Giant cell myocarditis (GCM) is an aggressive inflammatory myocardial disease. Immunosuppression is an effective treatment for some cases. However, the duration of action of agents such as muromonab CD3 is short and others such as the calcineurin inhibitors may lead to renal failure. Here we describe the outcome of a novel approach to treatment using rabbit anti-thymocyte globulin (RATG). A retrospective analysis of 6 patients treated with RATG for GCM was performed. Diagnosis was confirmed by endomyocardial biopsy, and RATG was administered with a high dose of corticosteroids. None of the patients had cytokine release syndrome or leukopenia, and 5 had thrombocytopenia (2 of them severe). Only 1 had a serious bleeding event that occurred after implantation of mechanical circulatory support. None developed impaired renal function after the treatment. Five were successfully discharged home with an increase in global left ventricular ejection fraction of 29%. Four are currently alive without recurrent disease, 1 of them after heart transplantation, with a mean follow-up of 970 days (423 to 1,875 days), left ventricular ejection fraction of 53%, and all in current New York Heart Association Classification class ≤II. Only 1 case had GCM recurrence. There were 2 deaths: one because of intracranial bleeding after mechanical circulatory support implantation and the other caused by primary graft dysfunction. In conclusion, patients with GCM can be successfully immunosuppressed with RATG and corticosteroids, thereby avoiding renal impairment. Early thrombocytopenia is the main adverse event. Larger cohorts of patients are necessary to compare the different immunosuppressant strategies available for GCM in a randomized fashion.
Rabbit anti-thymocyte globulin (RATG) is a preparation of rabbit polyclonal antibodies against human T cells. Its primary effects are depletion of peripheral T lymphocytes and suppression of the alloimmune response. RATG has been widely used as immunosuppressant for aplastic anemia and for prevention of rejection in bone marrow and renal transplantation. In heart transplantation, immunosuppressive induction with RATG is beneficial in patients at high risk of renal dysfunction with the intent to delay or avoid the use of a calcineurin inhibitor (CNI), or for patients at high risk of acute rejection. In our center, RATG is used systematically as induction immunosuppression for heart transplant patients. Additionally, T-cell suppression has been shown to prevent the progression of autoimmune myocarditis. Considering our experience with RATG in that field and that patients with giant cell myocarditis (GCM) may also benefit from the avoidance of the CNI nephrotoxic effect, we started to use RATG as our immunosuppressant of choice in combination with high dose of steroids for patients diagnosed with GCM. There are no previous reports with RATG as the elective immunosuppression treatment for GCM, although there is 1 case report of its use in combination with cyclosporine and extracorporeal membrane oxygenation support. Here we present our initial experience in the treatment of GCM with RATG.
Methods
We identified 6 cases of GCM treated with RATG at Harefield Hospital from 2008 to 2012. A retrospective analysis of their characteristics and follow-up was performed. GCM was diagnosed histopathologically by endomyocardial biopsy (EMB), characterized by a widespread diffuse or patchy inflammatory infiltrate of lymphocytes, histiocytes, and multinucleated giant cells with myocardial edema and myocyte necrosis in the absence of sarcoidosis or infection. Therapy was always started after histolopathologic diagnosis and consisted of 100 mg of RATG (Thymoglobulin; Sanofi, France) administered intravenously once daily during 3 consecutive days: 100 mg in 250 ml of normal saline or dextrose saline infused into a central vein at 10 to 50 ml/hour depending on patient’s hemodynamic tolerance. T-cell count was checked daily during the administration of RATG to confirm effectiveness. Simultaneously, a daily dose of 1 g of methylprednisolone was also administered intravenously during 3 consecutive days. The fourth-day oral prednisolone was prescribed at an initial dose of 1 mg/kg (maximum 70 mg) tapering 5 mg every day until reaching a baseline dose of 10 to 15 mg once a day, which was then maintained indefinitely. No other immunosuppressive agents were administered. If no contraindications were present, prophylactic therapy for Pneumocystis pneumonia and Cytomegalovirus was administered after starting RATG treatment (Co-trimoxazole and valganciclovir, respectively). Prophylaxis for steroid-induced osteoporosis with alendronate 70 mg once weekly was also prescribed. Thrombocytopenia was defined as platelet count <150 × 10 9 /L and severe thrombocytopenia as <50 × 10 9 /L. Normal serum creatinine level was defined as <120 μmol/L.
Continuous variables are presented as mean and range (minimum, maximum), and categorical variables are presented as percentage.
