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Patient Summary

A 58 year old woman with a history of non-ischemic cardiomyopathy s/p orthotopic heart transplantation in 2015 presented with worsening dyspnea upon exertion. Dyspnea in a post cardiac transplant brings forth a wide differential diagnosis spanning all the typical causes of dyspnea as well as causes more specific or common to the patient with a heart transplant. In this particular case, TTE showed newly reduced ejection fraction and valvular disease. Cell mediated rejection was considered highest on the differential and confirmed on endomyocardial biopsy. Given hemodynamic compromise with multiple foci of myocyte damage on biopsy, she was started on high dose steroids and anti-thymocyte globulin for treatment of rejection.  Early identification and management of cell mediated rejection is crucial to the survival of patients like ours. Final diagnosis: orthotopic heart transplantation rejection.

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Case Media – Orthotopic heart transplant rejection

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Episode Education

Pearls

1. New onset heart failure in a post cardiac transplant patient should raise concern for acute cardiac allograft rejection, as well as all the usual culprits in nontransplant patients.
   
2. Younger African American women and those with elevated HLA mismatches are key risk factors for cell mediated rejection.
   
3. Treatment for cell-mediated (i.e., T-Cell mediated) rejection includes steroids and antithymocyte immunoglobulin and regimens are based on the severity ofclinical and histologic features.
   
4. Though infrequent as an initial presentation of acute cellular rejection, new onset arrhythmias in a post cardiac transplant patient should raise concern for rejection as a possible etiology. 
   
5. Reversal of rejection should be verified with endomyocardial biopsy following treatment for rejection. The timing and frequency of biopsy will likely depend upon whether corticosteroids and/or antithymocyte therapy was utilized.

Notes – Cell mediated rejection and more!

1) What are some common complications of cardiac transplantation?

Common complications following cardiac transplantation can be divided into two major categories: graft-related complications and non-graft-related complications.

• Graft-related complications include:
  • Early graft dysfunction (EGD) – reversible and irreversible injury related to organ procurement and reperfusion. Remember it is common for transplant patients to require inotropic and vasopressor support coming off cardiopulmonary bypass. Furthermore, LV diastolic dysfunction is also common after transplantation usually reflecting reversible ischemia or reperfusion injury and normally resolves over days to weeks, depending on the severity of reperfusion.
    • Primary graft dysfunction (PGD) is a severe form of EGD that presents as a left, right or biventricular dysfunction occurring within the first 24 hours of transplantation for which there is no identifiable secondary cause (e.g. hyperacute rejection, prolonged ischemic time from massive intra-operative bleeding. The etiology is likely multifactorial including but not limited to reperfusion injury, the effect of donor brain death, and pre-existing donor heart disease.
  • Early RV dysfunction related to pulmonary vascular resistance and fluid shifts early post-transplant may be particularly challenging. The RV is exposed to similar reperfusion injury or ischemic insults as the LV and typically RV dysfunction post-transplant includes RV dilation, subsequent poor coaptation of the tricuspid valve and tricuspid regurgitation. The “untrained” donor RV has to overcome potentially increased afterload (due to increased pulmonary vascular resistance) in the recipient, and as has been covered in previous Cardionerds episodes, the RV systolic function is highly sensitive to changes in afterload.
  • Acute allograft rejection – either cellular-mediated rejection or antibody-mediated rejection, occurring due to the recipient’s immune system reacting against graft antigens (e.g., mainly, but not only, the human leukocyte antigen (HLA) mismatches). Hyperacute rejection is rare and commonly fatal complication of cardiac transplantation. It is mediated by preformed anti-donor antibodies and can lead to diffuse hemorrhage and thrombosis in the allograft. In the current era of panel-reactive antibody screening (PRA) where we screen for preformed anti-HLA recipient antibodies to donor lymphocytes, hyperacute rejection is rare but remains a possibility (especially in highly sensitized patients and/or depending on the technique of obtaining PRAs). See more below on antibody- and cell-mediated rejection.
  • Cardiac Allograft Vasculopathy – an important cause of morbidity and mortality late following heart transplant related to both immune- and nonimmune-mediated coronary injury causing accelerated atherosclerosis and fibroproliferation with diffuse intimal hyperplasia resulting in allograft ischemia. For a detailed discussion on CAV, enjoy Ep #69.
• Non-Graft-Related Complications
  • Infections – related both to nosocomial exposures and immunosuppression, the typical infectious agents and syndromes predictably vary according to time from transplant. Early following transplant, the recipient is particularly susceptible due to post-operative nosocomial exposures (e.g., surgical wound, vascular access, urinary catheter, etc) and high dose peri-transplant immunosuppression. As such, wound/line/urinary infections and infections involving fungal and multidrug resistant bacterial organisms are common in the early phase (<1 month). In the mid-term (1-6 months), pneumonia, UTIs, and viral infections (CMV, HSV, VZV) are common. In the late-term, after the first post-transplant year, opportunistic infections become less common, and the typical community-based pathogens predominate.
  • Acute and chronic renal injury – renal dysfunction is a common and important complication post-cardiac transplantation. Etiologies are varied and interrelated and include pre-transplant renal dysfunction, acute injury pre-operatively, calcineurin inhibitor toxicity, cardiorenal syndromes related to graft dysfunction, and chronic injury due to long-term metabolic complications (diabetes, hypertension).
  • Malignancies – major problem in transplant recipients with rising cumulative risk over time. Post-transplant cancer risk is related to both immunosuppression dulling the normal immune system’s cancer surveillance and viral triggers for carcinogenesis. Common malignancies include lung cancer (especially as a significant proportion of patients with ischemic cardiomyopathy have a history of tobacco use), skin cancer, lymphomas, and breast and colon cancer. Post-transplant lymphoproliferative disorder (PTLD) is an EBV-associated proliferation of B-lymphocytes that is typically related to the degree of immunosuppression.

