Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes

BACKGROUND: IL-5 is a cytokine critically involved in regulating several aspects of eosinophils including their production, activation, and tissue recruitment. As such, IL-5 may be involved in the pathogenesis of hypereosinophilic syndromes, a group of poorly treated diverse disorders characterized by sustained peripheral blood and/or tissue eosinophilia. OBJECTIVE: We aimed to assess the safety and efficacy of a humanized blocking monoclonal antibody against IL-5 (mepolizumab) in patients with several forms of hyper-eosinophilic syndromes. METHODS: We performed an open-label trial of anti-IL-5 in which 3 intravenous doses (10 mg/kg, maximum 750 mg) were administered at 4-week intervals to 4 patients with hypereosinophilic syndromes (defined by peripheral blood and/or tissue eosinophilia). The effects of treatment on safety, eosinophil levels (in peripheral blood and/or diseased tissue), pulmonary function, and quality of life were measured over a 28-week period. RESULTS: Anti-IL-5 was well tolerated in all patients and lowered peripheral blood eosinophil counts despite ongoing systemic glucocorticoid therapy. The decline in circulating eosinophil counts was sustained for at least 12 weeks after the last dose of anti-IL-5. In addition, anti-IL-5 improved clinical and quality of life measurements. In one patient with striking tissue eosinophilia (eosinophilic esophagitis), anti-IL-5 resulted in a 10-fold reduction in tissue eosinophil levels. CONCLUSIONS: These results suggest that anti-IL-5 is safe, effective in lowering eosinophil levels, and has potential glucocorticoid-sparing effects in patients with a variety of hyper-eosinophilic syndromes. As such, anti-IL-5 may have significant therapeutic potential for hypereosinophilic syndromes.     

Selective priming of peripheral blood eosinophils in patients with idiopathic hypereosinophilic syndrome

The idiopathic hypereosinophilic syndrome (HES) is characterised by blood eosinophilia associated with organ involvement. Elevated numbers of blood neutrophils have been observed during episodes of active HES. However, an increased responsiveness of eosinophils to chemotactic and chemokinetic stimuli may explain the selective eosinophil infiltration of the tissue. We have studied the migratory responses of blood eosinophils and neutrophils from 9 patients with HES and from 13 healthy control subjects. Chemokinetic and chemotactic responses to factors acting on both cell types were analysed by means of a modification of the Boyden chamber technique. We found increased migratory responses of the eosinophils, but not of the neutrophils, from the patients with HES. Increased blood neutrophil counts in three of the patients did not coincide with alterations of the neutrophil migratory responses. Our finding of increased migratory responses of eosinophils from patients with HES towards non-specific chemoattractants suggests selective priming of eosinophils in this disease. Interleukin (IL)-5 has previously been shown to prime eosinophils for migratory responses, and successful anti-IL-5 therapy of patients with HES indicates an important role for this cytokine in the development of hypereosinophilia.     

An 8-year-old boy with hypereosinophilic syndrome

Hypereosinophilic syndrome (HES) is a heterogeneous group of uncommon disorders characterized by the presence of marked peripheral blood eosinophilia and tissue eosinophilia, resulting in a wide variety of clinical manifestations. We present the case of an 8-year-old boy with HES. He complained of recurrent abdominal pain, general fatigue, and diarrhea. Laboratory data showed marked eosinophilia, elevated total IgE with positive specific IgE antibodies to common inhalant and food allergens, and elevated serum CCL17/TARC. A chest CT scan revealed central bronchiectasis, bronchial wall thickening, a mosaic attenuation pattern, and multiple small nodules in lung parenchyma; abdominal CT showed a thickened bladder wall. Gastrointestinal endoscopy revealed scarring in the gastric mucosa and mucosal erosion in the duodenum. Immunohistochemical examination demonstrated numerous eosinophil infiltrations with extensive extracellular eosinophil major basic protein deposition in the gastric mucosa. Only high-dose oral steroid was effective and cyclosporine appeared to have a steroid-sparing effect. HES is extraordinary rare in children and the long-term prognosis in pediatric HES is not well known. Comprehensive diagnostic procedures are vital for the early detection and management of complications in pediatric HES.     

Eosinophil membrane antigens: phenotypic frequencies in normal individuals and patients with the hypereosinophilic syndrome

The membrane antigen phenotype of eosinophils from six normal individuals and eight patients with the hypereosinophilic syndrome (HES) were examined to see whether subpopulations of eosinophils exist. Experiments were done with a panel of 6 monoclonal antibodies, using the fluorescent activated cell sorter, and immunocytochemistry. All six antibodies bound eosinophils and neutrophils, but not lymphocytes, monocytes, platelets or erythrocytes. The phenotypic frequencies of five of the six antibodies were increased in patients' eosinophils (p less than 0.005). This increase was associated with the intermediate-density eosinophils, while the antigen detected by antibody Eon 7 was associated with the light-density eosinophils. Normal eosinophils could be induced to increase their expression of these membrane antigens by incubation with mononuclear cell supernatants which are known to increase the cytotoxic capacities of eosinophil, 'activation'. It was concluded that there is a single eosinophil which undergoes post-mitotic differentiation in the blood, leading to activation and degranulation. The heterogeneity seen in patients' eosinophils reflect different stages of cell maturation and activation.     

