CASE REPORTS Cardiac Transplantation for Pediatric Giant Cell Myocarditis Bibhuti B. Das, MD,a Michael Recto, MD,a Christopher Johnsrude, MD,a Lisa Klein, MD,a Karen Orman, MD,b Lawrence Shoemaker, MD,c Michael Mitchell, MD,d and Erle H. Austin, MDd Giant cell myocarditis (GCM) is an organ-specific, autoimmune disease that infrequently affects children and generally has a more aggressive (often fatal) course than other forms of myocarditis. No data are available about the epidemiology of GCM in children. We describe a 13-year-old girl who presented with ventricular tachycardia and rapid hemodynamic deterioration that required extracorporeal membrane oxygenation (ECMO) as a bridge to heart transplantation. Histopathologic examination of the explanted heart revealed GCM. We review the demographic features, clinical course and post-transplant immunosuppressive therapy of all patients aged 19 years and younger reported to have had GCM. J Heart Lung Transplant 2006;25:474 – 8. Copyright © 2006 by the International Society for Heart and Lung Transplantation. The clinical course of giant cell myocarditis (GCM) is usually characterized by progressive congestive heart failure, frequently associated with refractory ventricular arrhythmia. The diagnosis of GCM cannot be established without myocardial biopsy. Right ventricular endomyocardial biopsy (EMB) with adequate sampling has high sensitivity in diagnosing GCM in patients with a fulminant clinical course and helps in early listing for cardiac transplantation, which is an effective treatment for GCM.1 Despite this, many patients often die before a donor heart is available.2 The use of mechanical circulatory support, such as extracorporeal membrane oxygenation (ECMO), a left ventricular assist device (LVAD) and a bi-ventricular assist device (BiVAD), may be required in patients with acute fulminant heart failure as a bridge to transplantation.3–5 The overall histologic recurrence rate of GCM in the transplanted heart is about 20% to 25%. Recurrences have been reported to occur from 3 weeks to 9 years after transplantation, with earlier presentation and aggressive character described commonly in younger patients. The only predictor of recurrence is pre-transplant use of mechanical circulatory support. Fortunately, allograft failure or death due to recurrence is rare in GCM. From the Divisions of aCardiology, bCritical Care and cNephrology, Department of Pediatrics, University of Louisville, Louisville, Kentucky; and dDepartment of Surgery, Division of Cardiothoracic Surgery, Kosair Children’s Hospital, University of Louisville, Louisville, Kentucky. Submitted August 14, 2005; revised November 3, 2005; accepted November 10, 2005. Reprint requests: Bibhuti B. Das, MD, Division of Cardiology, Department of Pediatrics, University of Louisville, 571 South Floyd Street, Suite 334, Louisville, KY 40202. Telephone: 502-852-3876. Fax: 502-852-3877. E-mail: bdas99@hotmail.com Copyright © 2006 by the International Society for Heart and Lung Transplantation. 1053-2498/06/$–see front matter. doi:10.1016/ j.healun.2005.11.444 474 Only 14 cases of idiopathic GCM have been described in patients aged 19 years or younger.1,3,4,6 –15 Currently, the optimal immunosuppressive regimen for GCM after transplantation is not known. We describe a case of idiopathic GCM in a 13-year-old girl presenting with polymorphic ventricular tachycardia and severe bi-ventricular dysfunction, who required ECMO support before successfully undergoing orthotopic heart transplantation. We discuss her immunosuppressive treatment and post-transplant surveillance biopsy results during the 30 days after heart transplantation, and provide a brief review of the published cases. CASE REPORT Clinical Data A 13-year-old white girl with a 5-day history of upper respiratory infection (URI) symptoms, presented to an outside hospital emergency room with wide complex tachycardia. She was initially treated with both amiodarone (two 150-mg intravenous bolus infusions) and lidocaine (75-mg intravenous bolus followed by continuous infusion). She was then cardioverted with 200 J and was transferred to our center for further management. On admission, she was