Lymphocyte-variant hypereosinophilia

Did You Know?

• Supernatant fluid from the patient's T cells induced eosinophil CFUs from a non-identical donor's bone marrow cells.
• The T cells from that patient expressed CD4 but not CD8, suggesting they were cytokine-secreting helper T cells.

Presentation

The typical patient presents with an extended history of hypereosinophilia and cutaneous allergy-like symptoms. Skin symptoms, occurring in over 75% of patients, include erythroderma, pruritus, eczema, poikiloderma, urticarial, and episodic angioedema. The episodic angioedema resembles that seen in Gleich's syndrome, which involves a sub-population of CD3(-), CD4(+) T cells, suggesting Gleich's syndrome is a subtype of this disorder. Biopsies of skin lesions often show prominent eosinophil accumulations. Other presentations include lymphadenopathy in about 60% of patients, eosinophil infiltrations in the lung (often diagnosed as eosinophilic pneumonia) in about 20%, episodic angioedema-related gastrointestinal symptoms similar to irritable bowel syndrome in about 20%, rheumatologic manifestations of inflammatory arthralgias in about 20%, and splenomegaly in about 10%. Cardiovascular complications such as eosinophilic myocarditis and vascular thrombosis are not prominent, occurring in fewer than 10% of patients. Lymphoid neoplasms can be associated with eosinophilia due to secretion of eosinophil-stimulating cytokines by malignant cells, commonly seen in cutaneous T cell lymphoma, adult T-cell leukemia/lymphoma, and angioimmunoblastic T cell lymphoma, and less often in B cell neoplasms like Hodgkin's lymphoma and B cell acute lymphoblastic leukemia with the t(5;9)(q31;p24) translocation creating a JAK2-IL3 fusion gene.

Pathogenesis

Studies identified interleukin 5 (IL5) as the eosinophil growth-stimulating cytokine produced by T cells from patients with idiopathic hypereosinophilic syndrome, and later from patients with lymphocyte-variant hypereosinophilia. The disorder is characterized by hypereosinophilia secondary to pathological production of eosinophil growth factors, particularly IL5 but possibly also IL4, IL13, and GM-CSF, by aberrant T cell clones. The immunophenotype of these clones varies, with common types including CD3(-), CD4(+) T cells; CD3(+), CD4(+), CD8(-) T cells; CD3(+), CD4(+), CD7(-) T cells bearing αβ+ T cell receptors; CD3(+), CD4(+), CD7(-) T cells; and CD3(+), CD4(+), CD2(-) T cells. Chromosome abnormalities such as breakage of the long arm of chromosome 16, partial deletions in the q arm of chromosome 6 or p arm of chromosome 10, and trisomy 7 are occasionally detected. These T cells typically express CD45RO plus HLA-DR and/or IL2RA (CD25), markers of activated memory T cells.

Diagnosis

Criteria for diagnosis have not been strictly set forth. Other causes of eosinophilia must first be ruled out, including allergies, drug reactions, infestations, autoimmune diseases, eosinophilic leukemia, clonal eosinophilia, systemic mastocytosis, and other malignancies. Diagnostic criteria include long-term hypereosinophilia (eosinophil blood counts over 1,500 per microliter) with associated physical findings and symptoms; bone marrow analysis showing high eosinophil levels; elevated serum levels of immunoglobulin E, other immunoglobulins, and CCL17; eosinophil infiltrates in afflicted tissues; increased numbers of blood or bone marrow T cells bearing abnormal immunophenotype cluster of differentiation markers as defined by fluorescence-activated cell sorting; abnormal T cell receptor arrangements as defined by polymerase chain reaction; and evidence of excessive IL-5 secretion by lymphocytes. In many clinical settings, studies on T cell receptor and IL-5 are not available. The finding of T cells bearing abnormal immunophenotype markers is critical to making the diagnosis.

Treatment

The disorder usually takes a benign and indolent course. Long-term treatment with corticosteroids lowers blood eosinophil levels and suppresses complications in over 80% of cases, but signs and symptoms recur if dosages are tapered. Alternate treatments for corticosteroid-resistant disease or as corticosteroid-sparing substitutes include interferon-α or peginterferon alfa-2a, mepolizumab (an anti-IL-5 antibody), ciclosporin, imatinib, methotrexate, hydroxycarbamide, and alemtuzumab. Most patients treated with these alternate drugs have shown good responses. Reslizumab, an anti-IL-5 antibody, may also be of use. Patients with minimal or no complications may go untreated. In 10% to 25% of patients, mostly 3 to 10 years after diagnosis, the disease escalates to angioimmunoblastic T-cell lymphoma, peripheral T cell lymphoma, anaplastic large-cell lymphoma (anaplastic lymphoma kinase-negative), or cutaneous T cell lymphoma. This transformed disease is aggressive with poor prognosis; recommended treatment includes chemotherapy with fludarabine, cladribine, or the CHOP combination followed by bone marrow transplantation.