From an isolated right ventricular thrombus to the diagnosis of the hypereosinophilic syndrome

Summary

This case concerns a 58-year-old male who presented with abdominal pain, anorexia, nausea, and exertional dyspnea of one month's duration. On further evaluation peripheral eosinophilia was conspicuous and eosinophilic infiltration was found in the gastrointestinal system and bone marrow. Echocardiography showed an isolated right ventricular thrombus with tricuspid valve involvement. Cardiac magnetic resonance imaging helped to confirm the diagnosis of cardiac involvement in hypereosinophilic syndrome without requiring a cardiac biopsy.

Introduction

In 1936, Löffler [1] reported a specific type of fibrosing endomyocarditis in two patients with marked peripheral eosinophilia. The disease was named Löffler endocarditis. It was believed that other organs, such as the spleen, liver, eyes, skin, and lungs, may also be involved in this disorder. In 1968, Hardy and Anderson codified these entities into a spectrum of diseases as the end-organ damage that can be seen in association with eosinophilia and named them as hypereosinophilic syndrome (HES) [2]. In 1975, Chusid et al. reviewed the findings in patients with eosinophilia and presented the defining features of HES, which are still considered valid today. These diagnostic criteria for HES are presence of a persistent eosinophilia (1500/mm³) for more than 6 months with signs or symptoms of organ involvement and lack of evidence for parasitic, allergic, or other known causes of eosinophilia [3]. The prevalence of HES is unknown, although Spry [4] postulated a rate of 1 case per 200,000 people. It affects mostly men between 20 and 50 years of age, with a peak in the 4th decade of life while there are few cases reported in children [5], [6].

However, the diagnosis of this entity can be difficult because presentation of the patients and progression of the disease are variable.

Case report

A 58-year-old Caucasian male presented with a one month history of abdominal pain, anorexia, and nausea. He had been in apparently good health until one month previously, when the mentioned symptoms developed along with exertional dyspnea (New York Heart Association Functional Class II) and generalized fatigue. He had lost 14 kg of his weight during this time. His past medical history was unremarkable. On physical examination the patient appeared fatigued, but not acutely ill. His temperature was 36.8 °C, blood pressure was 130/90 mmHg, pulse rate was 100/min, and respirations were 20/min. On cardiovascular examination, the heart rate and rhythm were regular and S1 and S2 heard muffled. Jugular venous pressure was 10 cm H₂O. Carotid artery pulses were brisk and equal bilaterally. No carotid, aortic, or femoral bruits were heard. Peripheral pulses were intact and symmetrical. No peripheral edema, clubbing, or cyanosis was present. On abdominal examination mild ascites was detectable. The patient was admitted to the hospital for evaluation of gastrointestinal complaints and significant weight loss. Laboratory test results were as follows: hemoglobin, 14.9 g/dL; hematocrit, 47.7%; leukocytes, 7.1 × 10⁹/L; eosinophils making up 47% of all leukocytes; and platelets, 258 × 10⁹/L. The erythrocyte sedimentation rate was normal (10 mm/h) and C-reactive protein level was elevated (12 mg/L). Chest radiography was normal. Electrocardiography showed a prolonged QT interval and sinus bradycardia with ST-segment and T-wave abnormalities. Stool exam was negative. Endoscopy and colonoscopy were performed and tissue samples were taken which showed infiltration of the colonic and cecal mucosa by a mixture of eosinophils and a few polymorphonuclear leukocytes, lymphocytes, and plasma cells (Fig. 1A). Oxyntic and antral gastric mucosa were infiltrated by eosinophils. In differential count of bone marrow cellularity in bone marrow aspirated samples early and late eosinophilic series made up to 10% and 22% of hematopoietic elements, respectively. Bone marrow biopsy was interpreted as normocellular with normal trilineage hematopoiesis associated with reactive changes and eosinophilia (Fig. 1B). After transthoracic echocardiography showed an isolated large right ventricular (RV) apical thrombus (Fig. 2) an ECG-gated cardiac magnetic resonance imaging (MRI) was performed on a 1.5 T scanner (Avento, Siemens, Erlangen, Germany). Multiple sequences were obtained, including single-shot and retrospective gated balanced gradient-echo (true fast imaging with steady-state precession [FIPS] cine; fat-suppressed half-Fourier acquisition single-shot turbo-spin echo; unenhanced and enhanced T₁-weighted gradient-echo and delayed, enhanced viability (inversion recovery prepared turbo fast low angle shot) obtained after a 10 min delay following intravenous administration of double-dose gadolinium (0.15 mmol/kg). Comprehensive descriptions of the cardiac MRI results are included in the related figure legends (Fig. 3).