hypotensive and lethargic and developed convulsions. Immediate endotracheal intubation with fluid resuscitation was necessary. While in the intensive care unit she developed incessant ventricular tachycardia, requiring multiple boluses of amiodarone and electrical cardioversions. Despite all measures, her rhythm deteriorated into persistent ventricular fibrillation requiring closed-chest cardiac massage, and she was then placed emergently on arteriovenous ECMO by cannulating the left femoral vessels. ECMO flow was limited from poor venous return and echocardiography demonstrated a dilated fibrillating left ventricle and an inter-atrial septum bulging from left to right. To decompress the left heart, improve venous return to the ECMO system, and minimize severe pulmonary venous hypertension, the patient was taken The Journal of Heart and Lung Transplantation Volume 25, Number 4 Das et al. emergently to the catheterization laboratory for bladeand-balloon atrial atrioseptostomy (BBAS). Initial hemodynamic measurements revealed a left atrial pressure of 32 mm Hg and a right atrial pressure of 12 mm Hg. BBAS was successfully performed with relief of left atrial hypertension. An additional ECMO venous cannula was then placed percutaneously via the internal jugular vein to further enhance venous return. After BBAS, left and right atrial pressures decreased to 16 mm Hg. Ventricular fibrillation persisted except for brief periods of sinus rhythm such that her circulation was entirely dependent on ECMO flow. She received gammaglobulin 1 g/kg/day for 2 days for a presumed diagnosis of myocarditis. Serial echocardiography performed over the next 3 days showed no improvement in systolic ventricular function, hence she was listed for urgent cardiac transplantation. 475 Figure 2. Photomicrograph of an explanted heart demonstrating infiltration of the myocardium mostly by mononuclear inflammatory cells, scattered eosinophils and multinucleated giant cells (arrows), and associated myofiber necrosis (hematoxylin– eosin stain). Past Medical, Family and Social History The patient had normal growth and development and an unremarkable prior medical history. She had no prior hospitalizations and no chronic illness. A maternal grandfather was diagnosed with scleroderma. She lived with an 8-year-old sibling and her mother, both of whom were healthy. Laboratory Tests Electrolytes, complete blood count and liver function tests were normal. Electrocardiogram (ECG) revealed polymorphic ventricular tachycardia (Figure 1). Evaluation for infectious etiologies of cardiomyopathy included negative antibody titer for enterovirus, measles, mumps, rubella, cytomegalovirus, hepatitis viruses (A, B, C) and human immunodeficiency virus. She had low-titer IgM for herpes simplex, but the serum polymerase chain reaction (PCR) was negative. She was reported to have had a positive rapid slide test (monospot) in the outside hospital, but the serology and PCR for Epstein–Barr virus were negative. Figure 1. Electrocardiogram tachycardia. showing polymorphic ventricular Management and Follow-up The initial plasma reactive antibody was very high (66%) requiring plasmapheresis (1.5 vol) and gammaglobulin (Cytogam)16 before orthotopic heart transplantation on Day 5 of hospitalization. Microscopic examination of the explanted heart showed extensive myocyte necrosis, diffuse infiltration with mononuclear cells, lymphocytes and multinucleated giant cells (Figure 2). Immunoperoxidase stains with CD68 and CD20 highlighted the macrophages and lymphocytes, respectively. Flow cytometry of the peripheral blood before immunoglobulin therapy showed T cells (56%) (CD4, 41%; CD8, 15%; CD4:CD8, 2:1) and B cells (41%) with polyclonal surface immunoglobulin light-chain expression (kappa:lambda chain ratio 3.4:1). Initial immunosuppressive therapy included methylprednisolone, tacrolimus (FK 506), mycophenolate mofetil (MMF) and daclizumab 1 mg/kg intravenously within 24 hours of transplantation, and every 2 weeks thereafter. On Day 1 post-transplant, the serum crossmatch with donor T cells was negative. The immediate post-transplantation course was complicated by oliguric acute renal failure. Tacrolimus trough