Hypereosinophilic Syndrome

Hypereosinophilic syndrome is a persistent blood eosinophilia of 1.5 x 109/L or more (on 2 occasions at least 1 month apart) with eosinophil related organ damage, and no secondary cause. It includes myeloid, lymphocytic, idiopathic and overlap forms.

Pathophysiology. Eosinophils release toxic granule proteins and cytokines that injure heart, lung, skin, gastrointestinal tract, nerves and blood vessels, and promote thrombosis. Causes are clonal myeloid neoplasms (PDGFRA, PDGFRB, FGFR1, JAK2 rearrangement), IL-5-producing T cell clones, and unknown mechanisms.

Disease is rare, and usually appears in adults aged 20 to 50.

Organ damage, in particular cardiac (endomyocardial fibrosis, thrombus) and neurological, determines outcome.

• Fatigue, fever, weight loss, night sweats
• Skin: itching, eczema, urticaria, angio oedema, ulcers
• Cardiac: heart failure, endomyocardial fibrosis, mural thrombus, valve regurgitation
• Respiratory: cough, wheeze, pulmonary infiltrates
• Gastrointestinal: pain, diarrhoea, eosinophilic oesophagitis and colitis
• Neurological: neuropathy, stroke, encephalopathy
• Thromboembolism and splenomegaly
• Hepatosplenomegaly in myeloid disease

• Blood eosinophil count: 1.5 x 109/L or more on 2 occasions at least 1 month apart (or tissue hypereosinophilia), with organ damage attributed to eosinophils.
• Exclusion of secondary causes: parasites (stool microscopy, Strongyloides and Toxocara serology, including travel history), drugs, allergy, EGPA (ANCA), lymphoma, solid tumour, adrenal insufficiency, HIV.
• Baseline tests: tryptase, vitamin B12, IgE, immunoglobulins, liver enzymes, troponin, creatinine, ANCA.
• Organ assessment: ECG, echocardiogram and cardiac MRI, chest CT, lung function, abdominal imaging, nerve conduction as indicated.
• Clonality tests: FIP1L1-PDGFRA by FISH or RT-PCR (blood), bone marrow biopsy with cytogenetics, and testing for PDGFRB, FGFR1 and JAK2 rearrangements.
• Lymphocyte immunophenotype and T cell receptor clonality for the lymphocytic variant.

Differential diagnosis.

• Secondary (reactive) eosinophilia: parasitic, drug, allergic
• Eosinophilic granulomatosis with polyangiitis
• Chronic eosinophilic leukaemia and myeloid neoplasm with eosinophilia
• Lymphoma and T cell neoplasm
• Systemic mastocytosis with eosinophilia
• Idiopathic hypereosinophilia without organ damage

• Treat parasites first: in patients from or travelling to endemic regions, give ivermectin 200 microgram/kg orally once daily for 2 days before corticosteroids, to prevent Strongyloides hyperinfection.
• Emergency (organ threatening) disease: prednisolone 1 mg/kg orally daily (maximum 60 mg), tapered over 4 to 8 weeks to the lowest effective dose. For suspected PDGFRA-positive disease with cardiac involvement, give prednisolone before imatinib.
• PDGFRA-positive disease: imatinib 100 mg orally once daily (400 mg daily if PDGFRB positive or cardiac involvement), with remission in most. Monitor troponin and echocardiogram during the first weeks.
• FIP1L1-PDGFRA negative, corticosteroid dependent disease: mepolizumab 300 mg subcutaneously every 4 weeks.
• Alternatives: hydroxycarbamide 500 mg orally twice daily (adjust to blood count), interferon alpha, and ciclosporin or methotrexate for steroid sparing.
• Cardiac disease: heart failure treatment, and anticoagulation with warfarin or a direct oral anticoagulant for thrombus or thromboembolism.
• Refractory or aggressive myeloid disease: referral for tyrosine kinase inhibitor therapy and allogeneic stem cell transplant.
• Supportive care: *Pneumocystis* prophylaxis (co-trimoxazole 960 mg three times weekly) on prolonged corticosteroids, with bone protection.

Special groups.

• Patients with mural thrombus or embolism: anticoagulation reduces further events.
• Pregnancy: avoid imatinib, and use prednisolone with specialist input.

Monitoring. Eosinophil count and troponin at every visit. Echocardiogram and cardiac MRI every 6 to 12 months. Blood count, liver enzymes and creatinine every 3 months. Imatinib: troponin and echo in the first weeks.

Referral and escalation. Refer urgently to haematology, with cardiology and immunology input. Emergency for heart failure, stroke, thromboembolism or respiratory distress.