Eosinophil-Associated Diseases

Diagnosis

Indications for Testing

  • Known or suspected eosinophil involvement in disease either by the presence or absence of identifiable intact eosinophils in tissue and/or peripheral blood
    • When eosinophils degranulate in disease, their presence and contribution to pathogenesis may not be identified by routine tissue staining

Laboratory Testing

  • Eosinophilic esophagitis (EoE) evaluation – food allergy testing using serum IgE specific tests or skin prick testing
    • Consider for EoE presenting in children
  • Pulmonary symptoms – consider the following disorders
    • Allergic bronchopulmonary aspergillosis (ABPA) testing
      • Primary diagnostic criteria for ABPA (IDSA, 2008)
        • Asthma
        • Peripheral eosinophilia
        • Immediate scratch test reactivity to Aspergillus antigen
        • Precipitating antibodies to Aspergillus antigen
        • Elevated serum IgE concentrations
        • History of pulmonary infiltrates (transient or fixed)
        • Central bronchiectasis
      • Aspergillus specific IgE and IgG are usually present in the sera of patients with ABPA
      • Total serum IgE should be followed during disease – increase in IgE may herald a relapse of disease
    • Eosinophilic granulomatosis with polyangiitis
      • pANCA testing
      • Histology
    • Disease-specific testing for other eosinophil-associated diseases
  • Hypereosinophilia
    • Exclude reactive causes – including those listed above
    • Screen for mutations using PCR/FISH (FIP1L1-PDGFRA)
    • Bone marrow biopsy with cytogenic evaluation

Histology

  • Biopsy of appropriate tissue site with staining for eosinophil major basic protein (eMBP)
    • Eosinophil-associated skin diseases – skin biopsy demonstrates few to many intact eosinophils
      • Biopsy staining typically reveals extracellular eMBP; often out of proportion to number of intact eosinophils
    • Eosinophilic fasciitis – skin, fascia biopsy
    • EoE – esophageal biopsy demonstrating >20 epithelial eosinophils per high-power field (HPF)
      • Biopsy staining also reveals extracellular eMBP
    • Eosinophilic vasculitis – angiocentric eMBP staining
    • Extracellular eMBP found in urticaria and atopic dermatitis
  • Bone marrow biopsy – necessary to rule out malignancy
    • Should include cytogenetics, immunophenotyping 
      • T-cell and B-cell markers
      • CD34, CD25
      • Tryptase
      • Platelet marker
      • c-Kit mutation

Differential Diagnosis

  • See list of disorders in Clinical Background

Clinical Background

Eosinophil-associated diseases occur in all epithelial organs, including the skin, upper and lower respiratory tract, gastrointestinal tract, urinary tract, and heart. Following is a partial list of eosinophil-associated diseases.

  • Allergies, including allergic conjunctivitis and allergic rhinitis
  • Allergic inflammation, other
  • Capillary leak syndrome (interleukin-2 associated)
  • Eosinophilic cystitis
  • Eosinophilic endomyocardial disease
  • Eosinophilic gastrointestinal disease (EGID)
    • Eosinophilic colitis
    • Eosinophilic enteritis
    • Eosinophilic esophagitis (EoE)
    • Eosinophilic gastritis
    • Eosinophilic gastroenteritis
  • Eosinophilic otitis media
  • Eosinophilic otorhinolaryngologic disease
    • Allergic fungal sinusitis
    • Chronic rhinosinusitis
  • Eosinophilic pulmonary disease
    • Acute eosinophilic pneumonia
    • Allergic bronchopulmonary aspergillosis (ABPA)
      • ABPA – inflammatory disease of the lungs
      • Symptoms
        • Severe asthma
        • Sputum production
        • Peripheral blood eosinophilia
        • Increased total serum IgE concentration
      • May progress to central bronchiectasis and ultimately pulmonary fibrosis and death if untreated
    • Asthma
    • Chronic eosinophilic pneumonia
    • Churg-Strauss syndrome
    • Eosinophilic bronchitis
  • Eosinophilic skin disease
    • Angiolymphoid hyperplasia with eosinophilia
    • Atopic dermatitis
    • Bullous pemphigoid and other immune-mediated blistering skin diseases
    • Eosinophilic cellulitis (Wells syndrome)
    • Eosinophilic pustular folliculitis
    • Eosinophilic ulcer of the oral mucosa
    • Eosinophilic vasculitis (EV)
    • Episodic angioedema with eosinophilia (Gleich syndrome)
    • Erythema toxicum neonatorum
    • Facial edema with eosinophilia
    • Kimura disease
    • Pachydermatous eosinophilic dermatitis
    • Prurigo nodularis
    • Urticaria, chronic, physical and idiopathic, and angioedema
  • Eosinophilic soft tissue/muscle disease (often shows skin manifestations)
    • Eosinophilic fasciitis
    • Eosinophilia myalgia syndrome
    • Eosinophilic myositis
    • Nodules, eosinophilia, rheumatism dermatitis, swelling syndrome
    • Toxic oil syndrome
  • Hematopoietic eosinophilia – eosinophilic leukemia, chronic myeloid leukemia
  • Hypereosinophilic disorders (Working Conference on Eosinophilic Disorders and Syndromes, 2011)    
    • Familial – hereditary (HEFA)
    • Primary – clonal/neoplastic (HEN)
    • Lymphocytic variant
    • Myeloproliferative variant 
    • Secondary – reactive (HER)
    • Undetermined significance (HEUS)
    • Hypereosinophic syndrome (HES)
  • Immunologic disorders
  • Malignancy-associated eosinophilia
  • Medication and food reactions, including drug hypersensitivity syndrome
    • Anti-seizure drugs
    • Anti-tuberculosis drugs
    • Contaminated rape seed oil in Spain
    • L-tryptophan
    • Sulfamethoxazole and other antibiotics
  • Parasitism, parasitic inflammation, ectoparasites
  • Sclerosing disorders

