Loeffler Endocarditis

Loeffler endocarditis (eosinophilic endomyocardial disease) is cardiac involvement by persistent eosinophilia. Eosinophil mediated injury of the endocardium leads to thrombus formation, then fibrosis, with restrictive filling, atrioventricular valve regurgitation and embolism.

It is the cardiac form of hypereosinophilic syndrome, defined as an absolute eosinophil count over 1.5 x 10^9/L on two occasions with tissue damage. Heart involvement occurs in roughly half of patients with hypereosinophilic syndrome, and is the main cause of death.

Causes include idiopathic hypereosinophilic syndrome, myeloid neoplasms (the FIP1L1-PDGFRA fusion, chronic eosinophilic leukaemia), lymphocytic variants driven by clonal T cells, eosinophilic granulomatosis with polyangiitis, parasitic infection (Strongyloides, Toxocara, filariasis, schistosomiasis), drug hypersensitivity and malignancy.

The disease passes through necrotic, thrombotic and fibrotic stages. The fibrotic stage resembles tropical endomyocardial fibrosis, which can occur without eosinophilia.

Pathophysiology.

Activated eosinophils release major basic protein, eosinophil cationic protein and peroxidase. These damage endothelium and myocardium, and are directly thrombogenic.

Early injury causes subendocardial necrosis and troponin release. Thrombus then lines the ventricular apices and inflow tracts. Later, fibrous organisation obliterates the apex, tethers the posterior mitral and tricuspid leaflets and causes restriction.

Staging matters. Immunosuppression helps most in the necrotic and thrombotic stages, while fibrotic disease often needs surgery.

Dyspnoea, fatigue, chest pain, palpitations and signs of right or left heart failure. Mitral and tricuspid regurgitation murmurs are common. Embolic stroke, limb or visceral ischaemia may be the first sign. Extracardiac features include fever, weight loss, rash, cough, neuropathy and hepatosplenomegaly. In tropical endomyocardial fibrosis, abdominal distension from ascites is often the presenting complaint.

• Full blood count with differential repeated, and blood film.
• Cause search: troponin and NT-proBNP, IgE, vitamin B12 and tryptase (raised in myeloid forms), FIP1L1-PDGFRA testing by FISH or PCR, bone marrow biopsy with cytogenetics, T-cell receptor clonality, ANCA, Strongyloides serology, stool and urine parasite examination, HIV test, and drug history.
• ECG: non-specific ST and T changes, atrial fibrillation.
• Echocardiography: thickened echogenic endocardium, apical obliteration, thrombus, restrictive filling, tethered posterior mitral leaflet and regurgitation.
• Cardiac MRI: subendocardial late gadolinium enhancement with overlying thrombus, giving a layered appearance; the key test.
• Endomyocardial biopsy only when imaging and bone marrow are unrevealing, and with care for perforation and embolism.

Differential diagnosis.

• Tropical endomyocardial fibrosis, apical hypertrophic cardiomyopathy and cardiac amyloidosis.
• Eosinophilic granulomatosis with polyangiitis and drug induced eosinophilic myocarditis.
• Lymphoma, carcinoid heart disease and infective endocarditis.
• Isolated left ventricular thrombus.

Before steroids in endemic areas: ivermectin 200 microgram/kg orally once daily for 2 days (repeat at 2 weeks) to prevent Strongyloides hyperinfection.

Immunosuppression (necrotic or thrombotic stage, FIP1L1-PDGFRA negative).

• Prednisolone 1 mg/kg orally daily (usual 40 to 60 mg; maximum 80 mg) for 1 to 2 weeks, then taper over 2 to 3 months to the lowest dose that keeps eosinophils under 1.5 x 10^9/L. For life threatening disease, methylprednisolone 1 g intravenously daily for up to 3 days. Monitor glucose, blood pressure, bone health and infection; co-trimoxazole 960 mg three times weekly while on 20 mg or more daily for over 4 weeks.
• Steroid sparing or refractory disease: hydroxycarbamide 500 to 1000 mg orally daily, titrated to a maximum 3 g daily by blood count (full blood count weekly for 4 to 8 weeks, then monthly; halve the dose when creatinine clearance is under 60 mL/min); or mepolizumab 300 mg subcutaneously every 4 weeks (age 12 years and over, where licensed). Interferon alfa is an alternative in specialist hands.

FIP1L1-PDGFRA positive disease. Imatinib 100 mg orally once daily (400 mg daily when the heart is involved), long term. Cover the first 1 to 2 weeks with prednisolone 1 mg/kg daily when there is cardiac involvement, because cardiogenic shock after starting imatinib is reported. Check troponin at baseline and at 1 to 2 weeks; monitor blood count, liver tests, fluid retention and FIP1L1-PDGFRA transcripts every 3 to 6 months. Reduce the dose by 25% in severe hepatic impairment, and adjust for CYP3A4 interactions.

Thrombus and embolism. Enoxaparin 1 mg/kg subcutaneously every 12 hours (once daily when creatinine clearance is under 30 mL/min) until the INR is 2.0 to 3.0 on two consecutive days, then warfarin to INR 2.0 to 3.0, continued while eosinophilia or thrombus persists. Evidence for direct oral anticoagulants is limited.

Heart failure and rhythm. Furosemide 20 to 80 mg orally daily, spironolactone 25 to 50 mg daily with potassium and creatinine checks, and cautious low dose ACE inhibitor. Beta blockers and digoxin are used cautiously because filling is rate dependent. Anticoagulate atrial fibrillation regardless of CHA2DS2-VASc score.

Surgery. Endocardial resection with mitral or tricuspid repair or replacement for refractory symptoms in fibrotic disease. Operative mortality is substantial (often 15 to 20% or more). Transplantation for end stage disease.

Monitoring. Eosinophil count weekly for the first month of treatment, then monthly; troponin and NT-proBNP; echocardiography every 3 to 6 months; MRI at 3 to 6 months and with change.

Referral and escalation. Refer urgently to haematology and cardiology. Admit for embolism, troponin rise, heart failure or eosinophil count over 20 x 10^9/L.

Special groups.

• Pregnancy: avoid imatinib and hydroxycarbamide; prednisolone and low molecular weight heparin are used.
• Children: weight based steroid dosing; imatinib 260 mg/m2 daily for FIP1L1-PDGFRA disease in specialist care.
• Region specific: parasitic causes and tropical endomyocardial fibrosis are frequent in Africa; exclude schistosomiasis, filariasis and Strongyloides in all patients.