Circulating Charcot-Leyden crystals in the hypereosinophilic syndrome

A patient who had malignant melanoma associated with the hypereosinophilic syndrome died of cardiovascular thrombotic lesions. Widespread tissue eosinophilia was accompanied by numerous Charcot-Leyden crystals in the tumor as well as in various organs, including the renal tubules. A unique observation, not previously described, is the finding of Charcot-Leyden crystals in the thrombi and vessels, including the renal glomeruli. While little is known of the significance of Charcot-Leyden crystals, it is speculated that the circulating crystals injure the endothelium and trigger intravascular coagulation, resulting in thrombosis. A search for the crystals in blood and/or urine may be of additional aid in the evaluation of the extent of the thrombotic process. A special staining method is proposed to facilitate recognition of the crystals, since these are virtually not visualized by routine stain. With the use of such a staining method, future observations in other cases of the hypereosinophilic syndrome may elucidate the role of Charcot-Leyden crystals in the pathogenesis of the thrombotic cardiovascular lesions of this syndrome.     

Immunologic reactivity in the hypereosinophilic syndrome.

Because previous studies have suggested an important link between eosinophilia and immunologic reactivity, we investigated various components of the immune system in a large number of patients with the idiopathic hypereosinophilic syndrome (HES) to elucidate a possible role for immunologic phenomena in the etiology and pathogenesis of this disease. Immunoglobulin G, A, or M levels were only rarely abnormal. However, in 8 of 21 (38%) patients with HES, IgE levels were markedly elevated suggesting an association of an IgE-mediated mechanism with eosinophilia in this subgroup. Severe dermatographism was present in three fourths of patients, and 2 patients with intermittently elevated histamine levels manifested an unusual form of immediate-pressure urticaria. Serum complement determinations showed elevated C4 and C3 levels in 27% and 77% of patients, respectively. Antigen-antibody complexlike material measured by C1q binding was elevated in the serum of 7 of 22 (32%) patients; this finding may relate to the known ability of eosinophils to avidly phagocytose antigen-antibody complexes. When compared with normals, lymphocytes from patients with HES showed a variety of abnormalities of lymphocyte surface receptors and lymphocyte function. Thus, patients with HES demonstrate a variety of immunologic abnormalities which may be related primarily or secondarily to the pathogenesis of this syndrome.     

A rat model of hypereosinophilic syndrome

Hypereosinophilia-occurring rats without chemical and antigen treatment have been maintained in our laboratory. The rat, Matsumoto Eosinophilia Shinshu (mes), showed hypereosinophilia at the age of 9 weeks or older and developed eosinophil-related inflammatory lesions in many organs. These lesions included: aortitis, granulomatous lesion in the mesenteric lymph node, inflammatory fibroid polyp of the stomach and pulmonary vasculitis with septal infiltration. These lesions were involved with cellular infiltration of eosinophils and macrophages, and deposition of eosinophilic crystals which immunohistologically showed major basic protein and eosinophilic peroxidase derived from eosinophilic lysosomal constituents. Although the distribution of lesions in mes is a little different from that of hypereosinophilic syndrome (HES) in humans, in that endomyocardial fibrosis appears in HES while aortitis appears in mes, mes is probably comparable with HES. The present paper describes the pathological aspects of the lesions in mes and discusses the pathogenesis of tissue injury related to eosinophilic infiltration.     

Evidence for the clonal nature of hypereosinophilic syndrome

Hypereosinophilic syndrome (HES) is a disease process of unknown pathogenesis. Although some cases are believed to be primary hematologic malignancies, this issue remains unsolved. We present a case of HES in whom we have observed a clone of cytogenetically abnormal cells in the bone marrow in parallel with a clinical picture of a hematologic disorder characterized by progressive proliferation and organ infiltration by eosinophils. The cytogenetic abnormality 46,XY,t(7;12)(q11;p11) is previously unreported. Our case, plus other evidence present in the literature, supports the concept that HES is a hematologic malignant neoplasia.     

Pulmonary involvement in idiopathic hypereosinophilic syndrome

A case of idiopathic hypereosinophilic syndrome (HES) is presented. The patient had been symptomatic and had documented peripheral blood eosinophilia for 9 years. The patients having only pulmonary involvement, seem to have a good prognosis and hence must be considered as a separate subgroup of HES.     

IgE antibodies to Staphylococcus aureus in the hypereosinophilic syndrome

A 16-year old boy with a 10-year history of circulating eosinophilia was diagnosed having the hypereosinophilic syndrome (HES) based upon the exclusion of other disorders. Eight years after the onset of his condition, he had a subcutaneous staphylococcal abscess followed by lymphangitis, rare clinical features of HES. As measured by radioallergosorbent techniques, there were significantly high serum levels of IgE antibodies to Staphylococcus aureus. The clinical significance of these antibodies is unknown, but their production may be due to persistent antigenic stimulation.