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Hypereosinophilic Syndrome

(Idiopathic Hypereosinophilic Syndrome)

By

Jane Liesveld

, MD, James P. Wilmot Cancer Institute, University of Rochester Medical Center

Last full review/revision Jun 2020| Content last modified Jun 2020
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Hypereosinophilic syndrome 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 secondary 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.

Hypereosinophilic syndrome is traditionally defined as peripheral blood eosinophilia > 1500/mcL (> 1.5 × 109/L) persisting 6 months. (See also Eosinophil Production and Function.)

Hypereosinophilic syndrome 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 hypereosinophilic syndrome but who do not fulfill the traditional hypereosinophilic syndrome definition for degree or duration of eosinophilia. Another limitation is that some patients with eosinophilia and organ damage that characterize hypereosinophilic syndrome require treatment earlier than the 6 months necessary to confirm the traditional diagnostic criteria. Eosinophilia of any etiology can cause the same types of tissue damage.

Hypereosinophilic syndrome 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 of hypereosinophilic syndrome (see table 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 B12 levels

  • Hypogranular or vacuolated eosinophils

  • Myelofibrosis

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

A small proportion of patients with the myeloproliferative variant of hypereosinophilic syndrome have cytogenetic changes involving platelet-derived growth factor receptor beta (PDGFRB) and may also be responsive to tyrosine kinase inhibitors such as imatinib (1). Other cytogenetic abnormalities include rearrangement of the gene for fibroblast growth factor receptor 1 (FGFR1) or janus kinase 2 (PCM1-JAK2).

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

  • Angioedema, skin abnormalities, or both

  • Hypergammaglobulinemia (especially high IgE)

  • Circulating immune complexes (sometimes with serum sickness)

Patients with the lymphoproliferative variant also more often respond favorably to corticosteroids and occasionally develop T-cell lymphoma.

Other hypereosinophilic syndrome variants include chronic eosinophilic leukemia, Gleich syndrome (cyclical eosinophilia and angioedema), familial hypereosinophilic syndrome mapped to 5q 31-33, and other organ-specific syndromes. In organ-specific eosinophilic syndromes, eosinophilic infiltration is confined to a single organ (eg, eosinophilic gastrointestinal disease, chronic eosinophilic pneumonia2).

Hyperleukocytosis may occur in patients with eosinophilic leukemia and very high eosinophil counts (eg, > 100,000 cells/mcL [> 100 × 109/L]). 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).

Table
icon

Subtypes of Hypereosinophilic Syndrome

Feature

Myeloproliferative Variant

Lymphoproliferative Variant

Genetics

Rearrangement of PDGFRAPDGFRB, FGFR1, or PCM1-JAK2

Clonal population of T cells with aberrant phenotype

Clinical manifestations and laboratory findings

Anemia

Elevated serum vitamin B12 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

T-cell lymphoma

Responsiveness to drugs

Imatinib and other tyrosine kinase inhibitors

Corticosteroids

General references

  • 1. Apperley JF, Gardembas M, Melo JV, et al: Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 347:481–487, 2002.

  • 2. Gotlib J : World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management. Am J Hematol 92:1243–1259, 2017.

Symptoms and Signs

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

Table
icon

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

Gastrointestinal (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/mcL [> 100 × 109/L]) develop complications of hyperleukocytosis, such as manifestations of brain or lung hypoxia (eg, encephalopathy, dyspnea, respiratory failure). Other thrombotic manifestations (eg, cardiac mural thrombi) may also occur.

Diagnosis

  • Exclusion of secondary eosinophilia

  • Tests to identify organ damage

  • Bone marrow examination with cytogenetic testing

Evaluation for hypereosinophilic syndrome should be considered in patients who have peripheral blood eosinophilia > 1500/mcL (> 1.5 × 109/L) 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.

Evaluation for organ damage should include blood chemistry tests (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-polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) is done to identify the FIP1L1/PDGFRA-associated fusion gene and other possible causes of eosinophilia.

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 and other responsive gene fusions. 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 or other similar gene fusions

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

  • Supportive care

Treatments include immediate therapy, definitive therapies (treatments directed at the disorder itself), and supportive therapies (1).

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 hours, 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 (or similar fusion genes) are usually treated with imatinib (2) 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 allogeneic 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) orally 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 weeks, then tapered. Patients without symptoms and organ damage are monitored for at least 6 months for these complications. If corticosteroids cannot be easily tapered, a corticosteroid-sparing drug (eg, hydroxyurea, interferon alfa) can be used.

Supportive care

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.

Investigational therapy

Mepolizumab and other anti‐interleukin‐5 antibodies are investigational treatments for hypereosinophilic syndrome. Mepolizumab is a fully human monoclonal antibody against interleukin 5 (a regulator of eosinophil production). Mepolizumab decreases eosinophilia and need for high-dose corticosteroid therapy (3) and is currently available for compassionate use in the US for patients with refractory hypereosinophilic syndrome.

Treatment references

Key Points

  • Hypereosinophilic syndrome is peripheral blood eosinophilia (> 1500/mcL [> 1.5 × 109/L]) not caused by parasitic, allergic, or other secondary causes of eosinophilia, that has persisted 6 months and caused organ damage or dysfunction.

  • Hypereosinophilic syndrome 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.

Drugs Mentioned In This Article

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