Approach Considerations
After a thorough workup has excluded causes for secondary eosinophilia, a diagnosis of hypereosinophilic syndrome is suspected in cases of persistent eosinophilia. Any such patients with a documented absolute eosinophil count (AEC) greater than 1500/µL on at least two occasions should be evaluated for hypereosinophilic syndrome, regardless of the presence of symptoms.
A complete blood cell (CBC) count and peripheral smear is warranted. [29]
Serum tryptase levels are elevated in FIP1LI-PDGFRA–positive hypereosinophilic syndrome, as well as systemic mastocytosis with chronic eosinophilic leukemia (SM-CEL). Hence, in such cases, the workup should include the following:
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Bone marrow tryptase levels
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Immunophenotyping of mast cells – Mast cells in systemic mastocytosis coexpress CD117 with CD2 and/or CD25
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Molecular genetic studies to detect FIP1L1-PDGFRA mutation (which is present in hypereosinophilic syndrome and systemic mastocytosis) and C-KIT mutation (which is present in systemic mastocytosis) are done to determine imatinib sensitivity
Bone marrow biopsy should be evaluated for the following :
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Morphologic examinations to look for features of myeloproliferative disorders (MPDs) and to look for dense aggregates of mast cells (greater than 15 cells) in systemic mastocytosis
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Special stains should include reticulin stain for myelofibrosis and tryptase staining for mast cells when serum tryptase levels are elevated
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Cytogenetics: Most patients with hypereosinophilic syndrome have normal karyotypes; in those who have cytogenetic changes, the changes may vary from aneuploidy to Philadelphia chromosome
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Molecular genetic studies: FIP1L1/PDGFRA should be evaluated in all patients with increased tryptase levels; this mutation is present in both hypereosinophilic syndrome and systemic mastocytosis; C-KIT mutation should also be evaluated in patients with increased tryptase levels
Human leukocyte antigen (HLA) typing should be done early in the course of hypereosinophilic syndrome for patients with aggressive disease, cytogenetic aberration, or the FIPL1/PDGFRA fusion gene.
Other studies include the following:
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T-cell immunophenotyping
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T-cell receptor gene rearrangement
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Interleukin-5 (IL-5) levels
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Computed tomography (CT) scanning of the chest, abdomen, and pelvis to look for lymphadenopathy and splenomegaly
Initial evaluation of suspected hypereosinophilic syndrome should include tests to look for any evidence of end-organ damage, as follows:
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Electrocardiography (ECG)
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Echocardiography
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Troponin levels: Increased levels indicate the presence of cardiomyopathy and predict the onset of cardiogenic shock due to imatinib therapy.
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Pulmonary function tests
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Tissue biopsy may be required in symptomatic patients, but is not always essential
Wang has proposed an algorithm for the workup of patients with hypereosinophilia. [30]
Blood Studies
Results of hematologic studies in patients with hypereosinophilic syndrome are as follows:
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Eosinophilia is present (> 1500 cells/µL).
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The overall neutrophil count may be normal, but it is often elevated in hypereosinophilic syndrome; many patients have absolute neutrophilia.
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Approximately 50% of patients with hypereosinophilic syndrome are anemic at presentation, often because of anemia of chronic disease
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Platelet counts are most often normal, but may be elevated.
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Eosinophils in the peripheral blood are mostly mature forms; immature eosinophilic precursors are rare in the peripheral blood.
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Morphologic abnormalities that have been described include nuclear hypersegmentation, hypogranularity, and hypergranularity.
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Cases of hypereosinophilic syndrome with features of myeloproliferative disorder (MPD) show circulating leukocyte precursor anemia and thrombocytopenia or thrombocytosis; teardrops and nucleated red blood cells may be seen.
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A National Institute of Health series indicated that the presence of eosinophils with vacuolization and hypogranularity is more commonly associated with cardiac disease. [24]
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Leukocytosis in excess of 90,000/µL carries a bad prognosis
Other blood study results are as follows:
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Increased serum tryptase level suggests a FIP1L1-PDGFRA mutation; always rule out C-KIT mutation, which is characteristic of systemic mastocytosis whenever serum tryptase is elevated, because disease from the most common form of C-KIT mutation in systemic mastocytosis, Asp 816 to Val, is not responsive to imatinib treatment.
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Interleukin-5 (IL-5 ) levels are elevated in cases of hypereosinophilic syndrome that are associated with clonal T-cell disease; interferon alpha should be considered in such cases due to its down-regulating effects on IL-5 production by T-helper 2 (TH2) cells
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Immunoglobulin E (IgE) levels may be elevated, and hypergammaglobulinemia is common; increased IgE levels have prognostic significance, as these patients have a lower risk of developing hypereosinophilic syndrome–associated cardiovascular disease and respond well to steroid therapy
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Serum vitamin B12 levels may be elevated in the presence of associated myeloproliferative features
Imaging Studies
Echocardiography is helpful in the initial evaluation and monitoring of cardiac disease in patients suspected with hypereosinophilic syndrome. [31] Intracardiac thrombi may be detected, as well as the fibrosis that appears not only as areas of increased echogenicity but often as posterior mitral valve leaflet thickening. Because the papillary muscles are often involved in hypereosinophilic syndrome, mitral and tricuspid dysfunction may also be detected by echocardiography.
CT scanning of the chest, abdomen, and pelvis is done to look for lymphadenopathy and splenomegaly.
Biopsy
An endocardial biopsy may be performed via cardiac catheterization if any question about the diagnosis of hypereosinophilic syndrome exists. [32]
Perform bone marrow aspiration and biopsy, and submit samples for cytogenetic studies. Occasionally, the findings may suggest an atypical presentation of chronic myelogenous leukemia. Cytogenetic abnormalities or the presence of a myeloproliferative picture in the bone marrow may be indicative of more aggressive disease.
If cutaneous involvement is present, skin biopsies may be performed to rule out other diagnoses that have similar skin presentations, such as the following:
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Drug eruptions
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Immunobullous diseases
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Vasculitis
Histologic Findings
Eosinophil infiltrates are present in affected tissues in patients with hypereosinophilic syndrome. Cutaneous histologic features vary with the pattern of presentation. In patients with papular or nodular lesions, perivascular mixed cellular infiltrates (eosinophils and other cell types) are present. However, vasculitis is not present.
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Indurated edematous plaques of hypereosinophilic syndrome on a patient's legs.
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Erythroderma in a patient with hypereosinophilic syndrome.
