Eosinophil-Related Disorders - Eosinophilia

Eosinophilia is an expansion of eosinophil numbers in the blood, due to either a reactive process, such as an allergic reaction or parasitic infection (secondary eosinophilia), or to a neoplastic process that involves clonal eosinophils or their precursors (primary eosinophilia). The eosinophil has potent proinflammatory, prothrombotic, and profibrotic activities. Eosinophilia can accompany a range of disorders from benign diseases, to eosinophilias with organ damage, to eosinophil neoplasms. Given the broad array of diseases associated with eosinophilia, a variety of presentations may prompt testing. The extent of peripheral blood eosinophilia (>500 or >1,500 cells/µL) and the impact of eosinophilia on major organs should be evaluated. Identifying the etiology is essential for treatment decisions, and treating the underlying disorder often will resolve the eosinophilia. In addition to the laboratory tests described below, histopathologic analysis of a tissue biopsy from a relevant site and/or a bone marrow biopsy may be necessary for diagnosis.

Quick Answers for Clinicians

Who should be tested for eosinophil-related disorders?

Patients with eosinophilia discovered during medical evaluations by blood testing or in tissue biopsy, or those with suspicion of eosinophilia based on clinical findings such as rash (particularly with urticarial/edema, pruritus, eczema, blisters) or signs suggestive of systemic illness, should be tested. Cutaneous involvement is a common presenting clinical manifestation.

What constitutes a workup for eosinophil-related disorders?

An initial workup involves a CBC with differential and peripheral blood smear analysis, and then screening for secondary causes (clinically driven testing). Reactive (secondary) eosinophilias are most common, and histopathologic examination of a tissue biopsy may be important for defining the condition. If primary eosinophilia remains likely, then the next steps are histopathologic analysis of a bone marrow biopsy and cytogenetic analysis.

What issues are most important to consider when evaluating a patient with a possible eosinophil-related disorder?

A broad range of conditions can result in secondary/reactive eosinophilia. The workup should be clinically driven to determine cause and should take into account the magnitude of peripheral blood eosinophilia and the effect of eosinophilia on major organs. Due to risks associated with the hyperinfection syndrome, consider testing patients for Strongyloides (Strongyloides immunoglobulin G [IgG] antibody testing) before glucocorticoid administration. Workup for primary/neoplastic eosinophilia should be pursued when secondary/reactive eosinophilia has been ruled out, or if indicated by hematologic signs, such as cytopenias or abnormal blood smear, and/or other specific signs or symptoms, such as fever or mucosal ulcers.

What issues are important when evaluating pediatric patients with possible eosinophil-related disorders?

The presentation and evaluation of eosinophilia may be similar across age groups (children, adolescents, and adults). Allergies and asthma commonly present in childhood. Food allergies and eosinophilic esophagitis may present with vomiting as a symptom (clinical symptoms of eosinophilic esophagitis vary with age). Eosinophilia accompanying immunodeficiency commonly presents in infancy.

What is important in monitoring patients with eosinophil-related disorders?

Monitoring should include assessment for possible end-organ damage because any organ system can be affected by persistent eosinophilia. Monitoring patients for thromboembolic phenomena and cardiac disease (eg, splinter hemorrhages, nail fold infarcts, and cardiac murmur) is also critical because these conditions can be associated with eosinophilia from any cause.

Which testing algorithms are related to this topic?

Indications for Testing

Peripheral blood eosinophilia may be discovered during a screening evaluation or workup for specific symptoms. Patient history (eg, medical or travel history, environmental exposure, drugs) should guide further evaluation.

The presence of eosinophilia in skin biopsy or other tissue biopsy should prompt further evaluation. Cutaneous involvement is a common presenting clinical manifestation.