2) What are acute cell mediated rejection and antibody mediated rejection?

• Acute cell mediated rejection (ACR) is a host T cell lymphocyte response directed towards allograft tissue, leading to T-cell mediated cytotoxicity of myocardial tissue. It can be seen anywhere from weeks to months after transplantation. Risk factors include younger donor and/or recipient age, African American ethnicity, and history of significant HLA mismatches.  
• Acute antibody mediated rejection (AMR) constitutes graft injury by circulating antibodies (immunoglobulin M or G) targeting antigens expressed by graft endothelial cells. Injury may be complement mediated or complement independent (e.g., by other inflammatory pathways within endothelial cells and/or by natural killer cells).

3) What are clinical manifestations of acute cell mediated rejection?

• Ideally, ACR is diagnosed prior to overt clinical manifestations from surveillance endomyocardial biopsies or Allomap testing (a blood test of gene-expression profiling of peripheral blood mononuclear cells used in select patients).
• Clinical manifestations of acute cell mediated rejection typically include symptoms of LV dysfunction including dyspnea, PND, orthopnea, palpitations, syncope or near-syncope. Signs of RV dysfunction causing right-sided congestion may include gastrointestinal symptoms such as nausea which could be a marker of hepatic congestion! Occasionally, patients can present with new onset atrial arrhythmias including atrial fibrillation or atrial flutter.
• Ultimately, cardiac transplant rejection is a form of myocarditis and so progressively severe forms may result in any of the manifestations of fulminant myocarditis including cardiogenic shock, atrial and ventricular arrhythmias, and conduction abnormalities. Thankfully, this is rare with modern immunosuppression and with routine rejection surveillance.

4) How is acute cell mediated rejection diagnosed and what are the histologic classifications?

• ACR is diagnosed via endomyocardial biopsy.
• Notably, there is wide interobserver variability in severity grading between pathologists and centers.
• Biopsy samples are graded histologically as follows:

Histological Grade	Interpretation
Grade 0R	Indicates no sign of cell mediated rejection.
Grade 1R	Represents mild cell mediated rejection with interstitial and/or perivascular infiltrate with up to one focus of myocyte damage.
Grade 2R	Represents moderate cell mediated rejection involving ≥2 foci of infiltrate with associated myocyte damage.
Grade 3R	Represents severe cell mediated rejection with diffuse infiltrate and multifocal myocytic damage, with or without edema, hemorrhage, or vasculitis.

