Diagnostic Approach for Severe Eosinopenia with Normal Tryptase Levels

Initial Evaluation

The National Comprehensive Cancer Network recommends a comprehensive diagnostic workup for patients with severe eosinopenia and normal tryptase levels, including bone marrow evaluation with cytogenetic and molecular testing to rule out myeloid/lymphoid neoplasms, along with laboratory tests to exclude reactive causes 1, 2
Complete blood count (CBC) with differential should be performed to confirm eosinopenia and assess for other blood count abnormalities (dysplasia, monocytosis, circulating blasts) 1, 3
Comprehensive metabolic panel with uric acid, lactate dehydrogenase, and liver function tests should be conducted 1, 2
Vitamin B12 levels should be checked, as they may be elevated in myeloproliferative variants 1, 3
Peripheral blood smear review is necessary 1
Serum immunoglobulin levels (including IgE) should be measured, as there may be an inverse relationship between IgE levels and blood eosinophil counts in certain conditions 4

Bone marrow aspirate and biopsy with immunohistochemistry (IHC) for CD117, CD25, tryptase, and reticulin/collagen stains for fibrosis should be performed 1, 2, 5
Conventional cytogenetics should be conducted 1
Fluorescence in situ hybridization (FISH) and/or nested reverse transcription PCR (RT-PCR) to detect tyrosine kinase (TK) fusion gene rearrangements should be performed 1, 2
Next-generation sequencing (NGS) via myeloid mutation panels should be used to establish clonality, particularly when no TK fusion gene rearrangements are detected 6, 3
Screening for TK fusion gene rearrangements (PDGFRA, PDGFRB, FGFR1, JAK2, ABL1, or FLT3) is recommended 6
Testing for KIT D816V mutation, which occurs in most patients with systemic mastocytosis, should be conducted 5
Testing for prognostically relevant mutations in other genes (TET2, SRSF2, CBL, ASXL1, RUNX1, JAK2, and/or RAS) is necessary 5

Serology testing for Strongyloides and other parasitic infections should be performed 1, 3
Testing for antineutrophil cytoplasmic antibodies and antinuclear antibodies is recommended 1, 3
Stool ova and parasites test and gastrointestinal polymerase chain reaction (PCR) should be conducted 1, 3
Erythrocyte sedimentation rate and/or C-reactive protein should be measured 1, 3
Aspergillus IgE to evaluate for allergic bronchopulmonary aspergillosis should be tested 1, 3

Flow cytometry (preferred) and/or IHC to identify an immunophenotypically aberrant T-cell population if lymphocyte-variant hypereosinophilic syndrome (L-HES) is suspected should be performed 1, 2
Molecular analysis to confirm T-cell clonality when flow cytometry results are equivocal is necessary 1

Normal tryptase levels do not rule out myeloid neoplasms, as a minority of patients with systemic mastocytosis have normal tryptase levels 5
Avoid premature closure of diagnosis without comprehensive genetic testing, as rare mutations may be present 6, 5