Löeffler endocarditis due to idiopathic hypereosinophilic syndrome

Sindromul hipereozinofi lic cuprinde un grup heterogen de manifestări hematologice şi non-hematologice, defi nit prin prezenţa eozinofi liei >1500/mm3, care persistă peste 6 luni şi afectarea eozinofi lică a organelor ţintă. Endocardita Löeffl er (EL) constituie cea mai frecventă manifestare cardiacă a sindromului hipereozinofi lic (SHE) şi reprezintă o formă acută de cardiomiopatie restrictivă. Raportăm cazul unei paciente în vârstă de 74 de ani, care se prezintă cu fenomene de insufi cienţă cardiacă şi scădere ponderală. La admisie, aceasta prezenta tahicardie şi sufl u sistolic gradul 2/6 în focarul mitralei. Biologic asocia eozinofi lie, sindrom de hepatocitoliză şi dislipidemie. Electrocardiograma (ECG) a arătat modifi cări nespecifi ce ale segmentului ST şi ale undei T. Ecocardiografi a a documentat prezenţa unui tromb la nivelul apexului ventriculului stâng care îngloba cordajele, cu mişcare restricţionată a cuspelor, determinând regurgitare mitrală. Diagnosticul de miocardită a fost confi rmat prin rezonanţă magnetică cardiacă, demonstrând prezenţa unei mase cu structură omogenă, cu hiposemnal faţă de miocardul ventricular şi captare tardivă de gadolinium difuză circumferenţială subendocardică. Pentru stabilirea etiologiei SHE au fost considerate următoarele: afectare hematologică, reactivă sau afectare secundară. Particularitarea cazului constă în prezenţa diagnosticului la o pacientă în vârstă, cu răspuns favorabil la corticoterapie. Cuvinte cheie: endocardita Löeffl er, sindromul hipereozinofi lic, afectare cardiacă, imagistica multimodală. Laura Benchea et al. Löeffl er endocarditis due to idiopathic hypereosinophilic syndrome Romanian Journal of Cardiology Vol. 31, No. 1, 2021 98 On presentation, the patient was afebrile, with a blood pressure of 170/100 mmHg, pulse rate of 100 beats/min, with a grade 2/6 systolic mitral murmur, absent breath sounds on right hemithorax, and peripheral oxygen saturation of 97%. Her physical examination was also notable for palmar and plantar rash (Figure 1 A, B) and lower lip and right lateral tongue ulcerations (Figure 1 C, D). The biological work up revealed leukocytosis (WBC=18140/mm3), an eosinophil (Eo) count of 2080/mm3, representing 11,5% (normal range, 0%4%), hepatocytolysis syndrome (ALT=45 U/L, AST=86 U/L), electrolyte imbalance (Na=129 mmol/L, Cl=97 mmol/L), and dyslipidemia (Total Cholesterol=226 mg/dL; HDL-Col=34 mg/dL, LDL-Col=166 mg/dL, TGL=181 mg/dL). Her serum NT-pro BNP level was 4070 pg/mL. The ECG showed sinus rhythm, ST-segment depression in leads V4-V6 and T-wave inversion in inferior leads (Figure 2). She was admitted to the department of cardiology for further evaluation. Transthoracic echocardiography revealed nondilated cardiac chambers, good left and right ventricular global systolic function (TAPSE=18 mm and Figure 1. A, B. Palmar and plantar rash. C, D. Lower lip and right lateral tongue ulcerations. Figure 2. ECG aspect: sinus rhythm, ST-segment depression in V4-V6, T-wave inversion in inferior leads. Romanian Journal of Cardiology Vol. 31, No. 1, 2021 99 Laura Benchea et al. Löeffl er endocarditis due to idiopathic hypereosinophilic syndrome Figure 3. Transthoracic Echocardiography: A. Apical four-chamber viewLeft ventricular apical obliteration with mural thrombus. B, C. Apical four chamber and two chamber view-mitral regurgitation. D. Apical four-chamber view-tricuspid valve regurgitation. E. Restrictive fl ow pattern across mitral valve. F. Left ventricular endomyocardial systolic dysfunction. Figure 4. Cardiac magnetic resonance: A, B. Left ventricular apical obliteration with mural thrombus. C. Moderate mitral regurgitation. D. Diffuse circumferential subendocardial LGE, Thrombotic lesion shows no contrast enhancement. E. Torax computed tomography-right pleural effusion. LVEF=53%). Apical four-chamber view showed a large echo density fi xed to the left apex (32/31 mm) (Figure 3A) with restriction of the mitral apparatus and moderate-severe mitral regurgitation (Figure 3B,C), and small ventricular cavity due to mural thrombus. Moderate tricuspid valve regurgitation and moderate pulmonary hypertension was also observed (Figure 3 D). Diastolic function was evaluated using a multiparametric approach including: mitral infl ow E/A wave (>2.5), E wave deceleration time (<150 msec), increLaura Benchea et al. Löeffl er endocarditis due to idiopathic hypereosinophilic syndrome Romanian Journal of Cardiology Vol. 31, No. 1, 2021 100 Figure 5. Transthoracic echocardiography: A. Four-chamber apical view-complete resolution of the left ventricular apical thrombus. B. Four-chamber apical view-Mitral regurgitation. C. Parasternal long-axis view-Moderate mitral regurgitation. ased left atrial volume index (43 ml/m2) (Figure 3-E). Overall left ventricular (LV) global longitudinal strain (GLS) was reduced to -10.4% indicating LV endocardial systolic dysfunction (Figure 3 F). Clinical impression and differential diagnosis Given the patient’s presentation and prior investigations, the few top diagnoses included apical thrombus, apical hypertrophic cardiomyopathy, left ventricular non-compaction cardiomyopathy, or Löeffl er endocarditis. Cardiac magnetic resonance (CMR) demonstrated left ventricular apical obliteration with mural thrombus with a low signal on steady-state free precession imaging, fi rst-pass perfusion and postcontrast late enhancement images (Figure 4-A, B, D), moderate mitral regurgitation (Figure 4-C), and diffuse circumferential subendocardial late gadolinium enhancement (LGE) (Figure 4-D). However, since subendocardial LGE is a hallmark of ischemic heart disease, coronary heart disease was excluded using computed tomography angiography. In addition, her hyper eosinophilia and skin rash prompted evaluation for others etiologies. Hematology was consulted and BCR-ABL (for chronic myeloid leukemia), CALR (for myeloproliferative neoplasms), and JAK-2 (for essential thrombocythemia, polycythemia vera, or myelofi brosis) mutation were all negative. Test results for parasitic infection were also negative. The patient’s immunoglobulin E level was normal (40.5 UI/mL, the upper normal limit is 100.0 UI/mL). The work up for cytoplasmic antineutrophil cytoplasmic antibody and perinuclear antineutrophil cytoplasmic antibody was negative. A complete computed tomography scan including thorax, abdomen and pelvis was performed in order to exclude the presence of a malignant mass. Right pleural effusion was observed (Figure 4 E) and laboratory analyses after transthoracic puncture revealed transudate. Thyroid function was in normal range. There were not enough criteria for Churg-Strauss syndrome. Therefore, the fi nal diagnosis was Idiopathic Hypereosinophilic syndrome with Löeffl er endocarditis. Management of this patient included gradual tapering of methylprednisolone guided by echocardiogram and biological work up, acenocumarol and heart failure treatment according to current guidelines6 with Furosemide 40 mg od, Spironolactone 25 mg od, Candesartan 16 mg od, and Bisoprolol 2.5 mg od. At seven-months follow-up, she was asymptomatic with no skin lesions, normal hemogram (Eo=360/ mm3) and resolution of left ventricular thrombus, but persisting mitral valve regurgitation and restrictive pattern diastolic dysfunction (Figure 5).


