Continuing Education Activity

Heart transplantation (HTx) is a procedure performed in patients with end-stage heart failure (HF) who remain symptomatic despite appropriate medical therapy. Heart transplant rejection occurs when the recipient immune system reacts to the foreign antigens in the donor organ by mounting an immune response. Patients will present with signs and symptoms of heart failure such as shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, palpitations, syncope, etc. This activity illustrates the evaluation and management of heart transplantation rejection and explains the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Summarize the pathophysiology of heart transplantation rejection.
• Review the ISHLT ACR grading of heart transplantation rejection.
• Outline the evaluation of heart transplantation rejection.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients with heart transplantation rejection.

Introduction

Heart transplantation (HTx) is a procedure limited to patients with end-stage heart failure (HF) who remain symptomatic despite being on optimal medical and device therapy. Guidelines identifying potential HTx candidates were updated in 2016 by International Society for Heart and Lung Transplantation (ISHLT). Stringent selection criteria and immunosuppressive therapy post-transplantation have led to improved prognosis. Despite the progress and improved overall outcomes, heart transplantation rejection (HTR) remains the Achilles heel of transplantation. The manifestation of rejection can occur as early as intraoperatively to many years after transplant. The timing of HTR plays a significant role in establishing cause and diagnosis. Based on timings, HTR can either be due to early graft dysfunction, occurring within first 24 hours or late graft dysfunction developing weeks to years after transplantation.

Etiology

Etiology for HTR varies based on the onset of rejection.

• Early graft dysfunction can be primary or secondary

Primary graft dysfunction (PGD): Universally accepted standard definition for PGD is lacking. Presence of ventricular dysfunction causing cardiogenic shock and requiring circulatory support such as inotropes/mechanical support devices in the absence of recipient alloimmune response or other discernible causes is endorsed as PGD. Various factors implicated in the development of PGD are:

1. Pre-existing donor heart disease
2. Re-perfusion injury immediately post-transplant
3. Allograft injury occurring during organ retrieval, conservation and implantation.[1]

 Secondary graft dysfunction (SGD): SGD results from identifiable causes such as:

1. Hyperacute graft rejection
2. Increased pressure or volume load on the right ventricle
3. Undiagnosed recipient pulmonary hypertension 

• Late graft dysfunction includes

Acute allograft rejection which, can be cellular or antibody (humoral) mediated. Risk factors include younger patients, female donors or recipient, and increased HLA mismatches.[2]

Cardiac allograft vasculopathy (CAV). Risk factors include elevated cholesterol level, cytomegalovirus infection, insulin resistance, coronary heart disease in the donor, younger recipient, and history of acute rejection.

Other causes of allograft failure include recurrence of myocardial conditions such as amyloidosis, sarcoidosis, giant cell myocarditis, hereditary hemochromatosis and malignancy such as primary cardiac lymphoma.

Epidemiology

According to ISHLT, a total of 5,074 heart transplants were performed in 2015. Median survival for cardiac transplants performed between 1982 and June 2015 was 10.7 years for adult recipients and 16.1 years for pediatric recipients. Survival rates in adults post-transplant were 94.8%, 84.1% and 72.3% after 1, 5 and 10 years respectively. The rates of HTR have steadily declined with the use of immunosuppressive therapy. HTR rates after discharge to 1 year of follow-up have declined from 30.5% in 2004-2006 to 24.10% in 2010-2015.[3]

The incidence of PGD varies from 20-40%. A 6-year follow-up study published in 2018 reported PGD incidence of 31% in post-transplant patients.[4] A similar study published in 2011 disclosed PGD incidence rate of 23%.[5] Deaths due to acute allograft rejection reach up to 11% in the first three years after transplant. Nearly half of heart transplant recipients developing rejection after 7 years of transplantation have evidence of antibody-mediated rejection. The overall prevalence of CAV increases with time. CAV is the leading cause of death between 1 and 3 years after transplantation.[6] CAV accounts for 17% of death after 3 years.[7]

Pathophysiology

Primary Graft Dysfunction

The “ischemic time” defined from cross-clamping the donor heart to implantation in the recipient patient, subjects donor heart to various forms of insult. The effect of ischemic time on PGD depends on donor age [8]. The donor body experiences catecholamine stress during the time of brain death. This catecholamine surge results in increased oxygen demand subsequently causing myocardial ischemia and desensitization of myocardial beta-receptor transduction system leading to the activation of multiple proinflammatory mediators. Hypothermic storage prior to implantation slows down metabolic activity of allograft. Prolonged storage can lead to loss of normal aerobic metabolism resulting in an anaerobic switch and causing lactic acidosis. Further at the time of implantation, reperfusion of allograft enhances calcium overload contributing to myocardial stunning.