Results
Patients’ baseline characteristics are described in Table 1 . Their mean age was 37 years: 3 were men and 5 were Caucasian. Only 1 had a history of an autoimmune disease (hyperthyroidism). The mean interval from symptoms to medical presentation was 9 days, and the most frequent presentation was cardiogenic shock. The echocardiogram showed a mean left ventricular ejection fraction (LVEF) of 20%, and the left ventricle (LV) was dilated (LV end-diastolic diameter >55 mm) in 50% of the cases with a mean end-diastolic LV dimension of 54 mm. Five patients required inotropic support with one of the following: adrenaline, noradrenaline, dobutamine, milrinone, or levosimendan. Two were treated with >1 inotropic drug. All the cases presenting with cardiogenic shock required mechanical circulatory support (MCS). Three patients had episodes of nonsustained ventricular tachycardia (VT), sustained VT, or ventricular fibrillation during admission.
| 1 | 2 | 3 | 4 | 5 | 6 | |
|---|---|---|---|---|---|---|
| Gender | Male | Female | Female | Male | Male | Female |
| Age (Years) | 33 | 49 | 28 | 21 | 46 | 48 |
| Presentation | Cardiogenic Shock | Cardiogenic Shock | Cardiogenic Shock | Cardiogenic Shock | Acute HF | ST-segment elevation |
| Time symptoms-admission (days) | 4 | 7 | 5 | 2 | 28 | 9 |
| Presenting ECG | VT | AF | SR | SR | SR | SR |
| LVEF admission (%) | 23 | 29 | 8 | 18 | 15 | 28 |
| LVEF discharge (%) | 49 | 50 | 55 | 44 | 42 | |
| Inotropes | + | + | + | + | – | + |
| IAOBP | + | – | – | + | – | + |
| MCS | BIVAD | ECMO | HVAD+BIVAD | |||
| Thrombocytopenia post-RATG | 96 | 112 | 44 | 122 | No | 50 |
| Renal injury post-RATG | No | Yes | No | No | No | No |
| Transplant (Days) | 331 | 123 | ||||
| Death (Days) | 346 | 16 | ||||
| Recurrence | No | No | No | No | Yes | No |
| Survival (days) | 1875 | 346 | 1003 | 423 | 582 | 16 |
| Current NYHA | II | II | II | I |
Mean interval from admission to immunosuppression treatment was 4 days. After RATG, none of the patients had a cytokine release syndrome or significant decrease in white cell count. Five had thrombocytopenia, and in 3 of them, this was of mild or moderate grade. There were 2 cases of severe thrombocytopenia, with the lowest count on the fourth day after starting RATG and both cases during concomitant MCS. Only 1 had a hemorrhagic event (intracranial bleeding) that occurred after biventricular short-term MCS support implantation (BIVAD, Centrimag; Thoratec Corporation, California), with platelet count of 89 × 10 9 /L on that day.
Regarding the renal function, 5 had normal creatinine levels both on admission and at the time of discharge or death. There were no cases of worsening renal function at discharge compared with the admission values. One patient had creatinine levels >200 μmol/L at the moment when RATG was started: this improved but chronic mild impairment continued after discharge.
Five patients were discharged home after the episode with a mean LVEF of 48% and a mean global LVEF improvement of 29%. One patient had recurrence of GCM 3 months after the first episode, underwent heart transplantation 1 month later, had a second recurrence in the allograft 24 days after the surgery, and an episode of 1R cellular rejection 3 months after transplant. There was another case of transplantation performed electively 9 months after the GCM diagnoses because of progressive worsening heart failure, without biopsy or cardiac magnetic resonance (CMR) evidence of recurrent GCM. This patient had primary graft dysfunction requiring venoarterial extracorporeal membrane oxygenation support to wean off the cardiopulmonary bypass and subsequent BIVAD support (Centrimag; Thoratec Corporation). She died 14 days after transplantation. Another death occurred 16 days after admission because of intracranial bleeding and 10 days after the implantation of MCS (see Figure 1 ).
Four patients are currently alive, being frequently reviewed at Harefield Hospital with a mean follow-up of 970 days (423 to 1,875 days). None of them have reached normal values of left ventricular function, but they have all improved, and their last mean LVEF is 53%. Although symptomatic nonsustained VT episodes have been described in all the survivors, only 1 of them has met criteria for implantable cardioverter defibrillator implantation for primary prevention, but he has not experienced anydischarge. They are all in the New York Heart Association Classification functional class I or II, and one has given birth to a healthy baby 2.5 years after the GCM episode. They all continue to receive chronic heart failure disease-modifying treatment according to the standard European guidelines and individual tolerance. Long-term immunosuppression has been maintained with oral prednisolone: mean dose 10.5 mg prescribed in a single daily administration. No side effects secondary to the chronic corticosteroid therapy have occurred.
Repeated histologic analysis was only performed after RATG treatment in 1 of the cases with a new EMB ( Figure 2 ). Five patients had a CMR scan, with a mean time to the investigation of 137 days and showing typical pattern seen after GCM ( Figure 3 ).
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
