A case of giant cell myocarditis mimicking cardiac sarcoidosis successfully maintained by prednisolone and tacrolimus

Abstract

A 45-year-old woman with no medical history underwent pacemaker implantation for a symptomatic complete atrioventricular block. On day 6, she noticed diplopia and then fever, general malaise, and elevation of serum creatinine kinase (CK). She was transferred to our hospital on day 21. Serum CK was elevated to 4543 IU/L, and echocardiography revealed a left ventricular ejection fraction of 43 %. We diagnosed her with giant cell myocarditis (GCM) via an emergent myocardial biopsy that revealed a proliferation of lymphocytes, eosinophils, and giant cells without granulomas. Initial treatment with high doses of intravenous methylprednisolone and immunoglobulin improved her symptoms in a few days, and prednisolone was given as follow-up treatment. CK was normalized in a week and a thinning of the interventricular septum mimicking cardiac sarcoidosis (CS) occurred. On day 38, we added a calcineurin inhibitor, tacrolimus, and maintained her with a combination of prednisolone and tacrolimus at a target dose of 10–15 ng/mL. Six months after the onset, there were no signs of relapse despite the persistent mild elevation of troponin I levels. We present a case of GCM mimicking CS successfully maintained by a combination of two immunosuppressive agents.

Learning objective

Recommended treatment for giant cell myocarditis (GCM), a potentially fatal disease, is a combination of three immunosuppressive agents. However, GCM shares many characteristics with cardiac sarcoidosis (CS), which is treated using prednisolone alone in many cases. Recent studies on GCM and CS suggest they are different spectrums of a common entity. Although they can clinically overlap, they have different progressive speeds and severities. We present a case of GCM mimicking CS successfully treated with a combination of two immunosuppressive agents.

Introduction

Giant cell myocarditis (GCM) is a rare fatal disease associated with acute heart failure, refractory ventricular arrhythmia, and atrioventricular block. Its recent treatment is a combination of three immunosuppressive agents similar to the maintenance treatment after heart transplantation. On the other hand, GCM shares a lot of pathological and morphological characteristics with cardiac sarcoidosis (CS), and it is often difficult to differentiate them [1], [2]. The present patient had slowly progressive GCM resembling CS that was treated by a combination of two immunosuppressive agents.

Case report

The patient is a 45-year-old woman with no remarkable medical or family history. On day 0, she complained of faintness, and her local doctor diagnosed her with a complete atrioventricular block (CAVB). At this time, the serum level of creatinine kinase (CK) and left ventricular wall motion on transthoracic echocardiography (TTE) were normal. A cardiac pacemaker was implanted on day 2. During hospitalization, she noticed diplopia on day 6, and after discharge, fever and general malaise gradually developed from day 8. On day 22, she was referred to our hospital by her local doctor.

On her arrival, physical examinations revealed no hypotension or hypoxia. There was no pitting edema although the jugular vein was distended. A chest X-ray revealed a cardiothoracic ratio of 51 % and no pulmonary congestion. The electrocardiogram showed a ventricular pacing rhythm and multiple monogenic non-sustained ventricular tachycardia (VT). There was no obvious ST-T abnormality. Laboratory evaluations showed elevations of cardiac and liver enzymes (CK 4543 U/L, troponin I 9420 pg/mL, aspartate aminotransferase 300 U/L, alanine aminotransferase 193 U/L), brain natriuretic peptide (1108 pg/mL), C-reactive protein (4.58 mg/dL), and soluble interleukin-2 receptor (746 U/mL). There was no abnormality in renal and thyroid functions, angiotensin-converting enzyme (11.0 U/L), and autoantibodies, including anti-neutrophil cytoplasmic antibodies. TTE revealed global systolic dysfunction with a left ventricular ejection fraction of 43 % and severe mitral regurgitation without intraventricular septal (IVS) thinning. Thoracoabdominal-pelvic computed tomography (CT) on admission showed old inflammatory changes in the right middle and left lower lobes, but no significant lymph node enlargement, including hilar lymph nodes. Acute myocarditis was suspected, and emergency cardiac catheterization and endocardial biopsy were performed. A right heart catheterization revealed Forrester's subset IV (pulmonary artery wedge pressure of 18 mmHg, and cardiac index by thermodilution method of 2.04 L/min/m²). The frozen section of an endomyocardial biopsy (EMB) specimen showed marked infiltration of lymphocytes, and we started a two-day course of intravenous immunoglobulin (50 g daily) and a three-day course of intravenous methylprednisolone (1000 mg daily) followed by daily intravenous soluble prednisolone (60 mg daily).