level was maintained at a lower range of 5 to 6 ng/ml for the first week, and the MMF trough level was maintained at 2 to 3 ng/ml. Methylprednisolone was continued at 20 mg/kg/day for the first 3 days, and then decreased to 1 mg/kg every 12 hours for the next 4 days. She also received three daily doses of rabbit anti-thymocyte globulin (ATG) during Days 1 to 3 post-transplant. On Day 5 post-transplant, the initial right ventricular EMB revealed normal myocardium, without any signs of rejection. Tacrolimus and MMF were continued, but the methylprednisolone dose was decreased to 1.0 mg/kg/day. A second EMB performed 476 Das et al. The Journal of Heart and Lung Transplantation April 2006 Table 1. Summary of Demographic and Clinical Data in Patients Aged ⱕ19 Years with GCM Cases 110 211 312 413 56 67 79 81 93 1014 111 124 1322 1415 Age 6 wk 16 m 7y 10 y 11 y 12 y 15 y 16 y 17 y 17 y 18 y 18 y 19 y 19 y Gender M F F F F F M F M F M M F F Clinical presentation Sepsis, gastroenteritis NA CHF CHF, CHD Syncope, complete AV block, LV failure, LVAD Near-syncope, VT, cardiac arrest, ECMO LV failure, VT, LVAD CHF CHF, LVAD VT, SVT, CHF VT, CHF URI, LV failure, VT, LVAD CHF, history of epilepsy NA Associated disease — — — — — CVID — — — UC — — Myositis — Diagnosis Autopsy Autopsy Autopsy Autopsy Wedge biopsy EMB EMB Autopsy EMB Autopsy EMB EMB Autopsy EMB Outcome D D D D CTx CTx CTx D CTx, D D CTx CTx, D D CTx M, male; F, female; NA, not available; VT, ventricular tachycardia; SVT, supraventricular tachycardia; LV, left ventricle; AV, atrioventricular; CHD, congenital heart defect; URI, upper respiratory infection; CTx, cardiac transplant; D, death; CHF, congestive heart failure. Other abbreviations are mentioned in the text. on Day 12 post-transplant demonstrated focal, dense mononuclear cell infiltrate associated with myocyte injury (Grade II ISHLT rejection). There were no multinucleated giant cells or eosinophils seen. She was treated with pulse methylprednisolone (10 mg/kg/day) for 3 days and tacrolimus dose was increased to maintain a level of 10 to 15 ng/ml. The patient’s renal function gradually improved, although she required intermittent hemodialysis for 14 days. On Day 17 post-transplant, a third EMB showed resolving rejection and absence of giant cells. Hemodynamic findings remained normal. Methylprednisolone was then changed to prednisone, which was tapered over the course of 1 week to 20 mg/day. Serial echocardiography revealed normal bi-ventricular systolic function, without evidence of rejection. One month post-transplant, repeat EMB demonstrated mild perivascular lymphoid infiltrate without myocyte injury or necrosis (ISHLT Grade 1A). She was discharged home on Day 30 post-transplant while on the aforementioned triple-drug immunosuppressive therapy (tacrolimus level 13.6 ng/ml, MMF level 3.8 ng/ml) and routine post-transplant prophylaxis. DISCUSSION Giant cell myocarditis was first described in 1905.17 Most reported cases have occurred in adults. The multicenter GCM registry8 recorded 63 patients (age range 16 to 69 years), of whom 34 underwent heart transplantation at a median of 6 months after the onset of symptoms. Five patients (15%) died within 30 days after transplantation; 9 (26%) died during a mean follow-up period of 3.7 years. Giant cell myocarditis is a specific autoimmune disease with evidence of upregulated Th1 chemokines and is often associated with concurrent infection or other illness.18 Eighteen cases of GCM have been reported in patients aged ⱕ19 years Of these, 3 were associated with infections13,19 and 1 lacked adequate clinical and demographic data for further analysis.20 This information is outlined in Table 1 for the remaining 14 cases. Based on the summary (Table 1), three observations can be made with regard to pediatric GCM: (1) it presents acutely and follows a fulminant course; (2) there is a female predominance; and (3) disorders associated with altered immune function occur in 21% of these children.7,14 Fulminant cardiac failure in pediatric GCM has required mechanical cardiovascular support in most reported cases of survival. Of these 6 reported cases, 4 utilized LVAD and 2 used ECMO as a bridge to