Eosinophilic Myocarditis Associated With Chronic Eosinophilic Leukemia

Abstract

Background

Eosinophilic myocarditis (EM) is a rare, dangerous complication of eosinophil-predominant disease. Its presentation varies greatly, with detrimental consequences including arrhythmia, heart failure, and sudden cardiac death.

Case Summary

A 58-year-old woman with chronic eosinophilic leukemia presented with worsening dyspnea and was found to have EM and left ventricular apical thrombus based on characteristic imaging findings. She was started on a heparin drip, corticosteroids, imatinib, and furosemide. She did not experience complications of myocarditis while admitted, and biventricular function was preserved.

Discussion

There is a paucity of established guidelines regarding the diagnosis of EM. However, there may be a crucial role for imaging modalities in workup and diagnosis, one that may save patients from invasive procedures.

Take-Home Messages

This case highlights the utility of noninvasive imaging as well as the importance of early recognition and multidisciplinary management. Clinicians should consider EM as part of the differential diagnosis when managing patients with eosinophilia and signs of cardiomyopathy.

Graphical Abstract

History of Presentation

A 58-year-old woman presented with a 2-week history of progressively worsening dyspnea, poor appetite, and intermittent vision changes. Vital signs were notable for tachycardia, with a heart rate of 102 beats/min, mean arterial pressure of 71 mm Hg, and appropriate saturation on room air. Physical examination was notable for jugular venous distention and accessory muscle use to aid breathing. The patient had no known allergies, travel history, or recent infections leading up to this presentation.

Take-Home Messages

• •This case highlights the utility of noninvasive imaging in diagnosing life-threatening cardiovascular pathology.
• •When caring for patients with eosinophilia and signs of cardiomyopathy, consideration should be given to eosinophil myocarditis as a rare but deadly cause of symptoms.

Past Medical History

The patient's prior medical conditions included biopsy-confirmed chronic eosinophilic leukemia and moyamoya disease on warfarin therapy.

Differential Diagnosis

The initial differential diagnosis included acute heart failure, cardiogenic shock, acute coronary syndrome, myocarditis, and leukostasis.

Investigations

Initial laboratory tests were notable for high-sensitivity troponin level of 2,200 ng/L that peaked at 2,299 ng/L (reference range: 0-14 ng/L), B-type natriuretic peptide level of 1,224 pg/mL (reference range: 0-100 pg/mL), international normalized ratio of 6.0 (reference range: 0.9-1.1), and white blood cell count of 83.9 × 10³/μL (reference range: 3.8-10.8 × 10³/μL). Differential was notable for 85% eosinophils (reference range: 0%-8%). Results of a bone marrow biopsy performed 2 weeks before this presentation were obtained from the hospital at which the patient had previously sought care; these were consistent with a recent diagnosis of chronic eosinophilic leukemia, and she had not started chemotherapy. Biopsy had been performed because of subacute intermittent left hemianopsia and concern for hyperviscosity. PDGFRA and FIP1L1 were not detected on fluorescence in situ hybridization analysis.

Head computed tomography (CT) and magnetic resonance imaging (MRI) were negative for hemorrhage or stroke but showed an incidental subdural hygroma that was not thought to contribute to her symptom of blurry vision; instead, this symptom was attributed to possible end-organ damage from hypereosinophilia. Electrocardiogram showed normal sinus rhythm without ST-segment changes (Figure 1). Repeat electrocardiograms were unchanged compared with the initial study. Transthoracic echocardiogram (TTE) demonstrated preserved left ventricular systolic function with severe apical hypertrophy and a layered apical mass concerning for thrombus (Figure 2). Cardiac MRI was performed on a 450-W 1.5-T scanner (Optima, GE Healthcare) and showed diffuse subendocardial late gadolinium enhancement and extensive layering apical thrombus at the apex and extending along the mid to basal anterior wall and midlateral wall (Figures 3 and 4; additional images are available as Supplemental Figures 1 to 5). The calculated left ventricular ejection fraction was 47%, with an estimated cardiac output of 3.8 L/min and a cardiac index of 2.1 L/min/m². T1-weighted mapping was performed using a modified Look-Locker inversion recovery sequence and showed elevated myocardial T1 time measuring 1,134 ms. T2-weighted mapping was overall nondiagnostic. Myocardial T2∗ time was 47 ms and was negative for iron overload. These findings, in conjunction with the overall flat rate of rise in troponin, were consistent with eosinophilic myocarditis (EM), as opposed to acute occlusive coronary disease. Right heart catheterization with biopsy was planned for when the patient became euvolemic but was ultimately deferred owing to high risk of perforation.

