Hypereosinophilia syndrome D72.1

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 14.05.2021

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Synonym(s)

HES; Hpyereosinophilic syndromes; Hypereosinophilic syndrome; hypereosinophilic syndromes; Idiopathic hypereosinophilic syndrome

History
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Griffin, 1919; Hardy and Anderson, 1968

Definition
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The term HES covers a heterogeneous group of rare diseases (hypereosinophilia syndromes), whose characteristics (high-grade, persistent blood and bone marrow eosinophilia (eosinophilia > 1500/ul in the blood for > 6 months; see eosinophilia below ) as well as indications of organ damage due to eosinophile infiltration (Valent P et al. 2012). Clear to unbearable permanent itching is a common indicative symptom of hypereosinophilia syndromes. Thus, the dermatologist is involved in the diagnostic process at an early stage.

Classification
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The following variants of the HES are distinguished:

  • Idiopathic HES (HES of unknown significance); no detectable causes, no end organ damage
  • Myeloproliferative HES in the context of a clonal myeloid, eosinophilic or stem cell disease
  • Lymphocytic HES (clonal and non-clonal proliferation of T cells with atypical phenotype (Valent P et al. 2012). Transition to T-cell lymphoma possible but rare.
  • Familial HES (familial accumulation, pathogenesis unclear)
  • HES-Overlap Syndrome (Eosinophilic Oesophagitis, Eosinophilic Pneumonia, Hypereosinophilic Dermatitis)

From a pathogenetic point of view a dichotomy can be made:

  • Primary HES: Myeloproliferative HES in the context of a clonal myeloid, eosinophilic or stem cell disease
  • Secondary HES: aetiologically heterogeneous, cytokine-directed, reactive, non-clonal hypereosinophilia

Etiopathogenesis
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Unknown;

In primary HES, mutations are located in multi- or pluripotent haematological stem cells

In the secondary (reactive HES) the stimuli for eosinophil proliferation are the cytokines IL-5, IL-3 and GM-CSF (granulocyte-macrophage colony factor). These cytokines increase the production and activity of eosinophils and inhibit primary cell death (apoptosis). S.a.u. eosinophilia.

Manifestation
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Mostly occurring in adults (mostly 20.-50. LJ), extremely rare in children. Men are affected 9 times more frequently than women.

Clinical features
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Usually general symptoms (weight loss, fever, loss of appetite) depending on the organ manifestation:

Skin: Hypereosinophilic dermatitis. Skin lesions are varied and changeable. Pruritus, urticarial erythema, papulovesicles, red papules and nodules, angioedema (see also Angioedema, episodic with eosinophilia), petechiae and lichenification are seen. In rare cases, erythroderma may develop. Raynaud's syndrome and digital necrosis have also been described in isolated cases.

Heart: Cardiac involvement (20%) with eosinophilic fibrosing endo- and myocarditis. Cardiac involvement is the most common cause of death (endomyocardial necrosis in the acute stage, thrombotic changes later. In the late stage endomyocardial fibrosis with facultative mitral or tricuspid regurgitation. Detection of these changes by endomyocardial biopsy and Doppler echocardiography).

Lung: Cough, diffuse or circumscribed eosinophilic pulmonary infiltrates, eosinophilic pleural effusions.

Vascular: Often decrease in intellectual performance, probably due to eosinophilic arteritis and cerebral thromboembolic processes.

Nervous system: Peripheral neuropathies or mononeuritis multiplex.

Gastrointestinal tract:

Musculature: Muscle weakness.

Diagnosis
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HES is a diagnosis of exclusion. It requires the obligatory criteria:

  • Bluteosinophilia > 1500/μl; persistence > 6 months (alternatively: detection of a blood eosinophilia > 1500/μl twice in intervals of 4 weeks (Valent P et a. 2012). It is important to discontinue external (absorption) as well as systemic glucocorticoids!
  • Exclusion of other causes (helminthic infections; advanced HIV infection; chronic graft-versus-host-disease, drug reactions, atopic diathesis, various diseases, etc.) autoimmune diseases (dermatomyositis, SLE, Sjögren's syndrome, primary biliary cirrhosis, bullous pemhigoid, allergic bronchopulmonary aspergillosis). Other reactive hypereosinophilia are described as paraneoplastic reactions, in hematological neoplasms (T- or B-cell lymphomas, Hodgkin lymphomas)
  • Evidence of symptomatic organ involvement.
  • An exact characterisation of hypereosinophilia is important, as this has considerable therapeutic consequences. Exemplary is the detection of the fusion proteins FIP1L1-PDGFRA by PCR or FiSH, since FIP1L1-PDGFRA-positive myelodysplastic neoplasias react very well to tyrosine kinase inhibitors such as imatinib.

Differential diagnosis
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Parasitoses of the skin; eosinophilic leukemia; malignancies with secondary eosinophilia; Churg-Strauss syndrome.

External therapy
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Symptomatic. Possibly topical glucocorticoids.