The biopsy specimens fixed using formalin and embedded in paraffin were ready on day 27 and clarified the infiltration of eosinophils, multinucleated giant cells, lymphocytes, as well as macrophages, and damage to the adjacent myocardium. But granuloma formation was not clear (Fig. 1). Ophthalmologic examinations found an upper and inner rotation disorder of her right eye, but no inferior rotation disorder, no pupillary irregularity, nor eyelid ptosis, suggesting a medial rectus muscle disorder rather than an oculomotor neuropathy. Head CT showed enlargement of the right medial rectus muscle. Neurologic examinations revealed normal manual muscle test (MMT), normal tendon reflexes, and no sensory deficits. On dermatological examination, there was no skin lesion. We diagnosed her with GCM rather than CS and increased the dose of soluble prednisolone to 100 mg/day, which was equivalent to 50 mg of oral prednisolone, 1.0 mg/kg/day for her, and switched to oral intake. Gallium scintigraphy performed on day 30 revealed no abnormal accumulation.

Fig. 1.

Endomyocardial biopsy (EMB) findings from the right ventricular septum. (A) EMB on admission revealed the infiltration of numerous inflammatory cells and multinucleated giant cells. This showed no existence of noncaseating epithelioid granuloma. The region in the rectangle is magnified in (B). (B) Infiltration of giant cells (white arrow), numerous eosinophils (black arrows), lymphocytes, and macrophages were seen in a high-power field. (C) EMB on day 37 revealed the disappearance of giant cells and eosinophils; however, the migration of lymphocytes persisted. (D) EMB on day 64 also revealed no noncaseating epithelioid granuloma. Hematoxylin and eosin staining was performed.

Her symptoms, including diplopia, disappeared, cardiac enzyme levels decreased sharply. While the treatment was effective, we considered that GCM required additional immunosuppression, and tacrolimus was added after the second EMB and adjusted to a target trough value of 10–15 ng/mL. The dose of prednisolone was reduced by 5 mg per week and maintained at 10 mg/day (Fig. 2). CAVB did not improve but sustained VT was controlled by d,l-sotalol subsequent to amiodarone. On day 67, cardiac resynchronization therapy with an implantable cardioverter defibrillator (CRT—D) was introduced after cardiac magnetic resonance imaging (MRI) and the third EMB. MRI revealed that the high signal in T2-weighted images and delayed enhancement by gadolinium were confined to the thin IVS (Fig. 3).

Fig. 2.

Clinical course and the adjustment of immunosuppressive medications. CK, creatinine kinase; TnI, troponin I; Tak, tacrolimus; IVIG, intravenous immunoglobulin; MRI, magnetic resonance imaging; EMB, endomyocardial biopsy; LVEF, left ventricle ejection fraction; PSL, prednisolone; mPSL, methylprednisolone; sPSL, soluble prednisolone; IVIG, intravenous immunoglobulin; PM, pacemaker; CRT-D, cardiac resynchronization therapy with a cardioverter defibrillator.

Fig. 3.

Morphological features and transitions. (A-1,2) Transthoracic echocardiography on day 22 (on admission) (A-1) and day 52 (A-2). The intraventricular septum (white arrows) in the left ventricle's long-axis image was thinning over time. (B-1) Cardiac magnetic resonance imaging on day 61 revealed a high signal from the middle to the outer ventricular septum in T2 enhancement. (B-2,3) With gadolinium enhancement, delayed enhancement was seen in the ventricular septum consistent with a high signal in T2 enhancement (white arrow).

