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      Eosinophilia Associated With CD3 CD4 + T Cells: Characterization and Outcome of a Single-Center Cohort of 26 Patients

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          Background: Lymphocytic variant hypereosinophilic syndrome is characterized by marked over-production of eosinophilopoietic factor(s) by dysregulated T cells leading to eosinophil expansion. In most cases, these T cells are clonal and express a CD3 CD4 + phenotype. As this is a rare disorder, presenting manifestations, disease course, treatment responses, and outcome are not well-characterized.

          Materials and Methods: In this retrospective single-center observational study, we reviewed medical files of all patients with persistent hypereosinophilia seen between 1994 and 2019 in whom CD3 CD4 + T cells were detected. Data collection included clinical and biological findings at presentation, treatment responses, disease course, and serial CD3 CD4 + T cell counts.

          Results: Our cohort comprises 26 patients, including 2 with hypereosinophilia of undetermined significance. All 24 symptomatic patients had cutaneous lesions and/or angioedema, and fasciitis was present in several cases. The aberrant T cell subset represented 2% or less total lymphocytes in 11 subjects. TCR gene rearrangement patterns on whole blood were polyclonal in these cases, while they all had serum CCL17/TARC levels above 1,500 pg/ml. Disease manifestations were mild and did not require maintenance therapy in roughly one third of the cohort, while two thirds required long-term oral corticosteroids and/or second-line agents. Among these, interferon-alpha was the most effective treatment option with a response observed in 8/8 patients, one of whom was cured of disease. Treatment had to be interrupted in most cases however due to poor tolerance and/or development of secondary resistance. Anti-interleukin-5 antibodies reduced blood eosinophilia in 5/5 patients, but clinical responses were disappointing. A sub-group of 5 patients had severe treatment-refractory disease, and experienced significant disease- and treatment-related morbidity and mortality, including progression to T cell lymphoma in three.

          Conclusions: This retrospective longitudinal analysis of the largest monocentric cohort of CD3 CD4 + T cell associated lymphocytic variant hypereosinophilic syndrome published so far provides clinicians confronted with this rare disorder with relevant new data on patient presentation and outcome that should help tailor therapy and follow-up to different levels of disease severity. It highlights the need for novel therapeutic options, especially for the subset of patients with severe treatment-refractory disease. Future research efforts should be made toward understanding CD3 CD4 + T cell biology in order to develop new treatments that target primary pathogenic mechanisms.

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          Most cited references 41

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          Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes.

          Eosinophilia is an important indicator of various neoplastic and nonneoplastic conditions. Depending on the underlying disease and mechanisms, eosinophil infiltration can lead to organ dysfunction, clinical symptoms, or both. During the past 2 decades, several different classifications of eosinophilic disorders and related syndromes have been proposed in various fields of medicine. Although criteria and definitions are, in part, overlapping, no global consensus has been presented to date. The Year 2011 Working Conference on Eosinophil Disorders and Syndromes was organized to update and refine the criteria and definitions for eosinophilic disorders and to merge prior classifications in a contemporary multidisciplinary schema. A panel of experts from the fields of immunology, allergy, hematology, and pathology contributed to this project. The expert group agreed on unifying terminologies and criteria and a classification that delineates various forms of hypereosinophilia, including primary and secondary variants based on specific hematologic and immunologic conditions, and various forms of the hypereosinophilic syndrome. For patients in whom no underlying disease or hypereosinophilic syndrome is found, the term hypereosinophilia of undetermined significance is introduced. The proposed novel criteria, definitions, and terminologies should assist in daily practice, as well as in the preparation and conduct of clinical trials. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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            The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature.

            Several closely related disease entities make up the idiopathic hypereosinophilic syndrome (HES). The syndrome is manifest by persistent and prolonged eosinophilia with organ damage. A group of 14 patients had hematologic, cardiac, and neurologic abnormalities attributable to this disease. Patient survival and response to chemotherapy was significantly better in this group than in previously reported patients. The etiology of HES remains unknown, as does the mechanism of tissue damage.
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              Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy.

              Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by persistent blood eosinophilia > or =1.5 x 10(9)/L, absence of a secondary cause, and evidence of eosinophil-associated pathology. With the exception of a recent multicenter trial of mepolizumab (anti-IL-5 mAb), published therapeutic experience has been restricted to case reports and small case series. The purpose of the study was to collect and summarize baseline demographic, clinical, and laboratory characteristics in a large, diverse cohort of patients with HES and to review responses to treatment with conventional and novel therapies. Clinical and laboratory data from 188 patients with HES, seen between January 2001 and December 2006 at 11 institutions in the United States and Europe, were collected retrospectively by chart review. Eighteen of 161 patients (11%) tested were Fip1-like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) mutation-positive, and 29 of 168 patients tested (17%) had a demonstrable aberrant or clonal T-cell population. Corticosteroid monotherapy induced complete or partial responses at 1 month in 85% (120/141) of patients with most remaining on maintenance doses (median, 10 mg prednisone equivalent daily for 2 months to 20 years). Hydroxyurea and IFN-alpha (used in 64 and 46 patients, respectively) were also effective, but their use was limited by toxicity. Imatinib (used in 68 patients) was more effective in patients with the FIP1L1-PDGFRA mutation (88%) than in those without (23%; P < .001). This study, the largest clinical analysis of patients with HES to date, not only provides useful information for clinicians but also should stimulate prospective trials to optimize treatment of HES.

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                11 August 2020
                : 11
                1Department of Internal Medicine, Hôpital Erasme, Université Libre de Bruxelles , Brussels, Belgium
                2Laboratory of Immunobiology, Hôpital Erasme, Université Libre de Bruxelles , Brussels, Belgium
                3Department of Medical Genetics, Hôpital Erasme, Université Libre de Bruxelles , Brussels, Belgium
                4Department of Pathology, Hôpital Erasme, Université Libre de Bruxelles , Brussels, Belgium
                5Institute for Medical Immunology, Université Libre de Bruxelles , Brussels, Belgium
                Author notes

                Edited by: Carlo Riccardi, University of Perugia, Italy

                Reviewed by: Bruce Scott Bochner, Northwestern University, United States; Subhash Varma, Fortis Hospital, India

                *Correspondence: Florence Roufosse froufoss@

                This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology

                †These authors have contributed equally to this work

                Copyright © 2020 Carpentier, Verbanck, Schandené, Heimann, Trépant, Cogan and Roufosse.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 6, Tables: 2, Equations: 0, References: 42, Pages: 20, Words: 13805
                Funded by: Fonds De La Recherche Scientifique - FNRS 10.13039/501100002661
                Original Research


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