Lymphocytic Variant Hypereosinophilic Syndrome

Lymphocytic variant hypereosinophilic syndrome is a hypereosinophilia driven by a clonal population of aberrant T cells that make interleukin-5. It mostly affects the skin, and carries a risk of progression to T cell lymphoma.

Pathophysiology. An abnormal T cell clone (most often CD3-negative CD4-positive, or CD3-positive CD4-negative CD8-negative) secretes IL-5, IL-4 and IL-13, which expand and activate eosinophils and raise IgE and IgM.

It is rare and affects adults. The skin is the main target, with lymph node enlargement and a chronic course.

Eosinophil counts may fluctuate, and organ involvement of the heart is uncommon compared with myeloid disease.

• Pruritic eczema, urticaria, angio oedema, erythroderma and skin nodules
• Lymphadenopathy
• Hypereosinophilia that varies over time
• Raised serum IgE and IgM, and polyclonal hypergammaglobulinaemia
• Gastrointestinal, pulmonary and neurological involvement in some
• Raised serum TARC and IL-5

• Blood eosinophil count: 1.5 x 109/L or more on 2 occasions at least 1 month apart, with exclusion of secondary causes (parasites, drugs, allergy, EGPA).
• Peripheral blood flow cytometry: aberrant T cell subset (CD3-negative CD4-positive, or CD3-positive CD4-negative CD8-negative, with CD5 loss).
• T cell receptor gene rearrangement (PCR) showing clonality.
• Serum IL-5, TARC, IgE and IgM.
• Exclude myeloid disease: FIP1L1-PDGFRA, bone marrow biopsy with cytogenetics, tryptase and vitamin B12.
• Skin and lymph node biopsy to look for lymphoma, and CT of chest, abdomen and pelvis.
• Cardiac assessment: troponin and echocardiogram.

Differential diagnosis.

• Myeloid variant hypereosinophilic syndrome
• Reactive eosinophilia and atopic dermatitis
• Cutaneous T cell lymphoma and Sezary syndrome
• Eosinophilic granulomatosis with polyangiitis
• Angiolymphoid hyperplasia with eosinophilia
• Episodic angio oedema with eosinophilia (Gleich syndrome)

• Treat parasites first: in patients from or travelling to endemic regions, give ivermectin 200 microgram/kg orally once daily for 2 days before corticosteroids.
• Corticosteroid: prednisolone 0.5 to 1 mg/kg orally daily (maximum 60 mg), tapered slowly to the lowest effective dose, which is often low dose maintenance.
• Mepolizumab 300 mg subcutaneously every 4 weeks as a steroid sparing agent; relapse or T cell clone expansion should be watched for.
• Steroid sparing and clone directed agents: interferon alpha 1 to 3 million units subcutaneously three times weekly, methotrexate 10 to 20 mg orally once weekly with folic acid 5 mg weekly, hydroxycarbamide 500 mg orally twice daily, or ciclosporin.
• Refractory disease or lymphoma: chemotherapy or alemtuzumab in haematology care.
• Skin care: emollients, topical corticosteroid, and antihistamine (cetirizine 10 mg daily; children 1 to 5 years 2.5 mg twice daily; 6 to 11 years 5 mg twice daily).
• Prophylaxis: co-trimoxazole 960 mg orally three times weekly while on prolonged corticosteroid or other immunosuppression, and bone protection.

Special groups.

• Patients with cardiac involvement: cardiology review and anticoagulation for thrombus.

Monitoring. Eosinophil count, IgE and IgM every 3 months. Lymph node examination at each visit. Whole body imaging yearly for lymphoma. Blood count, liver enzymes and creatinine every 3 months on methotrexate.

Referral and escalation. Refer to haematology and immunology. Urgent for new lymphadenopathy, a rapidly rising eosinophil count, cardiac symptoms, or skin nodules.