INTRODUCTION
Löeffl er endocarditis is a restrictive cardiomyopathy caused by eosinophilic infi ltration of the heart. It represents the cardiac manifestation of HES and is associated with high mortality and morbidity rates 4 . LE progresses through three stages: acute necrotic stage, thrombotic stage, and fi brotic stage. It is still unclear which is the best imaging method, but both non-invasive and invasive imaging modalities may be useful 5 .

CASE REPORT
We report the case of a 74-year-old patient, without family medical history, who addressed to emergency care unit for resting dyspnea, orthopnea, paroxysmal nocturnal dyspnea, atypical chest pain, weight loss, and skin lesion, since two weeks. Her past medical history was remarkable for autoimmune thyroiditis and dyslipidemia. Home medication included Levothyroxine 25 mcg per day. Abstract: Hypereosinophilic syndrome encompasses a heterogenous group of non-hematologic and hematologic disorders defi ned as peripheral blood eosinophilia >1500/mm 3 persisting more than 6 months and eosinophilic end organ complications 1,2 . Löeffl er endocarditis (LE) is the most common cardiac manifestation of the hypereosinophilic syndrome (HES) and represents an acute form of primary restrictive cardiomyopathy³. We report the case of a 74 years-old woman with symptoms related to congestive heart failure and weight loss. At admission the patient had tachycardia and a grade 2/6 systolic mitral murmur. Laboratory fi ndings revealed eosinophilia, hepatocytolysis syndrome and dyslipidemia. The electrocardiogram (ECG) showed non-specifi c ST-segment and T wave abnormalities. The echocardiography revealed left ventricular apical thrombus and entrapment of chordae tendineae with restricted motion of mitral leafl ets leading to mitral regurgitation. The diagnosis of myocarditis was confi rmed by the cardiac magnetic resonance imaging which showed the presence of a left ventricular mass with low signal on steady-state free precession imaging and diffuse circumferential subendocardial late gadolinium enhancement (LGE). When discussing the etiology of the HES the following were taken into consideration: hematologic, reactive or secondary disorders. This case is distinguished by diagnosis in an elderly woman and good response to corticosteroid therapy. Keywords: Löeffl er endocarditis, hypereosinophilic syndrome, cardiac involvement, multimodality imaging.
On presentation, the patient was afebrile, with a blood pressure of 170/100 mmHg, pulse rate of 100 beats/min, with a grade 2/6 systolic mitral murmur, absent breath sounds on right hemithorax, and peripheral oxygen saturation of 97%. Her physical examination was also notable for palmar and plantar rash (Figure 1 A, B) and lower lip and right lateral tongue ulcerations (Figure 1 C, D).
The ECG showed sinus rhythm, ST-segment depression in leads V4-V6 and T-wave inversion in inferior leads ( Figure 2). She was admitted to the department of cardiology for further evaluation.
Transthoracic echocardiography revealed nondilated cardiac chambers, good left and right ventricular global systolic function (TAPSE=18 mm and

