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

• CBC with differential
  • Blood eosinophilia frequent (usually <twofold)
  • Striking eosinophilia in hypereosinophilic syndromes (HES)
  • Repeat testing to determine if acute or chronic eosinophilia
• Food allergy testing in eosinophilic esophagitis (EoE) with serum IgE specific tests or skin prick testing
  • Consider for EoE presenting in children
• Pulmonary symptoms
  • Consider 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
• Disease-specific testing for other eosinophil-associated diseases – see references for suggested tests
• Persistent, prolonged eosinophilia from any cause should be evaluated for associated eosinophilic endomyocardial disease
• Emergent evaluation mandated for thrombotic events associated with hypereosinophilic syndromes
• Molecular – PCR, FISH identification of PDGFRA rearrangements in myeloproliferative variant of HES
  • Lack of rearrangement does not rule out HES
  • Tryptase may be increased
• T-cell subsets by lymphocytoflow; may have CD3-CD4+ clone in lymphocytic HES variant
  • Interleukin-5 level may be increased in lymphocytic variant

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 numbers 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
  • T-cell and B-cell markers
  • CD34, CD25
  • Tryptase
  • Platelet marker
  • c-Kit mutation
  • Molecular markers by PCR, FISH

Differential Diagnosis

• Neoplasm
  • Myeloproliferative neoplasms
  • Mast cell disease
  • Lymphomas – B-cell, T/NK-cell, CML
• Parasitic
  • Onchocerca volvulus
  • Schistosoma spp
  • Trichinella spiralis
• Connective tissue disorders
• Transplant rejection
• Drug reaction
• Atopic diseases
• Immune-mediated blistering disease (pre-bullous stage)

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 syndromes (HES)  
  • Familial
  • Lymphocytic variant
  • Myeloproliferative variant (also known as chronic eosinophilic leukemia)
  • Overlap
  • Undefined
• Immunologic disorders
  • Chronic granulomatous disease
  • Hyper IgE syndrome
  • Omenn syndrome
  • Sarcoidosis
• Malignancy-associated eosinophilia
  • Acute lymphoblastic leukemia
  • Eosinophilic granuloma
  • Hodgkin lymphoma
  • Langerhans histiocytosis including eosinophilic granuloma
  • Myelodysplastic syndromes
  • T-cell lymphoma, including cutaneous T-cell lymphomas, mycosis fungoides, and Sézary syndrome
• 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
  • Chronic fibrosing thyroiditis (Riedel struma)
  • Mediastinal fibrosis
  • Retroperitoneal fibrosis
  • Sclerosing cholangitis

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

• EV – connective tissue disease
• Eosinophilic esophagitis
  • Positive family history
  • History of severe food allergies

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 syndromes – eosinophilic count ≥1.5x10⁹/L x 6 months with end-organ damage and no other cause identified (consensus criteria definition)

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