Treatment of lymphocyte-variant hypereosinophilic syndrome (L-HES): what to consider after confirming the elusive diagnosis.

Lymphocyte-variant hypereosinophilic syndrome (L-HES) is a rare disease driven by immunophenotypically aberrant T cells producing eosinophilopoetic cytokines such as interleukin-5 (IL-5). Treatment is challenging because L-HES is relatively steroid resistant and not amenable to tyrosine kinase inhibitors. We searched the literature for clinical trials and observational studies, including case reports, of patients treated for L-HES. In all, 25 studies were selected; two were randomised controlled trials of IL-5 blockade, which included some patients with L-HES, and the rest were observational studies. Corticosteroids are often used as first-line therapy, but patients with L-HES have lower response rates than other types of HES. Treatments that reduce symptoms and steroid dependence in some patients include interferon-alpha (IFN-α), anti-IL-5 monoclonal antibodies, cyclosporine and mycophenolate. These drugs target T-cell activation and proliferation, or IL-5 directly. Although effective, IFN-α and cyclosporine were commonly reported to cause side-effects resulting in discontinuation. Alemtuzumab can induce remissions, but these are generally short lived. The anti-IL-5 monoclonal antibodies mepolizumab and benralizumab are effective and well tolerated, but with a high rate of relapse once withdrawn. Hydroxyurea, methotrexate, imatinib were unsuccessful in most patients studied. More prospective clinical trials are needed for patients with L-HES.

Molecular Pathogenesis and Treatment Perspectives for Hypereosinophilia and Hypereosinophilic Syndromes.

Hypereosinophilia (HE) is a heterogeneous condition with a persistent elevated eosinophil count of >350/mm3, which is reported in various (inflammatory, allergic, infectious, or neoplastic) diseases with distinct pathophysiological pathways. HE may be associated with tissue or organ damage and, in this case, the disorder is classified as hypereosinophilic syndrome (HES). Different studies have allowed for the discovery of two major pathogenetic variants known as myeloid or lymphocytic HES. With the advent of molecular genetic analyses, such as T-cell receptor gene rearrangement assays and Next Generation Sequencing, it is possible to better characterize these syndromes and establish which patients will benefit from pharmacological targeted therapy. In this review, we highlight the molecular alterations that are involved in the pathogenesis of eosinophil disorders and revise possible therapeutic approaches, either implemented in clinical practice or currently under investigation in clinical trials.

The Cellular Functions of Eosinophils: Collegium Internationale Allergologicum (CIA) Update 2020.

Eosinophils and their secretory mediators play an important role in the pathogenesis of infectious and inflammatory disorders. Although eosinophils are largely evolutionally conserved, their physiologic functions are not well understood. Given the availability of new eosinophil-targeted depletion therapies, there has been a renewed interest in understanding eosinophil biology as these strategies may result in secondary disorders when applied over long periods of time. Recent data suggest that eosinophils are not only involved in immunological effector functions but also carry out tissue protective and immunoregulatory functions that actively contribute to the maintenance of homeostasis. Prolonged eosinophil depletion may therefore result in the development of secondary disorders. Here, we review recent literature pointing to important roles for eosinophils in promoting immune defense, antibody production, activation of adipose tissue, and tissue remodeling and fibrosis. We also reflect on patient data from clinical trials that feature anti-eosinophil therapeutics.

When Blood Cell Counts Matter: Hypereosinophilic Syndrome as a Rare Cause of Ischemic Strokes.

Hypereosinophilic syndrome (HES) is a rare condition characterized by elevated eosinophil counts (>1.5 x 109 on two consecutive measurements), which are of myeloid clonal in origin or are driven by excess cytokines. One subtype of HES exhibits the Fip1-like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) fusion gene, a gain-of-function mutation resulting in a hyperactive tyrosine kinase. HES, especially the FIP1L1-PDGFRA variant, exhibits an excellent response to chemotherapy with imatinib. In this report, we present a 38-year-old patient with no contributory past medical history who experienced sudden-onset fatigue, ataxia, visual changes, and headaches. He was found to have multiple small acute infarcts in his cerebrum and cerebellum. A stroke work-up, including transthoracic echocardiogram (TTE), transesophageal echocardiogram (TEE), and computed tomography angiography (CTA), did not yield insight into the origin of his infarcts. On CBC, he was consistently hypereosinophilic, and a bone marrow biopsy revealed hypercellularity and the FIP1L1-PDGFRA fusion gene, confirming the diagnosis of HES. The patient was treated first with methylprednisolone and then imatinib with excellent response. It appears that, in our patient, strokes were not of a thromboembolic nature but rather due to hypercoagulability. In this report, we advocate for considering HES and emphasize the importance of revisiting basic laboratory studies such as a CBC if the standard stroke workup fails to elucidate the mechanism behind ischemic strokes with an embolic pattern.

