma and has also been applied to the autoimmune diseases scleroderma and rheumatoid arthritis. It involves ex vivo separation of leukocytes from erythrocytes and exposure of the leukocytes to 8-methoxypsoralen and ultraviolet light. The leukocytes that are rapidly proliferating (such as T-cells responding to alloantigens) are preferentially damaged. The damaged cells are returned to the patient and presumably induce counterimmune responses such as T-cell vaccination. Photopheresis is usually performed twice per week for four weeks.
When given to reverse cardiac transplant rejection, photopheresis appears to be as effective as high-dose methylprednisolone without the side effects of corticosteroids [32]. Photopheresis has also been successful in several reports in reversing refractory rejection and in reducing the frequency of recurrence of rejection in patients who are frequent rejectors [32-34]. One report, for example, described four patients with refractory grade 3A to 4 cardiac allograft rejection [33]. Three patients showed complete histologic reversal of rejection after photopheresis on two successive days. Complete recovery was more gradual in the fourth patient, occurring after three two-day treatments.
Photopheresis may also have a role for prophylaxis against rejection when used in combination with other therapies. As an example, one study randomized 60 recipients of primary cardiac transplants to standard triple therapy consisting of cyclosporine, azathioprine, and prednisone, or triple therapy in conjunction with 24 photopheresis treatments [35]. After six months, the number of episodes of acute rejection per patient was significantly reduced by photopheresis compared to conventional therapy alone (0.91 versus 1.44) and significantly more patients in the photopheresis had no or only one rejection (82 versus 52 percent). There was no significant difference in survival at 6 and 12 months.
Total lymphoid irradiation — Total lymphoid irradiation (at a dose of 30 Gy) has been used to treat recalcitrant cardiac and renal transplant rejection [36,37]. Side effects include leukopenia and nausea. This technique is also limited by being costly, time consuming, and slow.
Changes in maintenance immunosuppression — Alternative immunosuppressive agents have shown some benefit in the reversal of recurrent or recalcitrant cardiac allograft rejection.
Methotrexate — Methotrexate (5 to 20 mg/week in divided doses) may reduce the frequency of recurrent rejection episodes [38,39]. It is inexpensive and the risk of infection does not appear to be increased. The major side effects are pancytopenia and nausea. (See "Use of methotrexate in the treatment of rheumatoid arthritis".)
Tacrolimus — Tacrolimus (FK506) has shown a modest benefit in a small number of patients who had recurrent or recalcitrant rejection despite therapy with cyclosporine-based regimens [40,41]. In a study of 21 patients with recurrent episodes of steroid-resistant rejection, conversion from cyclosporine to tacrolimus reduced the number of acute rejection episodes per patient and the incidence of acute rejection per 100 patient days; tacrolimus was more cost effective than OKT3 in hemodynamically stable patients and the outcomes were similar [41]. In contrast, when used for primary immunosuppression, tacrolimus showed no benefit compared to cyclosporine in terms of reducing the frequency of rejection episodes or improving survival [40].
A potential advantage of tacrolimus is that, compared to cyclosporine, it significantly decreases the propensity to form thrombus, which suggests that it may have a favorable impact on the development of vasculopathy [42]. (See "Heart transplantation in adults: Cardiac allograft vasculopathy pathogenesis and risk factors".)
Mycophenolate — Mycophenolate mofetil has shown some benefit in reversing or preventing rejection in a small number of cardiac transplant recipients in whom it was substituted for azathioprine [43]. In addition, a multicenter clinical trial comparing the efficacy of mycophenolate to azathioprine (both given with cyclosporine and corticosteroids) in 650 first heart transplant recipients found that, at one year, mycophenolate therapy was associated with significant reductions in mortality (6.2 versus 11.4 percent) and requirement for treatment of rejection (66 versus 74 percent) [44]. The benefit persisted at three years, as patients treated with mycophenolate had significantly lower rates of mortality or repeat transplantation (11.8 versus 18.3 percent) [45].
Support for these observations comes from registry data of 5600 heart transplant recipients, all of whom were treated with cyclosporine plus either azathioprine or mycophenolate [46]. Actuarial survival at three years was significantly higher in the 12 percent of patients treated with mycophenolate compared to those treated with azathioprine (91 versus 86 percent, adjusted relative risk 0.62).
Sirolimus — Sirolimus is an immunosuppressant that inhibits cellular proliferation in response to alloantigen stimulation. The efficacy of sirolimus as an alternative to azathioprine for the prevention of cardiac allograft rejection was evaluated in an open-label trial in 136 new heart transplant recipients [47]. Subjects were randomly assigned to azathioprine or to one of two doses of sirolimus (3 mg or 5 mg per day); all patients received cyclosporine and corticosteroids.
At six months, the proportion of patients who had experienced a grade 3A or greater rejection episode was significantly lower with either the 3 mg or 5 mg dose of sirolimus than with azathioprine (32 and 33 versus 57 percent). There was also a reduction in the development of transplant vasculopathy with sirolimus. (See "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy".)
