Loeffler Endocarditis

Etiology

As mentioned earlier, Loeffler endocarditis is a rare manifestation of hypereosinophilic syndrome (HES), which is divided into idiopathic, primary, and secondary types based on the underlying etiology. Idiopathic hypereosinophilic syndrome is a rare entity with no obvious cause of elevated eosinophil count and is the most common cause of Loeffler endocarditis.[5] The primary type has been associated with an underlying myeloproliferative and stem cell disorders like leukemia and lymphoma. Secondary hypereosinophilic syndrome is reactive to an underlying non-neoplastic or paraneoplastic condition, causing expansion of non-clonal eosinophils like allergic conditions, parasitic, fungal infections, and tumors.

Epidemiology

Hypereosinophilic syndrome is a sporadic disorder with an annual incidence of 0.036 per 100,000 patients.[6] The disease is rare in North America and mostly includes temperate and tropical areas of Asia, Africa, and some areas of South America. This condition is usually diagnosed between the ages of 20 to 50 years of age but may present at extremes of age. Cardiac involvement is present in 50% of the cases. It has no gender predisposition, except for primary hypereosinophilic syndrome, which is more common in men than women.

Pathophysiology

The pathophysiology of HES is not well understood. Some experts suggest that if the eosinophil count remains elevated (greater than 1500 eosinophils 10/L of peripheral blood) over 5 months, the incidence of end-organ damage increases, which may involve the heart, lungs, central nervous system, lungs, spleen, and gastrointestinal (GI) tract.[7] When eosinophils infiltrate the heart, they secrete protein granules that damage the endocardium and myocardium by producing direct toxins, which, in turn, activate platelets. The activated platelets later combine to form intracavitary and intravascular thrombi, leading to further damage of the endocardium. Few other mechanisms include activation of VWF and factor XII which may disrupt endothelial lining that enhances the procoagulant activity and activate fibrin production.

Histopathology

A 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, a characteristic cardiac myocytolysis change showing disruption at the intercellular junctions is observed.[8] The endocardium of one or both ventricles is typically fibrosed and thickened, affecting the underlying myocardium. Large mural thrombi may develop in either the right or left ventricle, resulting in reduced ventricular cavity size, being a potential source of pulmonary and systemic emboli.[9] Histological features also comprise inflammation of the small intramural coronary vessels.

History and Physical

Patients with Loeffler endocarditis may present with signs and symptoms of acute heart failure. Dyspnea, palpitation, chest pain, cough, fatigue, shortness of breath, and unintentional weight loss are the common presentations. Sixty percent of cases present with the chief complaint of shortness of breath. Rare cases present with symptoms and signs of pericarditis (4%).[10] Thirty-eight percent may develop congestive heart failure. Eosinophilic infiltration may cause valvular abnormality and most commonly involve the mitral valve, causing mitral valve insufficiency (42%). It can also involve the aortic wall leading to aortic stenosis and regurgitation, present in 4% of the cases.

Evaluation

The following investigational studies can be done to diagnose endocarditis due to eosinophilic infiltration:

1. Electrocardiogram (ECG)
2. Echocardiogram
3. Cardiac magnetic resonance imaging (CMR)
4. Endomyocardial biopsy 

• There is no single pathognomic electrocardiogram finding of Loeffler endocarditis. ECG shows T-wave inversions, left atrial enlargement, left ventricular hypertrophy, incomplete right bundle branch block, and left axis deviation. These all are non-specific findings for Loeffler endocarditis.
• Two-dimensional echocardiography is used to test cardiac abnormalities due to eosinophilic deposition. Echocardiography shows left ventricular hypertrophy, endomyocardial thickening, bilateral ventricular apical thrombus, and posterior mitral valve cusp involvement (enmeshment chordae tendineae causing valvular regurgitation)  entrapment of the chordae tendineae with valvular regurgitation.[11] Later on, findings are more consistent with restrictive cardiomyopathy. 
• Cardiac magnetic resonance (CMR) imaging is the new diagnostic modality used for Loeffler endocarditis evaluation. It is more sensitive and specific than both transthoracic and transesophageal echocardiogram to diagnose ventricular mural thrombus. CMR with gadolinium should be done to visualize myocardial fibrosis and inflammation. CMR can differentiate between inflammation and fibrosis based on delayed enhancement intensity. The intensity of delayed enhancement due to fibrosis is more intense than the intensity of delayed enhancement due to inflammation.
• The gold standard diagnostic modality for eosinophilic endocarditis is still endomyocardial biopsy. Currently, clinicians prefer CMR over endomyocardial biopsy as it is non-invasive and a more practical way to diagnose Loeffler endocarditis.

Treatment / Management

Symptomatic management of Loeffler endocarditis can be achieved with supportive care with diuretics, digoxin, and conventional therapy for heart failure, including angiotensin-converting enzyme (ACE) inhibitor angiotensin II receptor blockers, beta-adrenergic blockers, and aldosterone antagonists.

Patients with Loeffler endocarditis typically need mitral valve replacement due to mitral regurgitation. 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. There is no indication for prophylactic anticoagulation in Loeffler endocarditis. However, if a ventricular thrombus is diagnosed via echocardiography or CMR, anticoagulation should be started. 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 HES should be started as soon as the diagnosis is made. Steroids are the first-line therapy for HES due to their anti-inflammatory effect. Hydroxyurea can be used as a second-line agent depending on the etiology of the condition. All patients diagnosed with HES with or without cardiac involvement should have genetic testing for FIP1L1-PDGFRA mutation as it affects the management of the disease. Those who are positive for mutation should be treated with imatinib, a tyrosine kinase inhibitor, which has provided a good treatment response in the literature.

Differential Diagnosis

1. Churg-Strauss syndrome
2. Giant cell myocarditis
3. Medication-induced hypersensitivity reaction
4. Tropical endomyocardial fibrosis

Staging

There are 3 pathological stages of Loeffler endocarditis.

• Stage 1: Acute endo-myocardial inflammation/necrosis (first 1 to 2 months) that results in eosinophilic infiltration with degranulation and release of toxic proteins.
• Stage 2: Thrombotic stage (after about 10 months) that results in endothelial damage and thrombus formation. May cause valve motion restriction
• Stage 3: Fibrotic stage (after 1 to 2 years) where the thrombi are replaced by fibrosis. The endomyocardium, valves, and chordae tendineae may be involved. This stage may be associated with restrictive cardiomyopathy and valve incompetence.[11][12]

Prognosis

Regarding prognosis, patients are divided into 2 groups: steroid responders and non-steroid responders.

Steroid responder patients have a good prognosis, and non-steroid responders have a poor prognosis.

Due to genetic mutation, patients with Loeffler syndrome also have a good prognosis after treatment with tyrosine kinase inhibitors.

Due to its rarity, clear-cut mortality has not been defined.

Complications

Complications include the following:

• Restrictive cardiomyopathy
• Congestive heart failure
• Ventricular apical mural thrombosis
• Splenic infarction
• Stroke
• Myocardial ischemia
• Mitral valve regurgitation
• Aortic valve regurgitation
• Aortic valve stenosis