Episodic angioedema with eosinophilia (Gleich syndrome; EAE) is an exceedingly rare eosinophilic disorder with less than 50 cases reported in the literature to date. It is characterized by episodes of angioedema and eosinophilia that occur at monthly intervals and resolve spontaneously without therapy. Despite the striking periodicity of this disorder, its similarity to other cyclic hematopoietic disorders with multilineage involvement has not been assessed. To characterize the involvement of cell lineages in the etiology and pathogenesis of episodic angioedema with eosinophilia, four subjects were evaluated over the course of 12 months. Surface marker expression was assessed on T cells by flow cytometry and T cell clonality was assessed by TCR gene rearrangement. Intracellular cytokine evaluation and serum IL-5 measurements were performed. Bone marrow biopsies and skin biopsies were performed during different parts of the cycle and evaluated histopathologically and immunohistochemically. Consistent with prior case reports, our subjects had cyclic eosinophilia and cycling symptoms, including angioedema, with a defined periodicity that was preceded by a rise in serum IL-5. The age of onset (10-32 years of age) was typical and despite prolonged and dramatic eosinophilia, none of the subjects experienced chronic, end-organ manifestations typical of hypereosinophilic syndrome (HES). All four subjects with definite EAE had elevated serum IgM levels, an uncommon laboratory abnormality in patients with HES. Serial complete blood counts demonstrated not only cyclic eosinophilia, but also cycling of other cell populations. The absolute neutrophil count showed a cyclic pattern in all four subjects with the peak neutrophil count preceding the peak eosinophil count in two subjects. Neutropenia was not observed. Absolute lymphocyte counts showed a cyclic pattern, peaking either with the absolute eosinophil count or slightly after the cycle with an approximate two-fold increase in absolute lymphocyte count around the time of the peak in all four subjects. The absolute monocyte and platelet counts and hemoglobin levels did not cycle. A novel finding in the present study was cycling of hematopoietic cell lineages other than eosinophils in all four subjects with definite EAE. This finding is similar to that in other cyclic hematopoietic disorders, including cyclic neutropenia and cyclic thrombocytopenia, and could be consistent with isolated involvement of a single lineage with secretion of cytokines or chemokines leading to secondary cycling of other cell types or alternatively, primary defect of a hematopoietic precursor. In order to explore the etiology of the cycling in EAE, serum and intracellular cytokine and chemokine levels were examined every 23 days over the course of an entire cycle. Serum levels of type II cytokines, including the primary eosinophilopoietic cytokine, IL-5, were consistently elevated prior to the eosinophilia in all subjects. All four of the subjects with EAE had detectable CD3 negative, CD4 positive aberrant T cells that were increased in number at the peak of eosinophilia. In three subjects, clonality could be demonstrated by TCR rearrangement studies. Intracellular staining of mitogen-stimulated lymphocytes at the peak and nadir of the cycle demonstrated an increased capacity for production of these cytokines by T lymphocytes prior to the development of eosinophilia in two subjects, consistent with a primary role of lymphocytes in driving the eosinophilia. Despite the presence of multilineage cycling in the peripheral blood, the skin biopsy findings were most consistent with a primary role for eosinophils in the angioedema of EAE. Bone marrow biopsies were performed at the peak and nadir of symptoms. The aspirate smear cell counts paralleled the findings in peripheral blood with 63% eosinophils at the peak and only 12% eosinophils at the nadir. The marrow core biopsy was hypercellular with prominent eosinophilia at the peak, and hypocellular with mild eosinophilia at the nadir. Immunostaining showed mild increases in CD117 and tryptase-positive mast cells, but no obvious cycling pattern. There was no increase in CD34+ blasts, CD20+ B-cells, CD5+ T-cells, or reticulin fibrosis at either time point. Since activated eosinophils are known to secrete a wide variety of mediators and cytokines, including the neutrophil chemoattractant IL-8, cyclic changes in eosinophil activation could, in turn, explain the variation in neutrophil counts. Although a primary stem cell disorder could also explain multilineage involvement in EAE, the bone marrow examination did not show changes in CD34 positive cell numbers. Moreover, lymphocytes, but not monocytes, appeared to be involved. In addition, human androgen receptor (HUMARA) assay analysis performed using purified eosinophils, neutrophils and lymphocytes from the one female subject failed to demonstrate clonality in any of the lineages tested. Although the etiology of episodic angioedema with eosinophilia is not yet known, we demonstrated that multiple lineages, including lymphocytes and neutrophils, are involved and may be related to disease pathogenesis. Whether these cells act directly or promote eosinophilia and eosinophil activation remains to be elucidated.
