Gleich Syndrom

Episodic angioedema with eosinophilia (EAE); episodic angioedema with eosinophilia; Gleich syndrome/Gleich’s syndrome; angioedema with eosinophilia, episodic type.

A rare, usually relapsing disorder characterized by recurrent episodes of angioedema and marked peripheral eosinophilia, often accompanied by urticarial or urticaria-like skin lesions. Episodes often occur at relatively regular intervals of several weeks and largely remit between flares. Fever, fatigue, myalgias, and rapid weight gain may occur concomitantly. In contrast to other hypereosinophilic syndromes, persistent end-organ damage is overall uncommon, but must be actively excluded.

A very rare disorder; robust incidence or prevalence data are lacking. The available evidence is based predominantly on case reports, small case series, and reviews. Occurrence in both children and adults has been described. Female predominance has been reported repeatedly, but cannot be reliably quantified because of the small number of cases.

In clinical usage, angioedema with eosinophilia is divided into two forms:

• episodic form: Gleich syndrome/EAE

• non-episodic form: NEAE

Gleich syndrome is characterized by recurrent flares with remission between episodes. NEAE is usually monophasic and self-limited. Diagnostically, Gleich syndrome belongs to the spectrum of eosinophilic or hypereosinophilic disorders and remains a diagnosis of exclusion. The key distinction is from:

• secondary/reactive eosinophilias

• lymphocytic hypereosinophilic constellations

• myeloid/clonal eosinophilic neoplasms

The pathogenesis has not been fully elucidated. Repeatedly described findings include:

• cyclic fluctuations in eosinophil counts, often with a periodicity of approximately 3–4 weeks

• elevation of type 2 cytokines, especially IL-5, before or during flares

• in a subset of patients, aberrant or clonal T-cell populations as a possible source of eosinophil-driving cytokines

Of dermatologic relevance is eosinophilic infiltration and degranulation in the skin and subcutis, which may contribute to edema, pruritus, and urticarial or eczematous skin changes.

The leading symptoms are recurrent angioedema and eosinophilia.

Typical manifestations

• swelling, often involving the face, eyelids, neck, and extremities

• urticarial lesions, erythematous plaques, or wheal-like eruptions

• pruritus

• substantial freedom from symptoms between flares

Frequent accompanying symptoms

• fever or a sensation of fever

• fatigue

• myalgias

• rapid weight gain, sometimes within a few days

• generalized edema

Papular, nodular, or eczematous skin manifestations have been described less frequently. Severity ranges from localized recurrent eyelid or facial edema to pronounced generalized edema with functional impairment. Lymphadenopathy may occur, but should not be regarded as an obligatory or definitively frequent feature.

There are no internationally agreed formal diagnostic criteria. In practice, the diagnosis is established as a diagnosis of exclusion.

Clinical core elements

• recurrent episodes of angioedema, often with urticaria or urticaria-like eruptions

• remission between flares

• peripheral eosinophilia, often marked and sometimes cyclic; in consensus papers, hypereosinophilia is typically defined as >1.5 × 10^9/L

Baseline work-up

• complete blood count with differential, preferably also serially

• inflammatory markers

• total IgE, and if indicated immunoglobulins including IgM

• renal and liver function tests, urinalysis

• depending on the clinical presentation, C4 and C1 inhibitor to distinguish other forms of angioedema

Exclusion of secondary causes

• drug reactions

• parasitoses/helminth infections

• allergic or inflammatory systemic diseases

• eosinophilic organ diseases of other etiologies

• neoplasms

Evaluation for clonal/primary eosinophilic disorders when clinically indicated

• peripheral blood smear, and if necessary bone marrow examination

• cytogenetics/FISH

• molecular diagnostics for relevant tyrosine kinase fusion genes

• immunophenotyping, and if necessary T-cell receptor rearrangement studies

Organ staging according to symptoms

• targeted assessment for cardiac, pulmonary, gastrointestinal, or neurologic involvement

• if clinically suspected, for example echocardiography, pulmonary function testing, or imaging

Supportive but non-mandatory findings include elevated immunoglobulins, especially IgM, as well as evidence of IL-5-driven activity or aberrant T-cell populations.

