Eosinophilic Myocarditis

Eosinophilic myocarditis is myocardial inflammation with infiltration by eosinophils, and is a form of eosinophilic cardiac disease that evolves from an acute necrotic stage through a thrombotic stage to fibrosis (Loeffler endocarditis, endomyocardial fibrosis) and restrictive cardiomyopathy.

Eosinophilia is defined as an absolute eosinophil count over 0.5 x 109/L and hypereosinophilia as 1.5 x 109/L or more, but counts can be normal at presentation, especially after steroid exposure or early in the course. Causes are:

• Hypereosinophilic syndromes (idiopathic, lymphocytic variant, or myeloid neoplasm with FIP1L1-PDGFRA fusion, also called chronic eosinophilic leukaemia)
• Eosinophilic granulomatosis with polyangiitis (EGPA), in which cardiac involvement is the leading cause of death
• Drug hypersensitivity, including drug reaction with eosinophilia and systemic symptoms (antibiotics such as penicillins and sulphonamides, carbamazepine, clozapine, dapsone, mesalazine, tetracyclines, some vaccines), usually 2 to 8 weeks after starting the drug
• Parasitic infection: toxocariasis, trichinellosis, schistosomiasis, strongyloidiasis, filariasis including loiasis, and others
• Malignancy, and rare immune checkpoint inhibitor reactions

Endomyocardial fibrosis is a related disease of the tropics, including Africa, in which eosinophils may play a role.

Pathophysiology. Eosinophil granule proteins (major basic protein, eosinophil cationic protein, peroxidase) injure myocytes and endothelium and activate coagulation.

Mural thrombi form on the damaged endocardium, mostly at the apex and inflow of both ventricles, and organise into a fibrotic shell that restricts filling and distorts the atrioventricular valves, causing regurgitation.

• Fever, rash, myalgia, dyspnoea, chest pain, palpitations, and heart failure or cardiogenic shock. Ventricular arrhythmia and conduction block.
• Embolic events (stroke, limb or visceral ischaemia) from mural thrombi.
• Features of the cause: asthma, sinusitis and neuropathy (EGPA), skin lesions, lymphadenopathy, hepatosplenomegaly and drug exposure (hypersensitivity), and travel or residence in a parasite endemic region.
• Late disease: restrictive physiology with raised venous pressure, oedema, ascites, mitral and tricuspid regurgitant murmurs.

Red flags.

• Cardiogenic shock, ventricular arrhythmia or high grade block
• Troponin rise with eosinophilia
• Left or right ventricular thrombus, or embolic events
• Eosinophil count of 1.5 x 109/L or more with organ damage
• Features of EGPA (asthma, ANCA positivity, neuropathy, sinusitis)
• Recent new drug, particularly 2 to 8 weeks earlier
• Risk of Strongyloides hyperinfection before steroids, or high Loa loa microfilaraemia before ivermectin

• Full blood count with differential and film. Eosinophil count, repeated. Blood film for dysplasia and blasts.
• Troponin, natriuretic peptide, ECG (non-specific ST-T change, conduction block, arrhythmia).
• Echocardiography. Thickened walls, apical obliteration with thrombus, restrictive filling, and mitral and tricuspid regurgitation.
• Cardiac MRI. Subendocardial late gadolinium enhancement, a layered pattern with overlying thrombus, and oedema.
• Endomyocardial biopsy. Eosinophilic infiltrate with degranulation and necrosis, and exclusion of giant cell and lymphocytic myocarditis. Coronary angiography or CT to exclude coronary disease and vasculitis.
• Cause workup. ANCA (anti-MPO), IgE, vitamin B12 and tryptase (raised in myeloid neoplasm), bone marrow examination with FIP1L1-PDGFRA testing and T-cell clonality, stool ova and parasites on 3 samples, serology for Strongyloides, Schistosoma, Toxocara and Trichinella, a blood film or day and night samples for filarial microfilariae including Loa loa count, HIV, and a drug history.

Differential diagnosis.