Radiation therapy
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Recently, good results have been described under PUVA therapy. In therapy-resistant cases a bone marrow transplantation can be considered.

Internal therapy
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  • The therapy is symptomatic and depends on the internal involvement, especially the extent of endomyocardial fibrosis leading to appositional thrombi. The reduction of eosinophil numbers is the determining factor. Successes are described with prednisone (e.g. Decortin H) 1.0 mg/kg bw/day and with the combination of prednisone and hydroxycarbamide (Litalir) e.g. 20-30 mg/kg bw/day.
  • Alternatively cytarabine (e.g. Alexan).
  • Also the combination of vincristine and mercaptopurine (puri-ethol) is effective.
  • If other therapy options fail, interferons ( interferon alfa-2a or interferon alfa-2b; dosage 8 million IU/day s.c.) can also be used.
  • Because of the risk of embolic complications, oral anticoagulation with systemic coumarins such as phenprocoumon (e.g. marcoumar) is recommended. In case of severe cardiac involvement (possibly valve insufficiency) therapy by cardiologists.
  • Good therapeutic results were shown in a multicenter study with a "targeted" therapy with mepolizumab, an anti-IL-5 antibody (see below Interleukin-5).
  • In patients with hypereosinophilia of unknown significance and with familial hypereosinophilia, regular checks for end organ damage are indicated, otherwise a wait-and-see attitude is justified (Gotlib J 2017).
  • The treatment of lymphocytic forms of hypereosinophilia syndromes with clonal or aberrant T-cell populations often requires high doses of glucocorticoids.

Literature
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  1. Barouky R et al (2003) Mucosal ulcerations revealing primitive hypereosinophilic syndrome. Eur J Dermatol 13: 207-208
  2. Cogan E, Schandené L, Crusiaux A et al (1994) Brief Report: Clonal Proliferation of Type 2 Helper T Cells in a Man with the Hypereosinophilic Syndrome. N Engl J Med 330: 535-538
  3. Gotlib J (2017) World Health Organization-defined eosinophilic disorders: 2017 update ondiagnosis
    , risk stratification, and management. On J Hematol 92:1243-1259.
  4. Hardy WR, Anderson RE (1968) The hypereosinophilic syndrome. Ann Internal Med 68: 1220
  5. Huss-Marp J et al ("Targeted therapy" - Anti-Interleukin-5 for the treatment of eosinophilic diseases. Allergo J 17:305-309
  6. Katz HT et al (2005) Pediatric hypereosinophilic syndrome (HES) differs from adult HES. J Pediatr 146: 134-136
  7. Kersey-Barrett Tet al.(2012) Hypereosinophilic syndrome associated with regulatory T-cell disruption as a complication of stem cell transplantation. J Investig Allergol Clin Immunol. 22: 453-455
  8. Khoury P et al (2017) Clinical and Biological Markers in Hypereosinophilic Syndrome. Front Med (Lausanne) 4:240.
  9. Liesveldt JL, Abboud CN (1991) State of the art; the hypereosinophilic syndromes. Blood Rev 5: 29-37
  10. Mahajan VK et al (2014) Idiopathic hypereosinophilic syndrome: a rare cause of erythroderma. J Dermatol Case Rep 8:108-114
  11. May LP et al (1990) Hypereosinophilic syndrome with unusual cutaneous manifestations in two men with HIV infection. J Am Acad Dermatol 23: 2202-204
  12. Narayan S et al (2003) Idiopathic hypereosinophilic syndrome associated with cutaneous infarction and deep venous thrombosis. Br J Dermatol 148: 817-820
  13. Ohtani T et al (2004) Digital gangrene associated with idiopathic hypereosinophilia:treatment with allogeneic cultured dermal substitute. EJD 14: 168-171
  14. Reyes M et al (2005) Hypereosinophilic syndrome with hepatobiliary masses and obstructive jaundice. Ann Allergy Asthma Immunol 94: 25-28
  15. Sigmund DA et al (1995) Hypereosinophilic syndrome - successful allogeneic bone marrow transplantation. Bone Marrow Transplantation 15: 647-648
  16. Smith SM et al (2015) Idiopathic Hypereosinophilic Syndrome With Cutaneous Manifestations and Flame Figures: A Spectrum of Eosinophilic Dermatoses Whose Features Overlap With Wells' Syndrome. On J Dermatopathol PubMed PMID: 25839890.
  17. Spry CJF, Davies J, Tai PC et al (1983) Clinical features of fifteen patients with the hypereosinophilic syndrome. Q J Med 52: 1-22
  18. Valent P et al (2012) Contemporary consensus proposal on criteria and classification of eosinophilicdisorders
    and related syndromes. J Allergy Clin Immunol 130:607-612.
  19. Wemmer U et al (1988) Hypereosinophilic syndrome (HES) - successful PUVA therapy. dermatologist 39: 42-44

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Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

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Last updated on: 14.05.2021