Loeffler Endocarditis

Etiology

Loeffler endocarditis is a rare manifestation of hypereosinophilic syndromes (divided into idiopathic, primary, and secondary types based on the underlying etiology). Idiopathic hypereosinophilic syndromes are a rare entity with no apparent cause of elevated eosinophil count and are the most common cause of Loeffler endocarditis. Underlying myeloproliferative and stem cell disorders such as leukemia and lymphoma have been associated with the primary type of hypereosinophilic syndromes. Secondary hypereosinophilic syndromes are reactive to an underlying non-neoplastic or paraneoplastic condition, including allergic conditions, parasitic, fungal infections, and tumors, causing the expansion of non-clonal eosinophils.[5] 

Epidemiology

Hypereosinophilic syndrome is a rare disorder with an annual incidence of 0.36 to 6.3 per 100,000 patients.[6] This condition most commonly occurs in people aged 20 to 50 years. However, children may also be affected—particularly those with immunodeficiencies.[7] Cardiac involvement is present in 50% of the cases and is more common in males; however, a close variant, endomyocardial fibrosis, affects both sexes equally. Loeffler endocarditis is rare in North America and primarily includes temperate and tropical areas of Asia, Africa, and some of South America. 

Pathophysiology

The pathophysiology of Loeffler endocarditis is common to the spectrum of hypereosinophilic syndrome. The basic event is eosinophil-mediated cell injury. Interleukin-5 is a cytokine that is specific for eosinophil differentiation. Interleukin-5, interleukin-3, and granulocyte-macrophage colony-stimulating factors work in the maturation and differentiation of eosinophils from myeloid progenitor cells. 

The overproduction of eosinophils results from either the over-production of cytokines or the proliferation of clonal eosinophils secondary to defects in hematopoietic stem cells or signal transduction responsible for eosinophil production. The net dysregulation in eosinophil production and maturation results in enhanced biological activity of eosinophils and consequently damages cells. 

When eosinophils infiltrate the heart, the protein granules secreted damage the endocardium and myocardium by producing direct toxins, activating platelets. The activated platelets later combine to form intracavitary and intravascular thrombi, leading to further damage to the endocardium. Other mechanisms include the activation of Von Willebrand factor, a large glycoprotein in the blood, and coagulation factor XII, which may disrupt endothelial lining that enhances the procoagulant activity and activates fibrin production.

Histopathology

The biopsy is the mainstay of diagnosis but requires invasive intervention. Light microscopy shows degranulated eosinophils and eosinophil cationic protein in the endocardium and activated eosinophils at the myocardial interstitium. On electron microscopy, characteristic cardiac changes from myocytolysis showing disruption at the intercellular junctions are observed.[8] The endocardium of one or both ventricles typically has fibrosis and thickening, affecting the underlying myocardium. Large mural thrombi may develop in the right or left ventricle, resulting in reduced ventricular cavity size, a potential source of pulmonary and systemic emboli.[9] Histological features also comprise inflammation of the small intramural coronary vessels.

History and Physical

History

Patients with Loeffler endocarditis may present with signs and symptoms of acute or chronic heart failure, including dyspnea on exertion or rest, easy fatiguability, orthopnea, and paroxysmal nocturnal dyspnea. Patients may present with constitutional symptoms such as unintentional weight loss or fatigue. Cardiac symptoms include palpitations, chest pain, presyncope, or syncope in patients with arrhythmia. Patients with valvular abnormalities present with symptoms of valvular heart disease, such as mitral regurgitation and aortic insufficiency. 

The chief complaint is shortness of breath, reported in 60% of cases. Rare cases present with symptoms and signs of pericarditis (4%).[10] Congestive heart failure may also develop in 38% of patients. Eosinophilic infiltration may cause valvular abnormality and most commonly involves the mitral valve, causing mitral valve insufficiency (42%). This condition can also involve the aortic wall leading to aortic stenosis and regurgitation, present in 4% of cases.

Physical Examination

On examination, patients have signs of biventricular failure, including elevated jugular venous pressure, pulmonary rales, congested liver, limb edema, third heart sound, and Kussmaul signs may be seen. Hepatomegaly and ascites may also be seen in advanced cases. Pulse is irregular in the presence of atrial fibrillation. Patients with end-stage disease may have cachexia and jaundice. 

Evaluation

Noninvasive diagnostic modalities have emerged as initial tools for diagnosing patients with Loeffler endocarditis.

CBC usually reveals persistent hyper-eosinophilia (>1.5 x 10/L) on at least 2 occasions.

An electrocardiogram may show non-specific ST-T changes, T-wave inversions, left atrial enlargement, left ventricular hypertrophy, incomplete right bundle branch block, left axis deviation, or evidence of bundle branch block. Atrial fibrillation and premature atrial and ventricular contractions may also be seen. There is no single pathognomic electrocardiogram finding of Loeffler endocarditis.