Figure 1.

Electrocardiogram Obtained on the Day of Admission

Electrocardiogram demonstrating normal sinus rhythm.

Figure 2.

2-Dimensional Transthoracic Echocardiogram

Transthoracic echocardiogram demonstrating severe apical hypertrophy and a layered apical mass highly concerning for thrombus formation, characteristic of eosinophilic myocarditis.

Figure 3.

Early Delayed Cardiac Magnetic Resonance Imaging Findings

Phase-sensitive inversion-recovery early delayed 4-, 2-, and 3-chamber cardiac magnetic resonance imaging (from left to right) with an inversion time of 600 ms demonstrating left ventricular apical thrombus (white star) extending along the anterolateral, anterior, and inferior walls of the myocardium (red arrows).

Figure 4.

Late Delayed Cardiac Magnetic Resonance Imaging Findings

Phase-sensitive inversion-recovery late delayed gadolinium-enhancement cardiac magnetic resonance imaging sequence demonstrating subendocardial late gadolinium enhancement (red arrows), indicative of fibrosis and a dark apical thrombus (white stars).

Management

The patient was then evaluated by the advanced heart failure and bone marrow transplantation teams. Anticoagulation with a heparin drip was initiated. She was started on oral prednisone 1 mg/kg/d (total 75 mg/d) to decrease inflammation, hydroxyurea (2,000 mg every 8 h) and imatinib (400 mg/d) for hypereosinophilia, and judicious diuresis with intravenous furosemide 20 mg/d to meet a goal net negative of 1 to 2 L/d. With these treatments, biventricular function remained preserved, and she did not experience life-threatening arrhythmias or fulminant heart failure. She was eventually transitioned from the heparin drip to apixaban with a plan for long-term anticoagulation; she was not a candidate for further warfarin therapy owing to interactions with imatinib. Serial limited TTEs continued to demonstrate presence of the apical thrombus, with size measured at 12 × 16 mm on the last TTE obtained (Figure 5). Prednisone was slowly tapered but had to be intermittently increased because of increases in absolute eosinophil count (Figure 6).

Figure 5.

Repeat 2-Dimensional Transthoracic Echocardiogram

Repeat limited 2-dimensional transthoracic echocardiogram showing continued presence of the apical thrombus.

Figure 6.

Absolute Eosinophil Count During Hospital Course

Absolute eosinophil count (measured in number of cells/μL) over the course of the patient's hospitalization, with specific notable points marked: (A) prednisone initiated at 75 mg/d (1 mg/kg/d), (B) dosage decreased to 50 mg/d, (C) dosage further decreased to 35 mg/d, (D) dosage increased to 40 mg/d owing to increase in eosinophil count to 1,380/μL, (E) dosage increased to 60 mg/d on the day of discharge, given increase in eosinophil count to 4,434/μL, with plans to assess for possibility of taper in the outpatient setting.

Outcome and Follow-Up

The patient's hospital course was somewhat protracted because of poor oral intake and deconditioning, but she was ultimately discharged on hospital day 30.

Discussion

EM is defined as “a rare form of myocardial inflammation, characterized by eosinophilic infiltration,”¹ and it is a potentially life-threatening manifestation of eosinophil-predominant conditions. Through eosinophil activation and extracellular granule deposition, the extent of myocardial damage evolves through 3 stages: (1) an acute necrotic stage, (2) a thrombotic stage, and (3) a subsequent fibrotic stage that can lead to severe valvulopathy or cardiomyopathy.^2,3 While the clinical presentation of EM is variable, complications can also include arrhythmias and sudden cardiac death.

Although up to 36% of cases of EM are idiopathic in nature, several syndromes have been associated with EM.¹ The most common of these has been reported to be hypersensitivity, representing 34% of cases; other reported conditions include eosinophilic granulomatosis with polyangiitis (13%), hypereosinophilic syndrome (8%), infections (5%), pregnancy, malignancy, and other immune disorders. EM is likely underdiagnosed for several reasons, including diagnostic complexity, variability in presentation, and sheer rarity. Despite this, the in-hospital mortality from EM can be high.

