Eosinophilic Diseases

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
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)

Eosinophil-associated diseases occur in all epithelial organs including the skin, upper and lower respiratory tract, gastrointestinal tract, urinary tract, and heart. The 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
- 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
- Eosinophilic 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)

Tests generally appear in the order most useful for common clinical situations

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

Identify eosinophilia

May need to repeat testing to confirm acute versus chronic disease

Test name: Eosinophil Granule Major Basic Protein in Tissues

ARUP #: 0090648

Methodology: Immunofluorescence/Affinity Chromatography

Use:

Semi-quantify eosinophils and eosinophil products in tissue biopsies and identify eosinophil granule protein deposition

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

Limitations:

Test cannot be performed on fluid specimens

Systemic glucocorticoids may reduce eosinophil involvement and affect test results

Follow-up:

Not a diagnostic test except in eosinophilic esophagitis

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

Test name: Eosinophilia Panel by FISH

ARUP #: 2002378

Methodology: Fluorescence in situ Hybridization

Use:

Diagnose and classify myeloid neoplasm presenting with eosinophilia

Probes include PDGFRA, PDGFRB, FGFR1 and CBFB

Limitations:

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

Is not positive in lymphocytic hypereosinophilic syndrome

Test name: CD34, QBEnd/10 by Immunohistochemistry

ARUP #: 2003556

Methodology: Immunohistochemistry

Use:

Aids histologic diagnosis of eosinophilic diseases

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

Test name: CD25 by Immunohistochemistry

ARUP #: 2003544

Methodology: Immunohistochemistry

Use:

Aids histologic diagnosis of eosinophilic diseases

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

Test name: CD117 (c-Kit) by Immunohistochemistry

ARUP #: 2003806

Methodology: Immunohistochemistry

Use:

Aids histologic diagnosis of eosinophilic diseases

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

Test name: Mast Cell Tryptase by Immunohistochemistry

ARUP #: 2003993

Methodology: Immunohistochemistry

Use:

Aids histologic diagnosis of eosinophilic diseases

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

Guidelines

General

ARUP Institute for Clinical and Experimental Pathology®

Sheikh J, Weller PF. Clinical overview of hypereosinophilic syndromes. Immunol Allergy Clin North Am. 2007; 27 (3) :333-355.PubMed

Comprehensive Review: August 2011
Last Update: August 2011

Allergic Disease

Anaphylaxis

Food Allergies

Hypersensitivity Pneumonitis

Mast Cell Disease