Typical sites of swelling are:

• face, especially eyelids and cheeks

• neck

• extremities

• trunk

Distribution may vary between flares. Urticarial lesions are frequently found on the face, arms, and trunk. Histologically and clinically, the edema primarily affects the deep dermis and subcutis.

A typical history is one of sudden-onset, recurrent episodes of swelling over months or years, often recurring at intervals of a few weeks. Patients also frequently report:

• wheals or urticaria-like skin changes

• itching

• fatigue

• a sensation of fever

• rapid weight gain during flares

Episodes often resolve within a few days, spontaneously or under systemic glucocorticoids. Clear triggers are often absent. A structured medication, infection, travel, and systemic history is important, as is inquiry about prior organ manifestations. A symptom diary with weight trends and serial blood counts can document the cyclic nature of the disease.

Histology is not pathognomonic, but may support the diagnosis.

Typical findings

• dermal edema

• perivascular and interstitial inflammatory infiltrates

• numerous eosinophils

• partial involvement of the subcutis

These findings are consistent with an eosinophilic inflammatory reaction with tissue degranulation. A skin biopsy is particularly useful when differential diagnoses such as urticarial vasculitis, Wells syndrome, or other eosinophilic dermatoses need to be distinguished.

Gleich syndrome usually runs a course without permanent organ damage; nevertheless, complications should be actively considered.

Possible complications

• pronounced edema with functional relevance

• pressure symptoms with paresthesias

• very rarely, compartment syndrome

• rarely, eosinophilic organ involvement, including cardiac manifestations

In an atypical course, persistent eosinophilia between flares, or systemic warning signs, the diagnosis must be reassessed and another form of hypereosinophilic disease excluded.

Specific primary prevention has not been established.

Reasonable secondary preventive measures

• symptom diary

• serial blood counts, preferably also during symptom-free intervals

• repeat exclusion diagnostics if the clinical picture changes

• early steroid-sparing strategy in steroid dependence or frequent relapses

The prognosis is favorable in most published cases. Recurrent but reversible flares with substantial or complete freedom from symptoms between episodes are typical. Systemic glucocorticoids usually lead to rapid clinical improvement. Long-term courses without end-organ damage have been described.

Correct classification within the spectrum of eosinophilic disorders is important for prognosis. If there are indications of a lymphocytic or other clonal constellation, closer interdisciplinary follow-up is advisable.

Therapeutic goals are rapid symptom control, reduction of eosinophilic inflammation, avoidance of unnecessary long-term steroid use, and recognition of possible organ involvement.

First line

• Systemic glucocorticoids are the most important acute therapy.

• In most cases, edema and skin symptoms regress rapidly, along with a marked decrease in eosinophilia.

• Dose and tapering are not standardized and depend on severity, organ involvement, and relapse tendency.

Supportive measures

• Antihistamines for urticaria or pruritus; as monotherapy, they are usually insufficient.

• Analgesia as needed.

• Edema management and functional relief in cases of pronounced swelling.

Steroid-sparing options in frequent relapses, steroid dependence, or refractory disease

• Mepolizumab: may reduce eosinophilia; however, in a pilot study, clinical flares were not reliably suppressed. The dose used was 300 mg subcutaneously monthly.

• Benralizumab and Reslizumab: positive individual case reports.

• These therapies are possible off-label options in selected cases, but are not standard.

Special situations/escalation

• If relevant tyrosine kinase fusion genes are detected, imatinib is a key targeted therapy.

• Without such evidence, imatinib is not standard in Gleich syndrome; benefit has been described only in individual cases.

• If a clonal or lymphocytic hypereosinophilic disorder is suspected, treatment planning should be interdisciplinary with hematology/immunology.

Practical notes

• Before escalation, always verify that the condition is truly Gleich syndrome and not secondary or clonal eosinophilia.

• Persistent eosinophilia between flares, organ signs, or atypical courses argue for expanded diagnostics.

• Long-term steroids should be avoided whenever possible; steroid-sparing strategies should be considered early if relapses are frequent.

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