Eosinophil-Associated Diseases

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics

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

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
    • Asthma
    • Chronic eosinophilic pneumonia
    • Eosinophilic granulomatosis with polyangiitis
    • 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
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.

CD34, QBEnd/10 by Immunohistochemistry 2003556
Method: Immunohistochemistry

Recommended Use 

Aid histological diagnosis of eosinophil-associated diseases

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

CD25 by Immunohistochemistry 2003544
Method: Immunohistochemistry

Recommended Use 

Aid 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

Recommended Use 

Aid 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

Recommended Use 

Aid histological diagnosis of eosinophil-associated diseases

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

Guidelines

Bernstein L, Li JT, Bernstein DI, Hamilton R, Spector SL, Tan R, Sicherer S, Golden DB, Khan DA, Nicklas RA, Portnoy JM, Blessing-Moore J, Cox L, Lang DM, Oppenheimer J, Randolph CC, Schuller DE, Tilles SA, Wallace DV, Levetin E, Weber R, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol. 2008; 100(3 Suppl 3): S1-148. PubMed

Bochner BS, Book W, Busse WW, Butterfield J, Furuta GT, Gleich GJ, Klion AD, Lee JJ, Leiferman KM, Minnicozzi M, Moqbel R, Rothenberg ME, Schwartz LB, Simon H, Wechsler ME, Weller PF. Workshop report from the National Institutes of Health Taskforce on the Research Needs of Eosinophil-Associated Diseases (TREAD). J Allergy Clin Immunol. 2012; 130(3): 587-96. PubMed

Gotlib J. World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management. Am J Hematol. 2014; 89(3): 325-37. PubMed

Klion AD, Bochner BS, Gleich GJ, Nutman TB, Rothenberg ME, Simon H, Wechsler ME, Weller PF. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol. 2006; 117(6): 1292-302. PubMed

Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis PA, Burks W, Chehade M, Collins MH, Dellon ES, Dohil R, Falk GW, Gonsalves N, Gupta SK, Katzka DA, Lucendo AJ, Markowitz JE, Noel RJ, Odze RD, Putnam PE, Richter JE, Romero Y, Ruchelli E, Sampson HA, Schoepfer A, Shaheen NJ, Sicherer SH, Spechler S, Spergel JM, Straumann A, Wershil BK, Rothenberg ME, Aceves SS. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011; 128(1): 3-20.e6; quiz 21-2. PubMed

General References

Aslan I, Fischer M, Laser KT, Haas NA. Eosinophilic myocarditis in an adolescent: a case report and review of the literature. Cardiol Young. 2013; 23(2): 277-83. PubMed

Carlson A, Chen K. Cutaneous vasculitis update: neutrophilic muscular vessel and eosinophilic, granulomatous, and lymphocytic vasculitis syndromes. Am J Dermatopathol. 2007; 29(1): 32-43. PubMed

Cottin V, Cordier J. Eosinophilic lung diseases. Immunol Allergy Clin North Am. 2012; 32(4): 557-86. PubMed

Dellon ES. Eosinophilic esophagitis: diagnostic tests and criteria. Curr Opin Gastroenterol. 2012; 28(4): 382-8. PubMed

Gleich GJ, Leiferman KM. The hypereosinophilic syndromes: current concepts and treatments. Br J Haematol. 2009; 145(3): 271-85. PubMed

Knutsen AP, Slavin RG. Allergic bronchopulmonary aspergillosis in asthma and cystic fibrosis. Clin Dev Immunol. 2011; 2011: 843763. PubMed

Lebeaux D, Sène D. Eosinophilic fasciitis (Shulman disease). Best Pract Res Clin Rheumatol. 2012; 26(4): 449-58. PubMed

Leiferman K, Beck L, Gleich G. Regulation of the Production and Activation of Eosinophils, Ch 31. In Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick’s Dermatology in General Medicine, 8th ed. San Francisco: McGraw-Hill Medical, 2012.

Leiferman K, Peters M. Eosinophils in Cutaneous Diseases, Ch 36. In Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick’s Dermatology in General Medicine, 8th ed. San Francisco: McGraw-Hill Medical, 2012.

Ogbogu PU, Bochner BS, Butterfield JH, Gleich GJ, Huss-Marp J, Kahn JE, Leiferman KM, Nutman TB, Pfab F, Ring J, Rothenberg ME, Roufosse F, Sajous M, Sheikh J, Simon D, Simon H, Stein ML, Wardlaw A, Weller PF, Klion AD. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol. 2009; 124(6): 1319-25.e3. PubMed

Tefferi A, Gotlib J, Pardanani A. Hypereosinophilic syndrome and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update. Mayo Clin Proc. 2010; 85(2): 158-64. PubMed

Valent P, Gleich GJ, Reiter A, Roufosse F, Weller PF, Hellmann A, Metzgeroth G, Leiferman KM, Arock M, Sotlar K, Butterfield JH, Cerny-Reiterer S, Mayerhofer M, Vandenberghe P, Haferlach T, Bochner BS, Gotlib J, Horny H, Simon H, Klion AD. Pathogenesis and classification of eosinophil disorders: a review of recent developments in the field. Expert Rev Hematol. 2012; 5(2): 157-76. PubMed

Valent P, Klion AD, Horny H, Roufosse F, Gotlib J, Weller PF, Hellmann A, Metzgeroth G, Leiferman KM, Arock M, Butterfield JH, Sperr WR, Sotlar K, Vandenberghe P, Haferlach T, Simon H, Reiter A, Gleich GJ. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol. 2012; 130(3): 607-612.e9. PubMed

Yen EF, Pardi DS. Non-IBD colitides (eosinophilic, microscopic). Best Pract Res Clin Gastroenterol. 2012; 26(5): 611-22. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Abraham S, Salama M, Hancock J, Jacobsen J, Fluchel M. Congenital and childhood myeloproliferative disorders with eosinophilia responsive to imatinib. Pediatr Blood Cancer. 2012; 59(5): 928-9. PubMed

Sheikh J, Weller PF. Clinical overview of hypereosinophilic syndromes. Immunol Allergy Clin North Am. 2007; 27(3): 333-55. PubMed

Wang SA, Tam W, Tsai AG, Arber DA, Hasserjian RP, Geyer JT, George TI, Czuchlewski DR, Foucar K, Rogers HJ, Hsi ED, Rea B, Bagg A, Dal Cin P, Zhao C, Kelley TW, Verstovsek S, Bueso-Ramos C, Orazi A. Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified. Mod Pathol. 2016; 29(8): 854-64. PubMed

Medical Reviewers

Gleich, Gerald J., MD, Consultant, Immunodermatology at ARUP Laboratories; Professor, Dermatology and Medicine; Emeritus Professor, Pediatrics, University of Utah

Leiferman, Kristin M., MD, Consultant, Immunodermatology at ARUP Laboratories; Co-Director, Immunodermatology Laboratory, Professor of Dermatology, University of Utah

Last Update: August 2017