Sirolimus was associated with an increased incidence of anemia, thrombocytopenia, hyperlipidemia, and abnormal renal function than azathioprine. Discontinuation of study drug was quite frequent by 12 months for both the 3 and 5 mg sirolimus doses and for azathioprine (44, 32, and 40 percent). Sirolimus was most often discontinued due to adverse reactions (primarily thrombocytopenia).
Everolimus — Everolimus is a derivative of sirolimus. In a multicenter clinical trial, 634 new heart transplant recipients were randomly assigned to azathioprine or one of two doses of everolimus (1.5 mg or 3.0 mg per day) in addition to cyclosporine and corticosteroids [48].
At one year, significantly more patients treated with azathioprine, compared to those treated with either 1.5 mg or 3.0 mg of everolimus, had reached the combined end point of grade 3A rejection (now called grade 2 R, moderate rejection), rejection associated with hemodynamic compromise, death, graft loss, or loss to follow-up (53, 42, and 32 percent, respectively). This difference was almost entirely due to a reduction in the incidence of a first episode of grade 3A rejection.
Everolimus treatment was also associated with a significant reduction in the severity of transplant vasculopathy as manifested by a significantly lower average increase in maximal intimal thickness at one year on intravascular ultrasonography (IVUS). However, IVUS was only performed in about one-third of patients who were not chosen randomly; impaired renal function was a common reason not to test, which means that the sickest patients were not evaluated [49]. (See "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy", section on 'Everolimus and sirolimus'.)
Side effects seen more often with everolimus than with azathioprine included increased serum creatinine concentration, hyperlipidemia, and thrombocytopenia. Viral infections, especially cytomegalovirus infection, were seen less often with everolimus than with azathioprine.
Everolimus was approved for clinical use in Europe in July 2003, but has not been approved in the United States. In November 2005, the Cardiovascular and Renal Drugs Advisory Committee of the Food and Drug Administration recommended against approval of everolimus for the prevention of cardiac transplant rejection until more information is available [49].
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●Basics topics (see "Patient education: Heart transplant (The Basics)")
●Beyond the Basics topics (see "Patient education: Heart transplantation (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS — We recommend the following approach to the treatment of acute cardiac allograft rejection. The regimen is related to the histologic severity of the rejection episode and the patient's hemodynamic status. (See 'ISHLT grading system' above.)
●Grade 1 R (grade 1A, 1B, or 2 in the 1990 system) cellular rejection episodes are not treated if the patient is hemodynamically stable. Concomitant hemodynamic compromise, as defined above, necessitates treatment with either high-dose corticosteroids or, for profound hemodynamic compromise, antithymocyte globulin. (See 'Hemodynamic compromise' above.)
A typical steroid regimen is to administer oral pulse prednisone (3 to 5 mg/kg for three to five days) or intravenous pulse methylprednisolone (500 to 1000 mg/day for three days). The patient is generally returned to the oral steroid dose he or she was taking after the high-dose regimen is completed. Gradual steroid tapering to the maintenance dose has been recommended in the past but offers no clinical advantage. Cyclosporine (or tacrolimus) doses are only changed if the blood levels are subtherapeutic. (See 'Grade 1 R' above.)
●Grade 2 R (previously called grade 3A) rejections without signs of hemodynamic compromise should be managed with oral or intravenous methylprednisolone. If two courses of therapy do not reverse the rejection, then antithymocyte globulin should be administered. (See 'Grade 2 R without hemodynamic compromise' above.)
Corticosteroid premedication with methylprednisolone (500 mg/day intravenously) is given on day one in lieu of the standard prednisone doses. Antihistamines and antipyretics are also given on day one.
Cyclosporine (or tacrolimus) and mycophenolate mofetil (or azathioprine) are continued at their pretreatment doses if therapeutic levels have been achieved. As an alternative, tacrolimus can be substituted for cyclosporine.
●Rejection episodes resistant to corticosteroids, grade 2 R rejections associated with hemodynamic compromise, and all grade 3 R rejections should be treated with antithymocyte globulin. (See 'Severe or refractory rejection' above.)
●Endomyocardial biopsy verification of reversal of rejection is generally obtained for all treated episodes of rejection (see 'Treatment options for acute rejection' above):
•For corticosteroids, a biopsy is generally obtained one week after the initial biopsy that showed rejection; a second biopsy should be performed one week later to verify that recurrence has not occurred.
•For antithymocyte globulin, the follow-up biopsies are typically obtained at the end of the course of therapy and then one week later.
●Therapy for rejection should be modified or stopped prior to completion of the full course if the patient has a documented infection with resolution of rejection on endomyocardial biopsy.
●For resistant or recurrent rejection, a course of intravenous methylprednisolone should be given, followed by another course of antibody therapy, if necessary. (See 'Resistant or recurrent rejection' above.)
For recalcitrant or frequently recurring rejection, the administration of photopheresis may be helpful. (See 'Photopheresis' above.)
●Antibody-mediated rejection (AMR) is often treated with a combination of plasmapheresis, intravenous gamma globulin, anti-thymocyte antibodies, and rituximab. (See 'Acute antibody-mediated (humoral) rejection' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Mariell Jessup, MD, who contributed to earlier versions of this topic review.