• Lymphocytic (viral) myocarditis and giant cell myocarditis
• Immune checkpoint inhibitor myocarditis
• Acute coronary syndrome and takotsubo syndrome
• Endomyocardial fibrosis without active inflammation
• Restrictive and hypertrophic cardiomyopathy, and amyloidosis
• Chagas disease
• Infective endocarditis and non-bacterial thrombotic endocarditis
• Peripartum cardiomyopathy
• Sarcoidosis

• Stop the culprit drug and treat any identified infection.
• Before corticosteroids in or from endemic regions: treat empirically for Strongyloides with ivermectin 200 microgram/kg orally once daily for 2 days, repeated after 2 weeks, with food. Check for Loa loa first: avoid ivermectin when microfilaraemia is 20,000/mL or more, because of the risk of encephalopathy, and involve a tropical medicine specialist. Contraindicated in pregnancy except for life threatening disease, and reduce or avoid in severe liver impairment.
• Corticosteroids (first line for severe disease). Methylprednisolone 500 to 1,000 mg intravenously once daily for 3 days for fulminant disease or shock, or prednisolone 1 mg/kg orally once daily (maximum 60 to 80 mg) for milder disease, then taper by 10 mg every 1 to 2 weeks as eosinophils, troponin and imaging allow, over 3 to 6 months or longer. Add calcium and vitamin D and a proton pump inhibitor. Prophylaxis with co-trimoxazole 960 mg orally three times weekly (or 480 mg once daily; halve at creatinine clearance 15 to 30 mL/min and avoid under 15 mL/min) if steroids last over 4 weeks.
• Cause directed therapy.
  • FIP1L1-PDGFRA positive disease: imatinib 100 mg orally once daily, increased to 400 mg daily if the response is inadequate, with steroid cover (prednisolone 1 mg/kg) for the first 7 to 10 days because of reported cardiogenic shock after starting it, and troponin monitoring. Check liver enzymes, full blood count and fluid retention. Reduce in severe liver impairment.
  • EGPA with cardiac involvement: prednisolone 1 mg/kg orally once daily plus cyclophosphamide 15 mg/kg intravenously every 2 weeks for 3 doses, then every 3 weeks (reduce the dose at creatinine clearance under 30 mL/min), with mesna and antiemetics, or rituximab 375 mg/m2 intravenously weekly for 4 weeks. Monitor full blood count at day 10 to 14. Contraindicated in pregnancy. Maintenance with azathioprine 2 mg/kg orally once daily (check TPMT or NUDT15) or mepolizumab 300 mg subcutaneously every 4 weeks for relapsing disease.
  • Idiopathic or lymphocytic hypereosinophilic syndrome needing a steroid sparing agent: mepolizumab 300 mg subcutaneously every 4 weeks.
  • Parasitic infection: praziquantel 40 mg/kg orally as a single dose for schistosomiasis, albendazole 400 mg orally twice daily for 5 to 14 days (by organism) for toxocariasis or trichinellosis, with infectious diseases input. Steroids are used with antiparasitic cover when inflammation is severe.
• Intracardiac thrombus: warfarin 5 mg orally once daily at the start (2 to 3 mg in older adults, liver impairment or interacting drugs), adjusted to an INR of 2.0 to 3.0, no fixed maximum, for at least 3 to 6 months, with INR every 2 to 3 days at the start, weekly until stable, then every 4 to 12 weeks. Use unfractionated heparin 80 units/kg bolus then 18 units/kg/h, adjusted to anti-Xa 0.3 to 0.7 IU/mL, as a bridge.
• Heart failure. Furosemide 40 mg orally once daily in the morning, increased to 80 to 120 mg daily as needed (higher doses in renal impairment under specialist care), with sodium, potassium and creatinine monitoring. Heart failure therapy otherwise as tolerated. Mechanical support for shock.
• Surgery. Endocardial resection with valve repair or replacement for advanced fibrotic restriction or severe valve disease. Transplantation is rare.

Special groups. Pregnancy: prednisolone is compatible, and imatinib, cyclophosphamide and methotrexate are not.

Monitoring. Eosinophil count and troponin weekly during the taper. Echocardiography or cardiac MRI at 1 and 3 months, then every 6 to 12 months. INR every 4 to 12 weeks once stable (target 2.0 to 3.0). Glucose, blood pressure and bone health on steroids.

Referral and escalation. Refer to a cardiology centre with biopsy and haematology access. Urgent for shock, arrhythmia, intracardiac thrombus or progressive eosinophilia.