Secondary graft dysfunction resulting from hyperacute rejection is either due to ABO incompatibility or from pre-formed cytotoxic antibodies that direct their activities against significant histocompatibility (MHC) antigens on allograft. 

Acute Allograft Rejection (Cellular versus humoral mechanism)

Acute Cellular Rejection (ACR): Major and minor histocompatibility antigens are not expressed equally among all individuals; this increases the potential of such proteins to act as alloantigens and activate alloimmunity by stimulating cytotoxic T cells. T cells respond to these donor antigens either directly or indirectly based on the method of antigen presentation. T cells can either directly recognize donor MHC molecules on allograft or target when presented indirectly by recipient antigen-presenting cells (APC).[9] interleukin-2 (IL-2), tumor necrosis factor-beta (TNF-beta), and interferon-gamma (IFN-gamma), all act as significant mediators during rejection.

Acute Humoral/Antibody Rejection (AMR)

Antibody-mediated humoral rejection is poorly understood. The antibody reacts to donor MHC antigens (HLA-I and II) leading to capillary endothelial changes. The deposition of immunoglobulin and complements within myocardial capillary bed are detectable by immunofluorescence.[10]

CAV

Endothelial damage in CAV can be immune or non-immune mediated. Endothelial damage leads to mild intimal thickening before progressing to diffuse fibrous thickening of the intima.[11] More recent research has established the role of effector B-cells with CAV.[12]

Histopathology

ACR presents as a mononuclear inflammatory response infiltrating myocardial tissue with predominant lymphocytic cells. Immunohistologic assessment can confirm the presence of CD-4 and CD-8 positive T lymphocytes with high affinity to interleukin-2 receptors. Presence of increased intercellular adhesion molecules with high MHC-II expression on cardiac myocytes is present. These findings should be distinguished from Quilty effect, which carries no clinical significance. Quilty lesions extend to the endocardial surface and include significant B-lymphocytes distinguishing from acute cellular rejection.

AMR leads to intravascular macrophage accumulation with interstitial edema, hemorrhage and neutrophilic infiltration in and around capillaries.

The predominant feature of CAV is a diffuse, progressive thickening of the arterial intima that develops in both the epicardial and intramyocardial arteries of the transplanted heart.

Histological Grading

ISHLT ACR grading

• Grade 0 – No rejection
• Grade 1 R, mild – Interstitial and/or perivascular infiltrate with up to one focus of myocyte damage. (grade 1A, 1B and 2 in 1990 system)
• Grade 2 R, moderate – Two or more foci of infiltrates with associated myocyte damage.  (grade 3A in 1990 system).
• Grade 3 R, severe – Diffuse infiltrate with multifocal myocyte damage, with or without edema, hemorrhage, or vasculitis. (grade 3B and 4 in 1990 system).

Immunopathologic findings for Acute AMR

Positive immunofluorescent staining for C4d, C3d, and Anti HLA-DR or immunoperoxidase staining for C4d and CD68 (or C3d)

AMR grading

• Grade 0- Negative histologic and immunopathologic findings
• Grade 1- Presence of positive histologic and immunopathologic findings
• Grade 2- Presence of both histologic and immunopathologic findings
• Grade 3- Presence of severe histologic plus immunopathologic findings

History and Physical

All patients with a history of HTx should have a thorough history and physical exam performed. Medication history and immunosuppressant therapy compliance are requisite parts of the patient intake process. Development of new ventricular dysfunction systolic, diastolic or mixed should raise suspicion for transplant rejection. The timing of rejection can act as a clue to the diagnosis.

