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Hypereosinophilic Syndrome

(Idiopathic Hypereosinophilic Syndrome)

by Jane Liesveld, MD, Patrick Reagan, MD

Hypereosinophilic syndrome (HES) is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the absence of parasitic, allergic, or other causes of eosinophilia. Symptoms are myriad, depending on which organs are dysfunctional. Diagnosis involves excluding other causes of eosinophilia plus bone marrow and cytogenetic tests. Treatment usually begins with prednisone and, in one common subtype, includes imatinib.

HES is traditionally defined as peripheral blood eosinophilia > 1500/μL persisting6 mo. HES was previously considered to be idiopathic but is now known to result from various disorders, some of which have known causes. One limitation of the traditional definition is that it does not include those patients with some of the same abnormalities (eg, chromosomal defects) that are known causes of HES but who do not fulfill the traditional HES diagnostic criteria for degree or duration of eosinophilia. Another limitation is that some patients with eosinophilia and organ damage that characterize HES require treatment earlier than the 6 mo necessary to confirm the traditional diagnostic criteria.

HES is rare, has an unknown prevalence, and most often affects people age 20 through 50. Only some patients with prolonged eosinophilia develop organ dysfunction that characterizes hypereosinophilic syndrome. Although any organ may be involved, the heart, lungs, spleen, skin, and nervous system are typically affected. Cardiac involvement can cause significant morbidity and mortality.

Subtypes

There are two broad subtypes ( Subtypes of Hypereosinophilic Syndrome):

  • Myeloproliferative variant

  • Lymphoproliferative variant

The myeloproliferative variant is often associated with a small interstitial deletion in chromosome 4 at the CHIC2 site that causes the FIP1L1/PDGFRA -associated fusion gene (which has tyrosine kinase activity that can transform hematopoietic cells). Patients often have

  • Splenomegaly

  • Thrombocytopenia

  • Anemia

  • Elevated serum vitamin B 12 levels

  • Hypogranular or vacuolated eosinophils

  • Myelofibrosis

Patients with this subtype often develop endomyocardial fibrosis and may rarely develop acute myeloid or lymphoblastic leukemia. Patients with the FIP1L1/PDGFRA -associated fusion gene are more often males and may be responsive to low-dose imatinib.

The lymphoproliferative variant is associated with a clonal population of T cells with aberrant phenotype. PCR shows a clonal T cell receptor rearrangement. Patients more often have

  • Angioedema, skin abnormalities, or both

  • Hypergammaglobulinemia (especially IgE)

  • Circulating immune complexes (sometimes with serum sickness)

They also more often respond favorably to corticosteroids and occasionally develop T-cell lymphoma.

Other HES variants include chronic eosinophilic leukemia, Gleich syndrome (cyclical eosinophilia and angioedema), familial hypereosinophilic syndrome mapped to 5q 31-33, and other organ-specific syndromes. Hyperleukocytosis may occur in patients with eosinophilic leukemia and very high eosinophil counts (eg, > 100,000 cells/μL). Eosinophils can form aggregates that occlude small blood vessels, causing tissue ischemia and microinfarctions. Common manifestations include brain or lung hypoxia (eg, encephalopathy, dyspnea or respiratory failure).

Subtypes of Hypereosinophilic Syndrome

Feature

Myeloproliferative Variant

Lymphoproliferative Variant

Genetics

Small interstitial deletion in chromosome 4

FIP1L1/PDGFRA -associated fusion gene

Clonal population of T cells with aberrant phenotype

Clinical manifestations and laboratory findings

Anemia

Elevated serum vitamin B 12 levels

Endomyocardial fibrosis

Hypogranular or vacuolated eosinophils

Myelofibrosis

Splenomegaly

Thrombocytopenia

Angioedema

Circulating immune complexes (sometimes with serum sickness)

Hypergammaglobulinemia (especially IgE)

Skin abnormalities

Increased risk of future disorder

Acute lymphoblastic leukemia

Acute myeloid leukemia

T-cell lymphoma

Responsiveness to drugs

Imatinib and other tyrosine kinase inhibitors

Corticosteroids

Symptoms and Signs

Symptoms are diverse and depend on which organs are dysfunctional ( Abnormalities in Patients With Hypereosinophilic Syndrome).

Abnormalities in Patients With Hypereosinophilic Syndrome

System

Prevalence

Manifestations

Constitutional

50%

Anorexia

Fatigue

Fever

Myalgias

Weakness

Weight loss

Cardiopulmonary

> 70%

Mural thrombi with emboli

Restrictive or infiltrative cardiomyopathy or mitral or tricuspid regurgitation with cough, dyspnea, heart failure, arrhythmias, endomyocardial disease, pulmonary infiltrates, and pleural effusions

Dermatologic

> 50%

Angioedema

Dermatographism

Pruritus

Rashes (including eczema and urticaria)

Hematologic

> 50%

Anemia

Lymphadenopathy

Splenomegaly

Thromboembolic phenomena

Thrombocytopenia

Neurologic

> 50%

Cerebral emboli with focal deficits

Diffuse encephalopathy with altered behavior and cognitive function and spasticity

Peripheral neuropathy

GI

> 40%

Abdominal cramps

Diarrhea

Nausea

Immunologic

40%

Circulating immune complexes with serum sickness

Elevated levels of immunoglobulins (especially IgE)

Occasionally, patients with very severe eosinophilia (eg, eosinophil counts of > 100,000/μL) develop complications of hyperleukocytosis, such as manifestations of brain or lung hypoxia (eg, encephalopathy, dyspnea or respiratory failure).

