A 24-year-old woman with a complex medical history that included idiopathic thrombocytopenic purpura requiring splenectomy and recent postpartum acute respiratory distress syndrome requiring five days of ventilatory support was transferred to our facility from a local hospital at three months postpartum in severe cardiogenic shock. She was found to have nonischemic cardiomyopathy which required emergent biventricular paracorporeal ventricular assist devices (Thoratec CentriMag, Thoratec Corp., Pleasanton, Calif, USA). After stabilization and recovery, she was listed as a UNOS status 1A (ABO, A-) for heart transplantation without detectable panel reactive antibodies (PRAs). Approximately two months subsequent to VAD placement, she underwent orthotopic heart transplantation with an HLA-compatible cadaveric heart (ABO, A+). She had a persistent postoperative coagulopathy requiring transfusion of multiple packed red blood cells, fresh frozen plasma, and platelets and eventual return to the operating room for washout and re-exploration within 24 hours of transplantation. Her retrospective cross-match was negative, and subsequent tests for donor-specific antibodies and anti-HLA circulating antibodies were negative using the Luminex solid-phase assays. She was tested for circulating antibodies multiple times throughout her care and during her final admission.
Her transplant course was complicated by multiple complications but most notably for recurrent severe infections mandating reduction in her immunosuppressive regimen. Her infections included severe genital wart outbreaks of the perineum requiring nine separate intraoperative fulgurations, as well as debridement of recurring perivulvar and peri-anal abscesses and fistula, CMV viremia and recurrent C. difficile diarrhea requiring oral vancomycin. Her medical complications included renal insufficiency, severe bifrontal chronic headaches requiring change in immunosuppression from tacrolimus to cyclosporine, recurrent supraventricular tachyarrhythmias with ablation therapy, antiphospholipid antibody syndrome requiring chronic warfarin anticoagulation and a thrombotic cerebrovascular accident without residual neurologic sequelae.
The patient's immunosuppressive regimen included tacrolimus, mycophenolate mofetil (MMF), and corticosteroids during the initial transplant period. Her steroids were weaned during the first three months and discontinued completely in the maintenance period because of the recurrent infections described above and her preoperative history of splenectomy. By fourteen months postoperatively, she was converted to cyclosporine. Her headaches resolved after the change in calcineurin inhibitor. For the last twelve months of her life, she was treated with two drug therapy, cyclosporin and MMF. Her cyclosporin dose was intermittently decreased when she presented with clinical infections. Her MMF dose was decreased during infections or episodes of neutropenia from 1000 mg twice a day to 500 mg twice a day but maintained at 1000 mg twice a day during her final 12 months. In her final week, her cyclosporine was reduced from 150 mg twice a day to 75 mg twice a day. Her trough cyclosporine levels were maintained at around 200 ng/mL in her final months but during periods of infection were allowed to drop below 100 ng/mL.
Despite the required changes in her immunosuppressive regimen, the patient had only one documented episode of mild cellular rejection diagnosed at biopsy in the first perioperative month. She gradually developed evidence for mild diastolic dysfunction over the first two years following transplantation. Based on left and right heart catheterization results and echocardiographic and biopsy results, there was concern that she was developing mild constrictive or restrictive physiology. Her ejection fraction gradually decreased from 70% in the first few months after transplantation to 50% at 29 months after-transplant. She showed no evidence of significant mitral or tricuspid regurgitation. Heart biopsies taken throughout her course and during the months that she developed cardiac dysfunction showed no evidence for cellular or humoral rejection. The evaluations included staining for C4d (complement product) and CD68 (a macrophage specific marker). She underwent two heart biopsies in her last nine months with the last being 4 months prior to her death. Again, both of these biopsies were negative for cellular and humoral rejection in the setting of worsening ventricular function. Left heart catheterization showed no evidence of coronary vasculopathy.
At approximately 29 months after transplantation, the patient was admitted for diarrhea, dehydration, emesis, and acute renal insufficiency. She responded well to rehydration; however, she experienced an episode of hypoxemia leading to complete heart block from which she was easily resuscitated but required intubation. A urine screen was positive for both temazepam and alprazolam, which the patient had been prescribed as an outpatient and the cause of her arrest was attributed to hypoxemia secondary to hypoventilation and sedation. She was subsequently noted to have right upper and left lower extremity swelling, and ultrasound revealed superficial venous thrombosis, despite continued Coumadin anticoagulation. A chest scan to rule out pulmonary embolism was performed and was negative. She became febrile and was placed on broad-spectrum antibiotics. On the day of her death, she developed recurrent third-degree heart block and ventricular tachycardia. Despite aggressive resuscitation efforts, she died that evening. An autopsy was performed, and although the initial gross evaluation failed to show the cause of her graft failure, histologic and pathologic myocardial sections eventually revealed severe but patchy cellular and antibody-mediated rejection. (Figures 1, 2(a), 2(b), and 3 show the pathologic findings of antibody-mediated rejection in the case described here.)