2-D transthoracic echocardiogram is universally the initial choice of investigation. Findings depend on the stage of the disease and are usually inconspicuous in the initial necrotic stage of the disease. Endomyocardial thickening and mural thrombi can be appreciated as the disease progresses. A thrombus in the ventricle apex and the absence of apical akinesia should prompt suspicion of the disease. In earlier stages, apical thrombi in the ventricles can be confused with an apical variant of hypertrophic cardiomyopathy. However, a layered structure with different degrees of echogenicity suggests the possibility of a thrombus rather than the hypertrophied apex. The obliterated apex gives a classical 'kissing ventricle' appearance on apical views. In the third stage, the fibrotic endocardium appears brighter (with greater echo) than the rest of the myocardium; this is seen by focusing on the apex, magnifying the image, and adjusting gain.[11] Shaper, et al, described the variable degree of endocardial involvement of the disease. One may see the involvement of apex alone, apex to valve, sub-valvular apparatus, apex, and valvular apparatus with intervening normal myocardium or patchy distribution.[12] In advanced stages, features of restrictive cardiomyopathy are noted. These include diastolic dysfunction, bi-atrial enlargement, and a small left ventricle cavity, albeit preserved ejection fraction. Any grade of diastolic dysfunction can be noted in Loeffler endocarditis.

The atrioventricular valve involvement results in thickened, fibrotic valves and regurgitation. There may be involvement of chordae and restricted/tethered mobility of valve leaflets, resulting in eccentric regurgitation. Pericardial effusion can be seen in 10% to 32% of patients with hypereosinophilic syndromes.[11] 

3-D transthoracic echocardiogram shows progressive circumferential/concentric obliteration of the LV cavity as one sees from base to apex. Through a multi-slice view, the extent of involvement can be fully appreciated. A 3D transthoracic echocardiography with contrast after multi-slice reconstruction can show the exact location and extent of the thrombus. The normal myocardium will appear opacified (perfused), whereas the thrombus will appear dark (nonperfused).[11] 

Cardiac magnetic resonance imaging has emerged as a robust, non-invasive imaging modality that helps detect the disease earlier, with good sensitivity and specificity, providing exact differentiation of the viable myocardium, fibrosis, thrombus, edema, or necrosis. The pivotal role of cardiac magnetic resonance imaging in Loeffler endocarditis is its ability to accurately assess right ventricle involvement, tissue characterization, detection of smaller thrombi, and early detection of even subtle endocardial involvement. The late gadolinium-enhanced images show typical sub-endocardial hyperenhancement at the top of the thrombus, not restricted to the distribution of one coronary artery, patchy or diffuse, extending up to inflow and sub-valvular region, in some cases. This pattern in the absence of obstructive coronary artery disease is characteristic of Loeffler endocarditis. Additionally, this imaging helps differentiate the stage of the disease, such as myocardial edema, on T-2 weighted images, which is suggestive of the inflammatory (acute) stage.

In contrast, the absence of edema and late gadolinium-enhanced images suggest a late stage of the disease. Contrast-enhanced images help demarcate ventricular thrombus. Cardiac magnetic resonance imaging accurately assesses right ventricular function and size in 3D. Some experts have used cardiac magnetic imaging to monitor therapy response in Loeffler endocarditis, while others have used this imaging to increase the yield of endomyocardial biopsy by targeted sampling.[13] There is some evidence that the quantification of late gadolinium-enhanced images by cardiac magnetic resonance imaging is an independent predictor of mortality in Loeffler endocarditis.[14]

Cardiac computerized tomography for Loeffler endocarditis is limited due to its inability to provide hemodynamic assessment, radiation exposure, use of nephrotoxic contrast agents, and lower temporal resolution compared to echocardiogram and cardiac magnetic resonance. However, computerized tomography may be useful in patients with poor acoustic windows or contraindications to cardiac magnet resonance. While computerized tomography may not help with the initial necrotic stage of the disease, this imaging can detect the presence and extent of the thrombus. Thrombi usually appear iso-dense; with contrast enhancement, thrombi remain non-enhanced. 

Endomyocardial biopsy is the gold standard diagnostic modality for eosinophilic endocarditis. However, this modality is reserved for patients with diagnostic uncertainty due to its invasive nature. Findings on endomyocardial biopsy depend on the stage of the disease. In the acute necrotic stage, endomyocardial biopsy demonstrates eosinophil-mediated myocardial damage, even without eosinophils; this is performed by staining antibodies to eosinophil granule proteins, such as major basic protein 1.[15] Thick and loose collagen filaments may be seen. 