Epidemiology

  • Incidence varies from rare to common
    • Common – asthma, allergies, atopic dermatitis
    • Rare – HES, Kimura disease, EV
  • Age
    • Eosinophil-associated diseases generally present in adults, except for asthma, allergies, atopic disease
  • Sex
    • M>F for myeloproliferative variant of HES, Kimura, EoE
    • M<F for eosinophilic cystitis, toxic oil syndrome, eosinophilic otitis media
  • Ethnicity
    • Asian – Kimura disease

Risk Factors

Pathophysiology

  • Eosinophilic activity
    • Eosinophilic activity is associated with allergies, parasitic diseases, multiple inflammatory diseases of epithelial organs, and neoplastic disease
    • Hypereosinophilia – absolute eosinophil count >1.5x109/L
  • Eosinophil major basic protein (eMBP)
    • Cationic protein toxic to mammalian cells and tissues
    • Extracellular eMBP in tissues represents eosinophilic activity in the presence or absence of intact eosinophils
    • If eMBP is mistakenly abbreviated MBP when ordering testing, it will be confused with myelin basic protein; order appropriately

Clinical Presentation (select diseases)

  • EV
    • Pruritus
    • Erythematous purpuric plaques
    • Angioedema
  • EGID
    • Children <2 years – feeding disorders, failure to thrive
    • Children 2-12 years – emesis, abdominal pain
    • >12 years – dysphagia, esophageal food impaction, vomiting, abdominal pain
    • Symptoms may mimic gastroesophageal reflux disease
  • Kimura disease – lymph node inflammation
  • Eosinophilic cystitis – frequency, dysuria, hematuria
  • Eosinophilic muscle diseases – weakness, pain, swelling muscles
  • Eosinophilic pulmonary disease – cough, dyspnea, wheezing
  • Hypereosinophilic disorders 
    • HE – eosinophilic count >1.5x109/L x 6 months without end-organ damage and no other cause identified
    • HES – above criteria for HE with end-organ damage present
    • Most common symptoms – weakness, fatigue, cough/dyspnea, myalgias, fever

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Eosinophil Granule Major Basic Protein in Tissues 0090648
Method: Immunofluorescence/Affinity Chromatography

Use to semi-quantify eosinophils and eosinophil products in tissue biopsies and identify eosinophil granule protein deposition that may be disproportionately present

In absence of intact eosinophils, identify clinical disease associated with eosinophil degranulation

Use for inflamed tissues to determine whether eosinophils have disrupted and are no longer morphologically identifiable with routine tissue stains

Test cannot be performed on fluid specimens

Systemic glucocorticoids may reduce eosinophil involvement and affect test results

Not a diagnostic test except in eosinophilic esophagitis

Consider concurrent histological evaluation of fixed tissue from affected area for additional diagnostic information

Use to follow eosinophil involvement in pathology

Eosinophilia Panel by FISH 2002378
Method: Fluorescence in situ Hybridization

Diagnose and classify specific eosinophilic myeloid neoplasms

Provide significant prognostic and predictive information for individuals presenting with acute or chronic leukemia with eosinophilia

Monitor therapeutic response

Probes include PDGFRA, PDGFRB, FGFR1, and CBFB

Other mutations may develop in myeloproliferative hypereosinophilic syndrome/chronic eosinophilic leukemia

 
CD34, QBEnd/10 by Immunohistochemistry 2003556
Method: Immunohistochemistry

Aids histological diagnosis of eosinophil-associated diseases

Stained and returned to client pathologist for interpretation; consultation available if needed

   
CD25 by Immunohistochemistry 2003544
Method: Immunohistochemistry

Aids histological diagnosis of eosinophil-associated diseases

Stained and returned to client pathologist for interpretation; consultation available if needed

   
CD117 (c-Kit) by Immunohistochemistry 2003806
Method: Immunohistochemistry

Aids histological diagnosis of eosinophil-associated diseases

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Mast Cell Tryptase by Immunohistochemistry 2003993
Method: Immunohistochemistry

Aids histological diagnosis of eosinophil-associated diseases

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Identify eosinophilia

Repeat testing to confirm acute versus chronic increased eosinophil counts