Clinical impression and differential diagnosis
Given the patient's presentation and prior investigations, the few top diagnoses included apical thrombus, apical hypertrophic cardiomyopathy, left ventricular non-compaction cardiomyopathy, or Löeffl er endocarditis.
Cardiac magnetic resonance (CMR) demonstrated left ventricular apical obliteration with mural thrombus with a low signal on steady-state free precession imaging, fi rst-pass perfusion and postcontrast late enhancement images (Figure 4-A, B, D), moderate mitral regurgitation (Figure 4-C), and diffuse circumferential subendocardial late gadolinium enhancement (LGE) (Figure 4-D). However, since subendocardial LGE is a hallmark of ischemic heart disease, coronary heart disease was excluded using computed tomography angiography.
In addition, her hyper eosinophilia and skin rash prompted evaluation for others etiologies. Hematology was consulted and BCR-ABL (for chronic myeloid leukemia), CALR (for myeloproliferative neoplasms), and JAK-2 (for essential thrombocythemia, polycythemia vera, or myelofi brosis) mutation were all negative. Test results for parasitic infection were also negative. The patient's immunoglobulin E level was normal (40.5 UI/mL, the upper normal limit is 100.0 UI/mL). The work up for cytoplasmic antineutrophil cytoplasmic antibody and perinuclear antineutrophil cytoplasmic antibody was negative. A complete computed tomography scan including thorax, abdomen and pelvis was performed in order to exclude the presence of a malignant mass. Right pleural effusion was observed (Figure 4 E) and laboratory analyses after transthoracic puncture revealed transudate. Thyroid function was in normal range. There were not enough criteria for Churg-Strauss syndrome.
Therefore, the fi nal diagnosis was Idiopathic Hypereosinophilic syndrome with Löeffl er endocarditis. Management of this patient included gradual tapering of methylprednisolone guided by echocardiogram and biological work up, acenocumarol and heart failure treatment according to current guidelines 6 with Furosemide 40 mg od, Spironolactone 25 mg od, Candesartan 16 mg od, and Bisoprolol 2.5 mg od.
At seven-months follow-up, she was asymptomatic with no skin lesions, normal hemogram (Eo=360/ mm³) and resolution of left ventricular thrombus, but persisting mitral valve regurgitation and restrictive pattern diastolic dysfunction ( Figure 5).

DISCUSSION
HES is a disorder characterized by persistent eosinophilia with damage to the multiple organs. After activation, eosinophils express several proteins including eosinophil major basic proteins (MBP1 and MBP2), eosinophil peroxidase (EPO) and eosinophil-derived neurotoxin (EDN) with numerous biological properties including direct cell toxicity 7 . Dermatologic involvement followed by pulmonary, gastrointestinal, and cardiac manifestations are the most common clinical implications reported². Cardiac involvement usually follows 3 stages: the fi rst stage, frequently asymptomatic, with acute necrosis, the second stage characterized by mural thrombi formation, and third stage with fi brosis and restrictive cardiomyopathy ensues 4,8 .
Our patient presented with symptoms of heart failure and demonstrated a moderately elevated eosinophil count. The underlying causes of HES are various. The patient received an almost complete workup to fi nd the underlying etiologies, and the negative results led to the diagnosis of idiopathic HES.
Transthoracic echocardiography plays an important role in both diagnosis and follow-up 5 . The most common echocardiographic fi ndings are endomyocardial thickening, left or right mural thrombus, frequently in apex, small ventricular cavity due to endocardial thickening and mural thrombus, atrioventricular valves implication with mitral or tricuspid regurgitation, biatrial enlargement, and pericardial effusion 5 . Cardiac magnetic resonance is crucial for LE diagnosis due to detection and characterization of ventricular thrombi and early detection of subendocardial thickening associated with myocardial tissue abnormalities. Due to the focal nature of the disease, the endomyocardial biopsy has a low sensitivity 4 .
Given the limited indication of endomyocardial biopsy for the diagnosis of LE because of numerous false-negative results, cardiac involvement was observed in transthoracic echocardiography and confi rmed by CMR.