5) How is acute cell mediated rejection treated?

• Treatment of ACR depends on the severity of rejection, as deemed both clinically and histologically.
• Clinical severity is determined by presence of hemodynamic instability (i.e., decrease in cardiac output, decrease in pulmonary artery oxygen saturation, elevated pulmonary capillary wedge pressure, symptoms of heart failure)
• Histologic severity is determined by the histologic grade as above.
• If there is ACR warranting immunosuppression escalation, serial endomyocardial biopsies are typically performed to verify resolution and guide further management.
• Anti-rejection therapy should typically be adjusted or discontinued if there is a documented infection with resolution of histologic rejection on subsequent biopsy.
• Antibiotic and antiviral prophylaxis is given with anti-rejection treatment (high-dose steroids +/- anti-thymocyte globulin)
• Treatment is (generally) as follows:
  • Grade 1R without hemodynamic compromise – generally does not warrant specific treatment.
  • Grade 1R w/ hemodynamic compromise – generally treated with high-dose corticosteroids or antibody therapy depending on the severity of hemodynamic compromise. If there is severe hemodynamic compromise, some centers will pursue more aggressive therapy with Grade 1R rejection including considering plasmapharesis.
  • Grade 2R without hemodynamic compromise – generally treated with a transient increase in the corticosteroid dose with subsequent return to the prior oral steroid dose. Select patients may even be treated as an outpatient if there is no hemodynamic compromise.
  • Severe or refractory rejection (Grade 2R w/ hemodynamic compromise, Grade 3R, or rejection unresponsive to corticosteroid therapy) – generally treated with pulse dose steroids with a slow taper as well as anti-thymocyte globulin (ATG). ATG is an infusion of horse or rabbit antibodies against human T cells to deflect a high immunologic burden. Other treatment options depending on the clinical situation include plasmapheresis, extracorpeal photopheresis (an apheresis and photodyamic therapy technique that uses 8-methoxy-psolaren and UV light to modulate T-cell therapy), and total lymphoid irradiation.

6) What is the surveillance schedule post cardiac transplantation for acute cell mediated rejection?

• Acute cell mediated rejection as mentioned above happens most frequently during the first three to six months after cardiac transplantation.
• A typical transplant center will perform endomyocardial biopsies weekly for the first four weeks after cardiac transplantation followed by biweekly for the next six weeks or so.
• Schedule switches slightly in that biopsies are then pursued monthly for the next three to four months before being switched to every three months until it has been a year since cardiac transplantation.
• This schedule does vary between transplant centers and it is common practice to pursue less invasive monitoring beyond the first few years after transplantation such as through peripheral blood gene expression profiling.

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References – Cell mediated rejection

1. Hamon D, Taleski J, Vaseghi M, Shivkumar K, Boyle NG. Arrhythmias in the Heart Transplant Patient. Arrhythm Electrophysiol Rev. 2014;3(3):149-155. doi:10.15420/aer.2014.3.3.149

2. Ramzy D, Rao V, Brahm J, Miriuka S, Delgado D, Ross HJ. Cardiac allograft vasculopathy: a review. Can J Surg. 2005;48(4):319-327.

3. Ludhwani, Dipesh. “Heart Transplantation Rejection – StatPearls – NCBI Bookshelf.” National Center for Biotechnology Information, https://www.ncbi.nlm.nih.gov/books/NBK537057/. Accessed 26 Jan. 2021.

4. Ingulli E. Mechanism of cellular rejection in transplantation. Pediatr Nephrol. 2010;25(1):61-74.

5. Potena, Luciano et al. “Complications of Cardiac Transplantation.” Current cardiology reports vol. 20,9 73. 10 Jul. 2018

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CardioNerds Case Report Production Team