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Hypereosinophilic syndromes. Hypereosinophilic syndromes (HES) is a protean condition defined by chronic blood eosinophilia ≥ 1.5 G/L (> 1 month) leading to eosinophilic-related organ damage. HES subtypes includes neoplastic (clonal) disorders (HESN, that comprises FIP1L1-PDGFRA- related chronic eosinophilic leukemia and myeloproliferative and myelodysplastic syndromes associated with eosinophilia) and reactive HES (HESR, that aggregates all conditions e.g. parasitic infections, adverse drug reactions, inflammatory or neoplastic diseases that lead to the production of Th2-related cytokines and thereby to non-clonal hypereosinophilia). HESR also includes the lymphoid variant of HES (HESL), a chronic clonal indolent T-cell lymphoproliferative disorder in which mature peripheral T cells secrete high amounts of IL-5, leading to the polyclonal expansion of eosinophils. Despite an extensive etiological workup, approximately 50% of HES remain of undetermined cause. HES-related clinical manifestations are highly diverse, but dermatological, respiratory and gastro-intestinal symptoms are the most frequent. The long-term prognosis is driven by cardiac involvement and, for patients with HESN and HESL, by the risk of acute transformation into high-grade hematological malignancies. Treatment of HESN relies on tyrosine kinase inhibitors (e.g. imatinib mesylate), while oral glucocorticoids are the usual the fist-line therapy for HESR (including SHEL). In this setting, second-line treatments include hydroxyurea and Peg-interferon alfa-2a. IL-5-targeted therapies are very promising (except for HESN). Yet, to date, their use is restricted to clinical trials and to a compassionate use program dedicated to severe and refractory patients., Competing Interests: M. Groh déclare des liens ponctuels avec GlaxoSmithKline et AstraZeneca (activité de conseil). G. Lefèvre déclare des liens ponctuels avec AstraZeneca et Sanofi-Genzyme (activités de conseil), GlaxoSmithKline (financement recherche, frais de congrès). F. Ackermann, et N. Étienne déclarent n’avoir aucun lien d’intérêts. J. -E. Kahn déclare des liens ponctuels avec GSK (activités de conseil, frais de congrès) et AstraZeneca (activités de conseil).

Among eosinophil-related diseases, many of them are linked to hypersensitivity mechanisms which are dependent or independent on the development of an IgE response. In certain patients a clear relationship can be identified with an environmental airborne allergen: allergic disorders associated with the presence of eosinophils present in blood or in the airway lumen include allergic asthma, perennial or seasonal allergic rhinitis, less often allergic sinusitis or some cases of chronic cough. In other clinical situations, proofs for a direct involvement of IgE are difficult to establish, for example in drug-induced pulmonary eosinophilias. In allergic bronchopulmonary aspergillosis, two distinct mechanisms are implicated: an IgE dependent process but also the proliferation of the fungal microorganism into the bronchial tree. Similarly in Churg++ and Strauss syndrome, it does not exist any demonstration for an IgE mechanism, although a large majority of patients are atopic, with high serum total IgE levels. So it appears that the border between IgE and non IgE related disorders remains at the present time poorly defined.

Interleukin-5 produced by Th2-type lymphocytes is involved in the pathogenesis of a number of hypereosinophilic disorders. We and others have identified clonal Th2 cells with abnormal surface phenotypes in peripheral blood of certain patients presenting the idiopathic hypereosinophilic syndrome. We took advantage of the CD3- CD4+ phenotype of our patients' T cells to determine the activation signals involved in their production of Th2 cytokines and expansion, independently of T cell receptor engagement. In vitro cocultures performed with dendritic cells demonstrated the critical role of co-stimulatory signalling through B.7/CD28 and LFA-3/CD2 pathways and the involvement of an autocrine IL2/IL2R loop in the activation of these Th2-type cells. The high-level spontaneous apoptosis displayed by these cells in vitro was drastically inhibited by IL2 and IFN-alpha. New therapeutic strategies could result from our observations. Indeed, the hypereosinophilic syndrome may represent an unexpected application of new immunomodulatory molecules such as CTLA4-Ig and anti-IL2R-alpha.

Hypereosinophilia may be seen in the blood or tissues of cancer patients. A part of lymphomas, the tumors more frequently involved in such eosinophilia, are digestive and respiratory tract carcinomas. The prevalence of cancer-associated eosinophilia is very variable among the different kind of tumors. These cancer-associated eosinophilia are the results of the secretion by tumor or inflammatory cells of interleukin-3 and -5 and GM-CSF. The anti-cancer properties of eosinophilic polymorphonuclear are poorly understood and the prognostic significance of cancer-associated blood or tissue eosinophilia has not been assessed by controlled studies.

Hypereosinophilia is often linked to the presence of pluricellular parasites in host tissues. Polynuclear eosinophils are sprung from the bone marrow. After multiplying and maturing, they are thrown into the blood flow and from the blood to the tissues where they are found in immediate contact with the parasite. Eosinophils are major components of the parasitic granuloma. Parasitic diseases are a major cause of hypereosinophilia and eosinophilia is mainly due to helminths. Protozoa do not produce hypereosinophilia, except for toxoplasmosis in which a low and discontinuous eosinophilia may be seen. Subsequently, maggots producing myiasis yield to hypereosinophilia too. In helminthiasis, the action of the eosinophil granulocyte is double. In tissues, it destroys the parasite and plays a regulatory role in mastocytes degranulation. Eosinophils which participate in the inflammatory reaction secrete factors which neutralize mediators liberated by mastocytes, histamine mainly, destroyed by histaminase. In a practical point of view, blood hypereosinophilia is a very useful tool for diagnosis. Eosinophilia reach early a high value, this before the parasitic infection becomes detectable by means of resources other than immunological. The eosinophils rates decreases rapidly as an effect of the anthelmintic drug, this confirming the efficacy and specificity of the prescribed treatment.