Patients most commonly present with orthopnea, shortness of breath,  paroxysmal nocturnal dyspnea, syncope, palpitations, nausea/loss of appetite, weight gain, edema, arrhythmias (atrial flutter), oliguria, and hypotension. The physical exam can reveal signs of heart failure such as elevated jugular venous pressure, extra sounds on auscultation and peripheral edema.

Evaluation

Presence of the above symptoms and signs should raise alarms for HTR. HTR commonly gets diagnosed during surveillance endomyocardial biopsies. Typically biopsies are performed every week for the first four weeks followed by every two weeks for the next six weeks, which is subsequently followed by monthly biopsies for three to four months and then every three months until the end of the first year. Routine myocardial biopsies after the first year have not shown superior benefits.[13] Chi NH et al. recommended event principle biopsies at the end of three years due to the low rate of rejection.[14] Diagnosis should be made based on the presence of above-mentioned histologic findings. Biopsy negative rejection is present in up to 20% of cases warranting use of noninvasive monitoring; this includes measurement of troponin, Doppler echocardiography; cardiac magnetic resonance imaging (MRI), imaging using radiolabeled lymphocytes, antimyosin antibodies or annexin-V.[15][16][17]. T2 weighted cardiac MRI has shown promise in detecting early myocardial edema.[18] Gene expression profiling has emerged as an alternative to endomyocardial biopsy. E-IMAGE study showed non-inferior and safe results with gene expression profiling compared to endomyocardial biopsy.[19] Histologic findings in AMR usually accompany serum antibodies directed against HLA class I and II allograft antigen. Presence of histologic evidence of AMR if present is diagnostic. In the absence of absent HLA antibodies, non-HLA antibodies such as anti-endothelial, anti-vimentin and anti-MCA/MICB also merit investigation.

During the first five years, in patients with normal kidney functions, surveillance for CAV is performed with annual coronary angiography. Annual dobutamine stress echocardiography for patients with significant kidney disease is necessary. After five years annual dobutamine stress echocardiography with or without coronary angiography should be done based on the risk status of the recipient. Intravascular ultrasound should be performed when angiographic evidence is insufficient. In comparison to coronary angiography, coronary CT angiography has offered a safer and equally accurate diagnostic approach for CAV.[20]

Treatment / Management

Treatment with immunosuppressant therapy post-transplant has significantly reduced rates of rejection. Immunosuppressive therapy usually consists of steroids, antiproliferative therapy such as cyclosporine, sirolimus/tacrolimus and antimetabolites like azathioprine, mycophenolate mofetil, and rapamycin. The thirty-fourth heart transplant consensus from the ISHLT registry reported a lower rejection rate when treated with tacrolimus-based immunosuppression compared to recipients receiving cyclosporine. Treatment strategy depends on the type of rejection

PGD is treated with high dose inotropes to improve ventricular function. Patients failing medical therapy benefit from mechanical circulatory support such as an intra-aortic balloon pump (IABP), extracorporeal membrane oxygenator (ECMO) or temporary ventricular assist device.

Hyperacute rejection is treatable with plasmapheresis, along with corticosteroids and intravenous immunoglobulin.

ACR

Treatment strategy usually involves oral or intravenous steroids, anti-thymocyte globulin, and murine monoclonal antibody OKT3. Steroids act by inhibiting the production of interleukin-1,2 and 6, TNF-alpha, and IFN-gamma. Anti-thymocyte globulin prepared from immunized rabbits or horse cause cell death by complement-mediated lysis. OKT3 is a murine monoclonal antibody that inhibits T-cell function by binding to CD-3 antigen. Selection amongst these options is dictated based on the hemodynamic status of the recipient and the histologic severity of rejection.

Hemodynamic compromise is defined by the presence of one or more of following

• Reduction in cardiac output (<4.0L/min) or cardiac index (<2.0L/min per m2)
• A decrease in pulmonary artery saturation (<50%)
• Elevation in the pulmonary artery to capillary wedge pressure (PCWP)

Histology-based treatment for ACR

1.) Recipients with Grade IR rejection (grade 1A,1B and 2 in 1990 system) do not require treatment unless hemodynamically compromised.[21] Low dose steroids are helpful in such cases.[22] For patients with hemodynamic compromise pulse dose steroids orally or intravenously have shown a significant response.

