Hypereosinophilia syndrome D72.1

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.

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

• Idiopathic HES (HES of unknown significance); no detectable causes, no end organ damage.
• Myeloproliferative HES in the setting of clonal myeloid, eosinophilic, or stem cell disease (see Myeloid Neoplasms with Eosinophilia)
• Lymphocytic HES (clonal and nonclonal proliferation of T cells with atypical phenotype (Valent P et al. 2012). Transition to T-cell lymphoma possible but rare.
• Familial HES (familial clustering, pathogenesis unclear).
• HES overlap syndrome(eosinophilic esophagitis, eosinophilic pneumonia, eosinophilic endomyocarditis, hypereosinophilic dermatitis).

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.

Unknown;

In primary HES, myeloproliferative HES, there is an intertitial deletion on chromosome 4q12. This mutation leads to the fusion of the FIP1-like-1 and the platelet-derived growth factor A gene(PDGFRA gene). The resulting gene product (FIP1L1/PDGFRA ) is a constitutively activated tyrosine kinase and is causally involved in eosinophilia. Other activating mutations affect the PDGFRB gene, the FGFR1 gene and gain-of-function (GOF) germline mutations in the JAK1 and STAT3 genes.

In secondary (reactive -lymphocytic- HES), the stimuli for the proliferation of eosinophils 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). See also eosinophilia.

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

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.

• 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.

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