Figure 1.

(A) Infiltration of the colonic mucosa by mixture of eosinophils and a few polymorphonuclear (PMN) leukocytes, lymphocytes, and plasma cells with permeation of some eosinophils and PMN leukocytes into glands resulting in cryptitis (arrow). (B) Cells of eosinophilic lineage are shown in bone marrow biopsy (dashed arrows).

Figure 2.

Right ventricular apex is obliterated by thrombus (arrow). Anterior tricuspid leaflet is involved in the clot. Right ventricle is severely enlarged. Septal tricuspid leaflet is shown with arrowhead. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Figure 3.

Electrocardiogram-gated cardiac magnetic resonance image. (A) Right ventricular thrombus separated from nearly isointense myocardium by thin zone of endocardium with increased signal density (arrow). Pericardial and pleural effusions are noted. (B) Large right ventricular homogenous mass (thrombus) separated from nearly isointense myocardium by thin zone of endocardium with increased signal intensity. Pericardial and pleural effusions are noted. (C, D) Intense hyper enhancement of right ventricle is an appearance consistent with fibrosis (arrow). Overlying thrombus (arrow head) has very low signal intensity, which extended from apex toward right ventricular outflow tract (C).

Discussion

Given the patient's laboratory data, the differential diagnosis included causes of an isolated right ventricular mural thrombus, gastrointestinal, and peripheral blood eosinophilia. Idiopathic HES was diagnosed in our patient with high eosinophil count greater than for a parasitic cause of eosinophilia. Cardiac involvement in idiopathic HES is the rule, occurring in more than 75% of patients with idiopathic HES [7], [8], [9] and is the major cause of morbidity and mortality in these patients. The cardiovascular manifestations in HES range from a progressive subendocardial fibrosis with overlying mural thrombus formation or valvular dysfunction to restrictive cardiomyopathy and heart failure [4], [10], [11]. Cardiac damage is caused by eosinophils and eosinophil-derived mediators which have toxic effects on the heart. Cardiac involvement is often biventricular [12]. Cardiac lesions are characterized by intense endocardial fibrotic thickening of apex of the ventricles, which reduces the ventricular cavity and diastolic filling, thus producing restrictive physiology. Overt cardiac dysfunction occurs in more than half of the patients [13]. Systolic function often is well preserved. Eventually valvular abnormalities and/or the resulting endomyocardial fibrosis may lead to overt congestive heart failure. Fibrosis and thrombus formation may also occur in mitral and tricuspid valves with resultant valvular regurgitation. Outflow tracts near the aortic and pulmonic valves are usually protected, although rarely these valves may be involved [14].

Although cardiac involvement is best confirmed by means of endomyocardial biopsy, at the fibrotic stage of the disease this technique may fail to obtain adequate samples and may be difficult to perform. Thus a number of noninvasive modalities have been used instead. These include echocardiography and cardiac MRI. The advantages of these modalities lie in fact that they can be used for follow up of the patients and evaluation of their reaction to treatment, they are noninvasive, and do not harbor risks of biopsy to the patients.

Echocardiography is a mandatory evaluation in HES patients and enables sufficient detection of thickened endocardium and intraventricular thrombus. It is valuable in detecting intracardiac thrombi and valvular involvement. Besides echocardiography can detect increases in endomyocardial echodensity in the area of fibrosis [13], [15], [16], [17], [18]. Common echocardiographic findings in this disease are endocardial thickening and mural thrombus.

Cardiac MRI proves a rapid noninvasive modality for diagnosing myocardial fibrosis with the use of an inversion-recovery prepared T1-weighted gradient-echo sequence after intravenous administration of gadolinium chelate [19] and allows the monitoring of the myocardial process and its response to therapy. The endomyocardial fibrosis detected by cardiac MRI may provide a diagnostic clue to the presence of HES.

Conclusion

The association of HES with thromboembolic events forces us to rule out hypereosinophilia as an important differential diagnosis in patients with a mural thrombosis who present with signs and symptoms of any organ damage even if they are extra-cardiac. Although eosinophilic thromboemboli most often are seen in left ventricle they also should be considered in isolated right ventricular mural thrombus. Cardiac biopsy gives the definite diagnosis. However, availability of noninvasive methods such as echocardiography and cardiac MRI can also confirm the diagnosis of HES and thus performing a myocardial biopsy is not always necessary.