transplantation.3,4,6,9 Both patients who received ECMO (including the present case) had no evidence of rejection during the first 30 days after transplantation. Of the 4 who received a LVAD, 1 died on the day of transplantation due to bleeding,3 1 had recurrence of GCM at 3 weeks,6 and 2 had no recurrence during the initial 30 days.4,9 The optimal post-transplantation immunosuppressive treatment for GCM after transplant is not known. The GCM registry was designed to address this issue, but the lack of data precludes any specific recommendations currently (personal communication from Leslie Cooper, MD). Nevertheless, in children ⬍19 years of age, most reports document benefit from triple-drug immunosuppression (cyclosporine or tacrolimus, azathioprine or MMF, and corticosteroid) and augmented immunosuppression, including OKT3 (muromonab-CD3) or total lymphocyte irradiation in cases of recurrent refractory GCM.6,21 Table 2 summarizes the post-transplantation data reported from 5 children plus the present case. Based on these data, it is not possible to determine the optimal immunosuppressive therapy. Despite this, we The Journal of Heart and Lung Transplantation Volume 25, Number 4 Das et al. 477 Table 2. Clinical Data Post-transplantation in 6 Pediatric Cases With GCM Variables Recurrence Allograft rejection Catheter findings Immunosuppressive therapy Follow-up and outcome Singh et al6 In 3 wk, C replaced by FK 506 ⫹ pulse S; recovery for 10 wk, MMF replaced by R, TLI None after TLI up to 15 mo 3 wk LV dysfunction; normal after TLI ATGAM for first 5 days; FK 506, R, S Complete AV block Day 5, pacemaker ⫻ 2 wk; doing well; F/U 15 mo Laufs et al7 None in first 22 days Laruelle et al9 None Shields et al1 NA Davies et al4 None up to 6.25 years None None NA None NA Normal NA NA Present case None in first 30 days; 4 EMBs, performed on Days 5, 12, 17 and 30 Grade II ISHLT on post-CTx Day 12 Normal C-based triple therapy Doing well, F/U 22 days A, C, S A, C, S Doing well, F/U 2 mo NA ATG ⫹ S; C, A, S Death due to CAD at 6.25 y ATG for first 3 days FK 506, MMF, S Resolving ARF; discharged home on Day 30 C, cyclosporine; S, steroid; R, rapamycin; A, azathioprine; TLI, total lymphoid irradiation; NA, not available; F/U, follow-up; ARF, acute renal failure; CAD, coronary artery disease. All other abbreviations are cited in the text. believe such therapy should be individualized, and aggressive immunosuppression should be reserved for severely ill patients who do not respond to standard therapy. Long-term outcome of transplanted children with GCM should be considered guarded, even in the absence of rejection or GCM recurrence, because death due to post-transplant coronary artery disease was reported in such a case nearly 6 years after an uneventful post-transplant course.4 In summary, this report highlights several management strategies supported by the literature. ECMO or LVAD will likely be required as a bridge to cardiac transplantation in patients with severe congestive heart failure and ventricular arrhythmia. Aggressive posttransplant surveillance with frequent biopsies helps to determine the adequacy of immunosuppressive therapy. Due to the high rate of recurrence and difficulty discerning recurrence from rejection, we recommend, at minimum, triple-drug immunosuppressive therapy with slow tapering of corticosteroid. More data on the use of immunosuppressive agents in GCM patients after cardiac transplantation are needed to determine the optimal therapeutic approach. The authors thank Dr John J. Buchino, MD, Department of Pathology, Kosair Children’s Hospital, University of Louisville, for providing the photomicrograph. REFERENCES 1. Shields RC, Tazelaar HD, Berry GJ, Cooper LT. The role of right ventricular endomyocardial biopsy for idiopathic giant cell myocarditis. J Card Fail 2002;8:74 – 8. 2. Moloney ED, Egan JJ, Kelly P, Wood AE, Cooper LT. Transplantation for myocarditis: a controversy revisited. J Heart Lung Transplant (in press). 3. Brilakis ES, Olson LJ, Berry GJ, et al. Survival outcomes of patients with giant cell myocarditis bridged by ventricular assist devices. ASAIO J 2000;46:569 –72. 4. 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