How to evaluate eosinophilia with normal laboratory results?

Evaluation of Eosinophilia with Otherwise Normal Laboratory Results

The evaluation of eosinophilia with otherwise normal laboratory results should begin with concentrated stool microscopy for all patients, followed by a systematic investigation based on travel history, geographical exposure, and clinical presentation. 1

Definition and Classification

Eosinophilia is typically defined as:

• Peripheral blood eosinophil count >500 cells/mm³
• Hypereosinophilia is defined as >1,500 cells/mm³ 2

Eosinophilia can be classified into:

1. Primary (clonal/neoplastic) - Hematologic disorders where eosinophils are part of the neoplastic process
2. Secondary (reactive) - Due to parasitic infections, allergic/inflammatory conditions, or malignancies where eosinophils are not part of the neoplastic process
3. Idiopathic - When no cause is identified after thorough evaluation

Initial Diagnostic Approach

Step 1: Travel and Exposure History

• Detailed travel history including exact timings of exposures:
  • Swimming in freshwater lakes (especially in Africa)
  • Walking barefoot
  • Drinking water sources
  • Foods consumed (raw fish, salads)
  • New medications
  • Recurrent infections 1

Step 2: Laboratory Investigations

1. Complete blood count with differential
2. Comprehensive metabolic panel with uric acid
3. Lactate dehydrogenase and liver function tests
4. Serum tryptase levels
5. Vitamin B12 levels
6. Peripheral blood smear review 1

Step 3: Stool Studies

• Concentrated stool microscopy for ova and parasites (mandatory for all patients with eosinophilia) 1
• Consider gastrointestinal PCR testing for parasites

Step 4: Additional Testing Based on Geographic Exposure

For travelers/migrants from Africa:

• Schistosomiasis serology
• Strongyloides serology
• Filariasis serology

For travelers/migrants from Asia:

• Strongyloides serology
• Filariasis serology
• Consider testing for gnathostomiasis

For travelers/migrants from Latin America:

• Strongyloides serology
• Consider testing for Chagas disease 1

Further Investigations for Persistent Unexplained Eosinophilia

If initial workup is negative:

Allergy Evaluation

• Serum IgE levels
• Allergen-specific IgE testing
• Consider Aspergillus IgE to evaluate for allergic bronchopulmonary aspergillosis 1

Autoimmune Evaluation

• Antineutrophil cytoplasmic antibodies
• Antinuclear antibodies
• Erythrocyte sedimentation rate
• C-reactive protein 1

Hematologic Evaluation

If primary eosinophilia is suspected:

• Bone marrow aspirate and biopsy with:
  • Immunohistochemistry for CD117, CD25, tryptase
  • Reticulin/collagen stains for fibrosis
  • Conventional cytogenetics
  • FISH and/or RT-PCR to detect TK fusion gene rearrangements (PDGFRA, PDGFRB, FGFR1, PCM1-JAK2) 1

Organ-Specific Evaluation

For gastrointestinal symptoms:

• Endoscopy with biopsies (at least 6 biopsies from different sites in the esophagus if eosinophilic esophagitis is suspected) 1

For pulmonary symptoms:

• Chest imaging
• Consider bronchoscopy with bronchoalveolar lavage (BAL eosinophils >10% suggest pulmonary eosinophilia) 3

Common Pitfalls to Avoid

1. Timing issues: Eosinophilia may be transient during tissue migration phase of parasitic infections. Stool samples may be negative during this phase but become positive later 1

2. Cross-reactivity in serological tests: For example, low-level positive filarial serology may occur in strongyloidiasis. Interpret serological tests in the context of epidemiological exposure 1

3. Overlooking drug causes: Many medications can cause eosinophilia and should be carefully reviewed

4. Premature diagnosis of idiopathic hypereosinophilic syndrome: This is a diagnosis of exclusion that requires:

   • Persistent eosinophilia ≥1,500/mm³ for at least 6 months
   • Evidence of end-organ damage
   • Exclusion of all other causes 4

5. Missing clonal disorders: Genetic mutations involving PDGFRA and PDGFRB can cause clonal eosinophilia and predict response to imatinib therapy 4

By following this systematic approach, the underlying cause of eosinophilia can be identified in most cases, allowing for targeted treatment to prevent eosinophil-mediated organ damage.