Molecular testing is recommended for all patients with suspected hypereosinophilic syndromes for FIP1L1-PDGFRA. Further evaluation of hypereosinophilic syndromes also includes T-lymphocyte phenotyping and bone marrow aspiration. 

Treatment / Management

Limited data exists regarding the outcomes of suggested treatment strategies for Loeffler endocarditis; however, the following measures can be taken:

• Symptomatic management of Loeffler endocarditis can be achieved with supportive care with diuretics, digoxin, and conventional therapy for heart failure, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-adrenergic blockers, and aldosterone antagonists.
• Rate control for atrial fibrillation and diuretics are the mainstay of treatment.
• Therapeutic pleural or ascitic tap can be performed as needed.
• There is no indication of prophylactic anticoagulation in Loeffler endocarditis per se. However, anticoagulation should be started if a ventricular thrombus is diagnosed via echocardiography or CMR. Warfarin or low molecular weight heparin can be used in patients with Loeffler endocarditis with ventricular thrombus or when a mechanical mitral valve is implanted.
• Treatment of the underlying hypereosinophilic syndromes should be started as soon as the diagnosis is made. Steroids are the first-line therapy for hypereosinophilic syndromes due to their anti-inflammatory effect. Hydroxyurea can be used as a second-line agent, depending on the condition's etiology. All patients diagnosed with hypereosinophilic syndromes with or without cardiac involvement should have genetic testing for FIP1L1-PDGFRA mutation, which can affect disease management. Patients positive for this mutation should be treated with imatinib, a tyrosine kinase inhibitor, which has provided a good treatment response in the literature.
• Surgical options include endomyocardial resection and valve replacement or repair. Patients with Loeffler endocarditis may need mitral valve replacement due to mitral regurgitation. Data on outcomes are limited. Tricuspid valve surgery is associated with increased postsurgical mortality (15%-30%). The mitral valve can be replaced with either a mechanical or bioprosthetic valve, but a biological valve is preferable due to a high incidence of mechanical valve thrombosis.

Differential Diagnosis

Differential diagnoses to consider and rule out include the following:

• Restrictive cardiomyopathy of any cause (amyloidosis, sarcoidosis)
• Diastolic dysfunction due to hypertensive heart disease
• Churg-Strauss syndrome
• Giant cell myocarditis
• Medication-induced hypersensitivity reaction
• Tropical endomyocardial fibrosis

Staging

There are 3 pathological stages of Loeffler endocarditis. Cardiac symptoms predominantly occur in Stages 2 and 3.[16] 

Stage 1: Acute endo-myocardial inflammation/necrosis (first 1-2 months) resulting in eosinophilic infiltration with degranulation and release of toxic proteins. Pathologically, there is myocardial damage and sterile microabscesses. This is usually a silent stage. Minor elevation in troponin and splinter or conjunctival hemorrhages may be found.[17] On diagnostic evaluation, echocardiography is usually normal. Cardiac magnetic imaging resonance helps in describing early eosinophilic-mediated myocardial involvement in the form of subendocardial hyperenhancement. Endomyocardial biopsy is the gold standard test for demonstrating eosinophil-mediated myocardial damage, even without eosinophils; this is done by staining antibodies to eosinophil granule proteins, such as major basic protein 1. 

Stage 2: Thrombotic stage (after about 10 months) resulting in endothelial damage and thrombus formation. There may be valve motion restriction. The eosinophil peroxidase forms hypothiocyanous acid, which induces the formation of tissue factors in endothelial cells. Eosinophils may also directly release tissue factors. The consequence is the formation of an endocardial thrombus. Patients in this stage are at heightened risk of thromboembolic events, such as stroke or limb ischemia.[18] 

Stage 3: Fibrotic stage (after 1-2 years), where the thrombi are replaced by fibrosis. The endomyocardium, valves, and chordae tendineae are involved. This stage is associated with restrictive cardiomyopathy and valve incompetence.[19][20] In this final fibro-inflammatory stage, patients manifest with signs and symptoms of right or left heart failure. Echocardiography usually shows obliteration of the ventricle apex. Cardiac magnetic resonance imaging shows extensive subendocardial hyperenhancement, characteristic of the disease. There may be evidence of myocardial damage secondary to coronary vasculitis and infarction. 

Prognosis

Steroid responders have a better prognosis than non-responders. Due to the rare nature of the disease, clear evidence about long-term morbidity and mortality is lacking. 

Complications

Complications can include the following:

• Restrictive cardiomyopathy
• Congestive heart failure
• Ventricular apical mural thrombosis
• Systemic and coronary embolism (stroke, myocardial infarction, renal infarct)
• Splenic infarction
• Mitral valve regurgitation
• Aortic valve regurgitation or stenosis
• Tricuspid valve disease