EMB on days 37 and 64 revealed the disappearance of giant cells and eosinophils, and lymphocyte infiltration gradually became sparse without forming noncaseating epithelioid granuloma (Fig. 1). Although troponin I levels remained above the normal range (60–90 pg/mL), a third immunosuppressive drug (azathioprine or mycophenolate mofetil) was not added. She was discharged on day 83 with oral prednisolone and tacrolimus. Six months after the onset, there were no signs of relapse despite the persistent mild elevation of troponin I.

Discussion

GCM is characterized by foci resembling lymphocytic myocarditis, eosinophil infiltration, necrotic lesions, and giant cells [3], [4]. It is often fatal; however, previous reports indicated that GCM is sometimes difficult to diagnose and is often missed until heart transplantation or autopsy, due to its variable clinical presentation and overlap with other cardiovascular conditions [5]. In particular, GCM often mimics CS. They are both forms of myocarditis with immune abnormalities that share pathological and clinical features (e.g. lymphocyte-mediated inflammation that has an association with thymic tumors, giant cell infiltration, and coexistence with extracardiac sarcoid granulomas) and are hard to differentiate [2], [3]. In one report, tissue samples of 73 cases formerly diagnosed as GCM were reexamined, and sarcoid granulomas were found in 45 cases leading to the correct diagnosis of CS [1].

On the contrary, GCM and CS have different drug strategies and long-term outcomes. Nordenswan et al. compared the prognosis of GCM cases treated with prednisolone alone or the triple combination of prednisolone, azathioprine, and cyclosporine with the prognosis of CS cases treated with various combinations of prednisolone, azathioprine, cyclosporine, methotrexate, infliximab, and mofetil mycophenolate. The estimated 5-year event-free survival was 27 % (95 % CI: 10 %–45 %) in GCM and 77 % (95 % CI: 72 %–82 %) in CS [2]. Bang et al. suggested that the use of immunosuppressive therapy for GCM typically involves corticosteroids and at least 1 or 2 additional immunosuppressive agents–cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, or, as an alternative, cyclosporine, and anti-thymocyte globulin or alemtuzumab [5]. Ekström et al. also suggested that patients with GCM who received triple immunosuppressive therapy with prednisolone, cyclosporine, and azathioprine were associated with a borderline reduction in the hazard of events compared with any other immunosuppressive therapy (p-value = 0.051); therefore, the use of three immunosuppressive drugs might be effective [6].

On the other hand, infection, represented by cytomegalovirus, is a major cause of morbidity and mortality in patients receiving triple immunosuppressive therapy, as shown in patients undergoing heart transplantation [7]. In addition, anti-infective therapies for patients treated with multiple immunosuppressants are challenging because of the significant incidence of drug toxicity and the high potential for drug interactions [8]. In the treatment of GCM, this is a critical issue.

This case raises the question of whether GCM can be clearly distinguished from CS and how immunosuppressive therapy should be modified for GCM cases mimicking CS. This was a case of GCM that progressed relatively slowly. The patient presented with CAVB without LV dysfunction and survived for three weeks without any immunosuppressive therapy despite the gradual elevation of CK. This clinical course was similar to that of a reported case of GCM that was controlled using prednisolone and ciclosporin [9]. After the successful initial treatment by methylprednisolone and intravenous immunoglobulin therapies to control acute myocarditis, the histological diagnosis of GCM by the first EMB, and the confirmation of the disappearance of giant cells and eosinophils by the second EMB, we only added tacrolimus to oral prednisolone, considering the risk of infection and drug interactions. The combination of methylprednisolone, intravenous immunoglobulin, prednisolone, and tacrolimus was reported to be effective in controlling the acute phase of GCM [10]. In our case, the third EMB after introducing tacrolimus revealed no eosinophils or giant cells, and no exacerbation of lymphocyte infiltration compared to the second one. Prednisolone and tacrolimus had been continued for more than 6 months by now, and there were no symptoms or signs of relapse in the outpatient clinic. This is the first case of slowly progressive GCM morphologically mimicking CS that was successfully controlled using maintenance therapy with tacrolimus and prednisolone.

Patient permission/consent statement

Written informed consent on the publication of her clinical details was obtained.

Declaration of competing interest

The authors declare no conflicts of interest associated with this manuscript.