Diagnostic Testing for Severe Eosinopenia with Normal Tryptase Levels
For patients with severe eosinopenia and normal tryptase levels, a comprehensive diagnostic workup should include bone marrow evaluation with cytogenetic and molecular testing to rule out myeloid/lymphoid neoplasms, along with laboratory tests to exclude reactive causes. 1
Initial Laboratory Evaluation
- Complete blood count (CBC) with differential to confirm eosinopenia and assess for other blood count abnormalities (dysplasia, monocytosis, circulating blasts) 1
- Comprehensive metabolic panel with uric acid, lactate dehydrogenase, and liver function tests 1
- Vitamin B12 levels (may be elevated in myeloproliferative variants) 1
- Peripheral blood smear review 1
- Serum immunoglobulin levels (including IgE) - important as there may be an inverse relationship between IgE levels and blood eosinophil counts in certain conditions 2
Bone Marrow Evaluation
- Bone marrow aspirate and biopsy with immunohistochemistry (IHC) for CD117, CD25, tryptase, and reticulin/collagen stains for fibrosis 1
- Conventional cytogenetics 1
- Fluorescence in situ hybridization (FISH) and/or nested reverse transcription PCR (RT-PCR) to detect tyrosine kinase (TK) fusion gene rearrangements 1
- Next-generation sequencing (NGS) via myeloid mutation panels to establish clonality, particularly when no TK fusion gene rearrangements are detected 1
Specific Genetic Testing
- Screening for TK fusion gene rearrangements (PDGFRA, PDGFRB, FGFR1, JAK2, ABL1, or FLT3) 1
- Testing for KIT D816V mutation, which occurs in most patients with systemic mastocytosis 1
- Testing for prognostically relevant mutations in other genes (TET2, SRSF2, CBL, ASXL1, RUNX1, JAK2, and/or RAS) 1
Evaluation for Secondary (Reactive) Causes
- Serology testing for Strongyloides and other parasitic infections 1
- Testing for antineutrophil cytoplasmic antibodies and antinuclear antibodies 1
- Stool ova and parasites test and gastrointestinal polymerase chain reaction (PCR) 1
- Erythrocyte sedimentation rate and/or C-reactive protein 1
- Aspergillus IgE to evaluate for allergic bronchopulmonary aspergillosis 1
Additional Considerations
- Flow cytometry (preferred) and/or IHC to identify an immunophenotypically aberrant T-cell population if lymphocyte-variant hypereosinophilic syndrome (L-HES) is suspected 1
- Molecular analysis to confirm T-cell clonality when flow cytometry results are equivocal 1
- Evaluation for infection, as severe eosinopenia (≤10/μL) has a high specificity (90%) for diagnosing infections 3, 4
Clinical Implications
- Severe eosinopenia with normal tryptase levels may represent a distinct clinical entity from conditions with elevated tryptase 5
- Patients with elevated tryptase are more likely to develop fibroproliferative end-organ damage and have poorer prognosis compared to those with normal tryptase levels 5
- Persistent eosinopenia has been associated with higher mortality in infectious conditions, while resolution of eosinopenia may indicate response to therapy 3, 4
Diagnostic Pitfalls to Avoid
- Do not rely solely on peripheral blood eosinophil counts for diagnosis, as they can fluctuate and may not correlate with tissue involvement 2, 6
- Normal tryptase levels do not rule out myeloid neoplasms, as a minority of patients with systemic mastocytosis have normal tryptase levels 1
- Avoid premature closure of diagnosis without comprehensive genetic testing, as rare mutations may be present 1
- Remember that the relationship between IgE levels and eosinophil counts is complex and may not follow consistent patterns in various clinical conditions 2, 7