2.) Grade 2R rejection (grade 3A in 1990 system) is treated the same way as grade IR rejection with hemodynamic compromise. Oral pulse steroid (3-5mg/kg for 3-5 days) or 500-1000mg/day of IV methylprednisolone can be used.[23] Repeat biopsies are obtained weekly for two weeks to verify resolution. A repeat pulse dose steroid can be attempted in the event of persistent rejection.

3.) Grade 2R rejection with hemodynamic compromise, grade 3R rejection, and steroid-resistant rejection episodes are treated with either anti-thymocyte globulin or OKT3 antibodies. The usual dose of OKT3 is 5mg/day intravenously for 10 to 14 days. Cyclosporine and mycophenolate are continued at pretreatment doses if therapeutic levels have been achieved. Other options include switching immunosuppressive therapy from cyclosporine to tacrolimus. Recipients treated with OKT3 antibodies should have levels of CD3 positive cells checked before, and three to five days after initiation of therapy.

Antibiotic, antifungal, and antiviral prophylaxis are conventional adjunct therapies for patients treated with high-dose steroids or anti-lymphocyte therapy.

AMR

AMR is hemodynamically more severe compared to ACR and has an association with a worse prognosis. Improved outcomes with Plasmapheresis in combination with corticosteroids and anti-thymocyte globulin or OKT3 antibody have undergone study. Treatment with CD20 monoclonal antibody Rituximab has shown some promise.

Recurrent or resistant rejection despite two to three courses of OKT3 or anti-thymocyte globulin requires alternative approaches. These include photopheresis, total lymphoid irradiation, and immunosuppressive regimen changes.

Differential Diagnosis

1. Primary graft dysfunction
2. Secondary graft dysfunction
3. Acute allograft rejection
4. Cardiac allograft vasculopathy
5. Amyloidosis
6. Sarcoidosis
7. Giant cell myocarditis
8. Hereditary hemochromatosis
9. Lymphoproliferative disorders such as non-Hodgkin lymphoma

Prognosis

One year survival rate post-HTx is close to 90%. Median survival for patients receiving HTx has improved significantly. Patients requiring extracorporeal membrane oxygenation support before HTx have a worse prognosis. Acute allograft rejection is responsible for 10% of deaths within the first three years. The incidence of CAV increases steadily after transplantation. Malignancy is the most common cause of mortality beginning at 5 years post-HTx. About 2-4% of heart transplant recipients end up receiving repeat retransplantation. Overall outcomes after retransplantation are inferior compared to primary HTx.

Complications

1. Repeated endomyocardial biopsy can cause tricuspid valve regurgitation.[24]
2. Graft failure
3. Atrial arrhythmia
4. Lymphoproliferative malignancy
5. Cardiac allograft vasculopathy
6. Acute graft rejection
7. Increased risk of secondary infections. 
8. Serum sickness due to anti-thymocyte globulin
9. Acute myocardial infarction
10. Repeat heart transplantation
11. Death

Deterrence and Patient Education

It is important to stress the importance of regular follow up and medication compliance after a recent heart transplant. Patients should receive education about the risk and benefits of immunosuppressive therapy, including the potential for rejection despite using immunosuppressive therapy. Teaching patients about early symptoms and signs of rejection can help prevent dangerous consequences. Knowledge about the increased risk of atrial arrhythmia and lymphoproliferative disorder due to immunosuppressive therapy should be provided to all heart transplant patients.

Enhancing Healthcare Team Outcomes

Heart transplantation and post-transplant care are demanding and critical. It requires an interprofessional approach with the involvement of the patient, heart transplant cardiologist, a heart transplant surgeon, social worker, nursing staff, pharmacists, financial educators, dietary assistants, and physical therapist. The ISHLT guidelines recommend an interprofessional approach at all HTx centers. (Level-I) The an interprofessional approach has demonstrated improved chronic illness management.[25] Implementation of daily an interprofessional rounds has shown improvement in recovery time post-HTx.[26] Interprofessional physician and nursing staff involvement after a heart transplant is equally important. Increasing patient education and explaining the importance of surveillance biopsy along with medical compliance can improve overall outcomes in HTx patients.