Diagnosis

  • Exclusion of secondary eosinophilia

  • Tests to identify organ damage

  • Bone marrow examination with cytogenetic testing

Evaluation for HES should be considered in patients who have peripheral blood eosinophilia >1500/μL present on more than one occasion that is unexplained, particularly when there are manifestations of organ damage. Testing to exclude disorders causing eosinophilia should be done (see Testing). Further evaluation for organ damage should include blood chemistries (including liver enzymes, creatine kinase, renal function, and troponin); ECG; echocardiography; pulmonary function tests; and CT of the chest, abdomen, and pelvis. Bone marrow aspirate and biopsy with flow cytometry, cytogenetic testing, and reverse transcriptase-PCR or fluorescence in situ hybridization (FISH) is done to identify the FIP1L1/PDGFRA -associated fusion gene and other possible causes of eosinophilia (eg, BCR-ABL abnormalities characteristic of chronic myelogenous leukemia).

Prognosis

Death usually results from organ, particularly heart, dysfunction. Cardiac involvement is not predicted by the degree or duration of eosinophilia. Prognosis varies depending on response to therapy. Response to imatinib improves the prognosis among patients with the FIP1L1/PDGFRA -associated fusion gene. Current therapy has improved prognosis.

Treatment

  • Corticosteroids for hypereosinophilia and often for ongoing treatment of organ damage

  • Imatinib for patients with the FIP1L1/PDGFRA -associated fusion gene

  • Sometimes drugs to control eosinophil counts (eg, hydroxyurea, interferon alfa, etoposide, cladribine)

  • Supportive therapy

Treatments include immediate therapy, definitive therapies (treatments directed at the disorder itself), and supportive therapies.

Immediate therapy

For patients with very severe eosinophilia, complications of hyperleukocytosis, or both (usually patients with eosinophilic leukemia), high-dose IV corticosteroids (eg, prednisone 1 mg/kg or equivalent) should be initiated as soon as possible. If the eosinophil count is much lower (eg, by 50%) after 24 h, corticosteroid dose can be repeated daily; if not, an alternative treatment (eg, hydroxyurea) is begun. Once the eosinophil count begins to decline and is under better control, additional drugs may be started.

Definitive therapy

Patients with the FIP1L1/PDGFRA -associated fusion gene are usually treated with imatinib and, particularly if heart damage is suspected, corticosteroids. If imatinib is ineffective or poorly tolerated, another tyrosine kinase inhibitor (eg, dasatinib, nilotinib, sorafenib) can be used, or allogenic hematopoietic stem cell transplantation can be used.

Patients without the FIP1L1/PDGFRA -associated fusion gene, even if asymptomatic, are often given one dose of prednisone 60 mg (or 1 mg/kg) po to determine corticosteroid responsiveness (ie, a decrease in the eosinophil count). In patients with symptoms or organ damage, prednisone is continued at the same dose for 2 wk, then tapered. Patients without symptoms and organ damage are monitored for at least 6 mo for these complications. If corticosteroids cannot be easily tapered, a corticosteroid-sparing drug (eg, hydroxyurea, interferon alfa) can be used. Mepolizumab, a fully human monoclonal antibody against interleukin-5 (a regulator of eosinophil production), is undergoing clinical trials.

Supportive therapy

Supportive drug therapy and surgery may be required for cardiac manifestations (eg, infiltrative cardiomyopathy, valvular lesions, heart failure). Thrombotic complications may require the use of antiplatelet drugs (eg, aspirin, clopidogrel, ticlopidine); anticoagulation is indicated if a left ventricular mural thrombus is present or if transient ischemic attacks persist despite use of aspirin.

Key Points

  • Hypereosinophilic syndrome (HES) is peripheral blood eosinophilia (> 1500/μL) not caused by parasitic, allergic, or other secondary causes of eosinophilia, that has persisted6 mo and caused organ damage or dysfunction.

  • HES appears to be a manifestation of a number of hematopoietic disorders, some of which have a genetic cause.

  • Any organ may be involved but the heart, lungs, spleen, skin, and nervous system are typically affected; cardiac involvement can cause significant morbidity and mortality.

  • Do tests for organ involvement, including liver enzymes; creatine kinase, creatinine, and troponin levels; ECG and echocardiography; pulmonary function tests; and CT of the chest, abdomen, and pelvis.

  • Do bone marrow examination with cytogenetic testing to identify a cause.

  • Give corticosteroids for severe eosinophilia and/or organ damage. Tyrosine kinase inhibitors such as low-dose imatinib may be of benefit in subtypes associated with distinct chromosomal abnormalities.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • GLEEVEC
  • RAYOS
  • No US brand name
  • HYDREA
  • ETOPOPHOS
  • SPRYCEL
  • TASIGNA
  • NEXAVAR
  • PLAVIX

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