Definition and Gradations of Peripheral Blood Eosinophilia and Tissue Hypereosinophilia in Eosinophil-Related Diseases
Peripheral Blood Eosinophilia^a	Counts/µL of Blood
Hypereosinophilia	>1,500 recorded on ≥2 determinations with minimum interval of 4 wks (unless immediate designation is required to initiate therapy because of eosinophil-related organ dysfunction)
Eosinophilia	>500-1,500
Normal level of eosinophils	50-500 (1-6% of WBC count range)
Tissue Hypereosinophilia
Percentage of eosinophils exceeds 20% of all nucleated bone marrow cells and/or histopathologic findings reveal extensive eosinophil infiltration or activation/degranulation
^aThe World Health Organization classifies peripheral blood eosinophilia as 1 of 3 levels: mild, with an AEC from the upper limit of normal to 1,500/µL; moderate, with an AEC 1,500–5,000/µL; or severe, with an AEC >5,000/µL. AEC, absolute eosinophil count; WBC, white blood cell Source: Modified from Table 1 in Valent, 2012

Laboratory Testing

Diagnosis

Initial Testing

First-level characterization of a possible eosinophil-related disorder involves a CBC with differential to determine AEC and the percentage of eosinophils within the WBC population. Repeat testing may be indicated for eosinophilia (typically considered >500 cells/µL) but may not be required if absolute counts exceed 1,500 cells/µL, especially in a symptomatic patient (anemia and thrombocytopenia detected on CBC may indicate a neoplasm).

A peripheral blood smear analysis by a hematopathologist can be used to assess eosinophils for abnormal granulation, nuclear segmentation, or size. Abnormal eosinophils may indicate a neoplasm, although abnormalities also can be observed in reactive processes. Abnormalities in other cell lines may contribute to diagnosis.

To identify eosinophil involvement in tissue, especially when eosinophil degranulation may have occurred and intact eosinophils are not identifiable, consider staining for eosinophil granule major basic protein 1 (eMBP1) or another eosinophil-specific marker.

Testing for Secondary/Reactive Eosinophilia

A broad range of conditions can result in secondary/reactive eosinophilia, and a clinically driven workup is needed to determine cause. Conditions commonly associated with eosinophilia include drug reactions, allergy/asthma, hypersensitivity conditions, pulmonary eosinophilic diseases, skin diseases, metabolic conditions, and infections (especially parasitic). Nonmyeloid leukemias also can be implicated. Additional rare conditions include Gleich syndrome and familial eosinophilia. Due to risks associated with hyperinfection syndrome, consider testing all patients for Strongyloides (Strongyloides immunoglobulin G [IgG] antibody testing) before glucocorticoid administration.

See Additional Testing below.

Hematopathologic Assessment

Once secondary causes have been ruled out, consider a tissue and/or bone marrow biopsy, as applicable. Assessment for a possible acute or chronic myeloid or lymphoproliferative disorder may involve the following^,:

Morphologic examination of the blood and bone marrow by histopathology and immunohistochemistry
Cytogenetics
Fluorescence in situ hybridization (FISH)
Flow immunocytometry
T-cell clonality evaluation

Additional Testing

A workup for a patient with eosinophilia may involve a range of other tests, based on history and physical findings. These might include:

Inflammatory, infectious, and immunologic marker tests, such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), antiproteinase 3 and antimyeloperoxidase (c-ANCA and p-ANCA), IgE level, other parasite serologies (in addition to Strongyloides), fungal or viral serologies (HIV, human T-cell leukemia-lymphoma virus), interleukin-5
Metabolic marker tests, such as liver function tests (including aspartate aminotransferase and alanine aminotransferase), renal function tests (including creatinine, blood urea nitrogen [BUN], and urinalysis for protein and sediment), B₁₂ serum level, mast cell/basophil tryptase level, Beta-2 (β₂) microglobulin, lactate dehydrogenase, coagulation factors, troponin (before imatinib treatment), angiotensin-converting enzyme, thyroid and adrenal function tests
Serum protein analyses, such as serum protein electrophoresis, quantitative immunoglobulins, IgG4 subclass level, and immunofixation electrophoresis for monoclonal proteins
Cytogenetic testing (see Hematopathologic Assessment above) to assess for specific chromosomal abnormalities such as FIP1L1-PDGFRA deletion or BCR-ABL1, JAK2 V617F, KIT D816V, or FGFR1 mutations, PDGFRA/PDGFRB rearrangements
Assessment for T-cell receptor gene rearrangement

Monitoring

Monitoring should include assessment for possible end-organ damage because any organ system can be affected by persistent eosinophilia.^, Physical examination as part of monitoring should include assessment for lymphadenopathy and organomegaly, observation for splinter hemorrhages and nail fold infarcts as indicators of thromboembolic phenomenon, and cardiac auscultation to detect murmurs associated with endomyocardial disease. Test selection is clinically driven and also may include imaging and other testing (such as electrocardiogram or pulmonary function tests).