We have reported the case of a patient with chronic eosinophilic leukemia who developed EM and left ventricular apical thrombus despite warfarin therapy. Malignancy overall represents <4% of syndromes associated with EM (given the prevalence of other conditions and the fact that 36% of cases are idiopathic), making our patient's case particularly rare. Even without the knowledge that our patient had an eosinophil-predominant condition, obtaining a differential was a simple way in which suspicion for EM increased. However, it is important to note that EM can occur in the absence of hypereosinophilia,¹ which complicates the initial workup. In such cases, pathognomonic imaging findings, such as those seen in our patient, can prove instrumental in saving patients from invasive procedures.

The gold-standard modality for the diagnosis of EM is endomyocardial biopsy (EMB), but this technique is not always available. Additionally, biopsy for EM has its own limitations, such as lack of sensitivity due to the focal nature of the condition.¹ In our patient's case, EMB was considered but was ultimately not pursued given the relatively increased risk of perforation during the active inflammatory state of EM.⁴ As such, noninvasive imaging modalities in the form of TTE and cardiac MRI proved indispensable in not only identifying the thrombus but also establishing a diagnosis for our patient. A case in China recently used positron emission tomography/CT imaging to visualize fibrotic changes in the final stage of EM, raising the question of whether additional imaging modalities have roles to play in the management of this condition.⁵

We recognize that a host of characteristics makes it difficult to establish guidelines for the diagnosis and management of EM. Currently, the only published guidelines are those from the Japanese Circulation Society,⁶ and although the guidelines mention cardiac MRI as a useful tool in the diagnosis of EM and other forms of acute myocarditis (and includes the differences in late gadolinium enhancement detection), EMB is still listed as the definitive diagnostic modality. As guidelines are developed and further evolve, a question to be addressed is whether confirmatory biopsy can be avoided when cardiac MRI and other imaging techniques can provide sufficient findings to establish the diagnosis of EM. Additionally, as recognition of EM increases, will there be a role for routinely screening patients with eosinophil-predominant conditions for myocarditis?

Our patient's management strategy involved several different medications, one of which was imatinib, a tyrosine kinase inhibitor. Imatinib has been shown to produce near-universal treatment response in FIP1L1-PDGFRA fusion–positive hypereosinophilic syndromes, and it can be used as a subsequent-line and steroid-sparing agent in patients without the fusion.⁷ However, imatinib does not play a role in the cardiac manifestations of these conditions; rather, initiation of corticosteroids is pivotal to combat the inflammatory response from eosinophil lysis and degranulation in the endomyocardium, which can lead to acute heart failure and cardiogenic shock.⁸ Identifying the EM-associated condition dictates choice of therapy¹ (eg, albendazole for Toxocara canis–associated EM, imatinib for myeloproliferative variants of hypereosinophilic syndromes); as such, imatinib is not a universal medication to be used in EM. In our patient, the addition of imatinib was necessary because her chronic eosinophilic leukemia was deemed to be steroid refractory (although her EM was not).

Curiously, our patient developed an intracardiac thrombus despite being supratherapeutic on warfarin. Hypereosinophilic syndromes are noted to be associated with increased rates of thrombosis,⁹ and the thrombotic stage of EM is thought to be mediated by increased expression of tissue factor and deposition of clots in eosinophil-rich regions.¹⁰ However, our patient has multiple confounding factors that complicate the reason underlying her thrombus formation. Whether this aspect of our patient's case represents treatment failure, the prothrombotic nature of her cancer, a complication of her myocarditis, or a different eosinophil-mediated process that superseded the mechanism of anticoagulation remains unclear.

Conclusions

EM presents a distinct diagnostic and therapeutic challenges for clinicians, given its variability in presentation and objective findings. However, in patients with eosinophil-predominant conditions who present with elevated cardiac biomarkers or signs and symptoms of heart failure, clinical suspicion of EM is warranted. While likely underdiagnosed, EM has the propensity to cause life-threatening complications. The importance of early recognition and multidisciplinary management to halt inflammation and reduce the risk of irreversible or possibly fatal myocardial injury cannot be overstated.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.