Hypereosinophilia syndrome D72.1

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 30.01.2023

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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 "hypereosinophilia syndrome", or "hypereosinophilic syndrome", HES for short, is used to describe a heterogeneous group of rare diseases (hypereosinophilia syndromes) with the following characteristics:

  • high-grade, persistent, blood and bone marrow eosinophilia/eosinophilia > 1500/ul in blood for > 6 months/(see eosinophilia below); damage to different organs due to eosinophil infiltration (toix effect of eosinophil products such as MBP and ECP).
  • No detectable cause for the occurrence of eosinophilia (e.g. parasitoses, allergies) (Valent P et al. 2012).

From the skin side (skin involvement up to 60% of cases), there is a clear, sometimes unbearable, permanent itching, often an indicative symptom of the hypereosinophilia syndrome. Thus, the dermatologist is often involved diagnostically at an early stage.

Classification
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The following variants of hypereosinophilia syndrome (HES) are distinguished:

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

  • Primary HES: Myeloproliferative HES in the setting of clonal myeloid, eosinophilic or stem cell disease (see below Myeloid Neoplasms with Eosinophilia (MLN-Eo).
  • Secondary (reactive) HES: etiologically heterogeneous, cytokine-driven, reactive, non-clonal hypereosinophilia with organ involvement.

Etiopathogenesis
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Unknown;

In primary HES, mutations are located in multi- or pluripotent hematologic stem cells. Mutations in the PDGFRA genes have been detected.

In secondary (reactive HES), the stimuli for eosinophil proliferation are increased cytokines IL-5, IL-3 , and GM-CSF (granulocyte-macrophage colony factor). These cytokines increase eosinophil production and activity 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 severe general symptoms: weight loss, fever, loss of appetite, lymphadenopathy.

Skin: Skin lesions (60% of affected persons) are multiform and variable. Severe pruritus is constant, urticarial erythema, papulovesicles, red papules and nodules(hypereosinophilic dermatitis). Furthermore: eosinophilic angioedema (see also angioedema, episodic with eosinophilia), petechiae and lichenifications. An independent clinical picture that can occur in the context of HES is eosinophilic anular erythema. In rare cases, complicating erythroderma may develop.

Heart(Eosinophilic Myocarditis): Cardiac involvement (20%) with eosinophilic fibrosing endomyocarditis and myocarditis. Eosinophilic endomyocarditis is the most common cause of death (endomyocardial necrosis in the acute stage, thrombotic changes later; endomyocardial fib rosis with facultative mitral or tricuspid regurgitation in the late stage. Detection of these changes are possible by endomyocardial biopsy and Doppler echocardiography).

Lung(eosinophilic pneumonia): nonproductive cough, dyspnea, diffuse or circumscribed eosinophilic pulmonary infiltrates (detectable in about 40% of patients), eosinophilic pleural effusions.

Vascular: Raynaud's syndrome and digital necrosis have been described. A decrease in intellectual performance is often perceived, probably as a result of eosinophilic arteritis and cerebral thromboembolic processes.

Nervous system: Peripheral neuropathies or mononeuritis multiplex.

Gastrointestinal tract: Gastrointestinal involvement with abdominal symptoms and hepatosplenomegaly. Furthermore, esophaguns and pancreas may be involved: eosinophilic esophagitis, eosinophilic pancreatitis.

Musculature: Polymyositis eosinophilic

Diagnosis
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HES is a diagnosis of exclusion. Prerequisite are the present obligatory criteria:

  • Blood eosinophilia > 1500/μl; persistence > 6 months (alternatively: detection of blood eosinophilia > 1500/μl 2x in intervals of 4 weeks (Valent P et a. 2012). Discontinuation of external (absorption) as well as systemic glucocorticoids is important!
  • Exclusion of other causes (helminthic infections; advanced HIV infection; chronic graft-versus-host disease, drug reactions, atopic diathesis, versch. Autoimmune diseases (dermatomyositis, SLE, Sjögren's syndrome, primary biliary cirrhosis, bullous pemhigoid, allergic bronchopulmonary aspergillosis). Other reactive hypereosinophilias are seen as paraneoplastic reactions, in hematologic neoplasms (T- or B-cell lymphomas, Hodgkin's lymphoma)
  • Evidence of symptomatic organ involvement.
  • Accurate characterization of hypereosinophilia is significant because it has important therapeutic consequences. Exemplary is the detection of the fusion proteins FIP1L1-PDGFRA by PCR or FiSH, as FIP1L1-PDGFRA-positive myelodysplastic neoplasms respond 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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Last updated on: 30.01.2023