French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes.

Eosinophilic-related clinical manifestations are protean and the underlying conditions underpinning eosinophilia are highly diverse. The etiological workup of unexplained eosinophilia/hypereosinophilia can be challenging, and can lead sometimes to extensive, inappropriate, costly and/or invasive investigations. To date, guidelines for the etiological workup and management of eosinophilia are mainly issued by hematologists, and thus mostly cover the scope of clonal hypereosinophilic syndromes (HES). Here, thanks to an extensive literature review, and thanks to the joint work of a large panel of experts involving physicians from both adult and pediatric medicine and from various subspecialties (as well as a representative of a patients' association representative), we provide recommendations for both the step-by step diagnostic workup of eosinophilia (whether unexplained or within specific contexts) as well as the management and follow-up of the full spectrum of eosinophilic disorders (including clonal, reactive, lymphocytic and idiopathic HES, as well as single-organ diseases). Didactic prescription summaries intended to facilitate the prescription of eosinophil-targeted drugs are also provided, as are practical diagnostic and therapeutic algorithms. Lastly, this set of recommendations also includes a summary intended for general practitioners, as well as an overview of the therapeutic patient education program set up by the French reference center for HES. Further updates will be mandatory as new validated information emerges.

Biologic therapies for hypereosinophilic disorders: From tyrosine kinase inhibitors to monoclonal antibodies. Towards an increasingly customized management?

Hypereosinophilic syndromes (HES) encompass a wide range of disorders characterized by persistent peripheral blood hypereosinophilia (HE) (i.e., an eosinophil count ≥1.5 × 109/L and ≥ 10% eosinophils preferably with a minimal duration of 6 months if documentation is available) associated with organ damage and/or dysfunction attributable to tissue eosinophilic infiltrate and release of granule contents. In most cases, HE is associated with atopic conditions/allergies, parasitic infections, medications, autoimmune disorders and/or solid tumors in most cases. More rarely, it can be one of the dominant manifestations of an underlying myeloid/lymphoid neoplasm. With regard to hematological forms, in recent decades the advances in understanding the pathogenic aspects of HES have led to a growing interest in these diseases, and in the 2016 WHO classification multiple subgroups were defined according to the molecular profile with the aim of better characterizing these syndromes and establishing which patients will benefit from specific pharmacological targeted therapies. This review article will provide a comprehensive overview of possible therapeutic approaches for HES in the light of each specific molecular alteration, considering both tyrosine kinase inhibitors and monoclonal antibodies, either implemented in clinical practice or currently still under development.

Hypereosinophilic Syndrome Endocarditis With Severe Biventricular Failure Complicated by Sepsis: A Challenging Case.

Hypereosinophilic syndrome (HES) is a myeloproliferative disorder characterized by persistent hypereosinophilia that is associated with multi-organ damage. Eosinophilic endocarditis is a serious complication of HES. The exact prevalence of the disease is unknown, and it is characterized by a persistently elevated eosinophil count, resulting in multi-organ involvement due to eosinophilic infiltration. We present a case of a 65-year-old Caucasian male patient who presented with one-week symptoms of feeling unwell and intermittent pleuritic chest pain. His medical history was significant for the idiopathic hypereosinophilic syndrome, eosinophilic myocarditis, hypertension (HTN), type 2 diabetes mellitus (T2DM), and chronic obstructive pulmonary disease (COPD). Inflammatory markers were raised, including eosinophil count, and a transthoracic echocardiogram (TTE) showed a mass attached to the mitral valve (MV) leaflets, suggesting vegetation or thrombus. The patient was commenced on intravenous antibiotics, inotropes for septic shock, and low molecular weight heparin (LMWH) for a possible thrombus. He showed mild biochemical improvement initially without any clinical improvement before further deterioration secondary to aspiration pneumonia. He was seen by the palliative care team and mental health team for confusion and agitation and was put on the palliative care pathway. All active medical treatment was stopped, and the patient succumbed to his illness three weeks into his admission.

Eosinophilic Myocarditis: A Challenging Diagnosis.

Eosinophilic myocarditis (EM) is a rare subtype of myocarditis that is characterized by eosinophilic infiltration of the myocardium and is associated with peripheral eosinophilia in most cases. The diagnosis is suspected in the presence of acute myocarditis and peripheral eosinophilia and is usually confirmed by endomyocardial biopsy (EMB) before starting steroid therapy. Here, we present a case of severe idiopathic eosinophilic myocarditis in a young man with a history of asthma and peripheral eosinophilia. He was treated with high-dose steroids despite negative EMB, and we noted a dramatic improvement in cardiac function. Our case highlights the importance of cardiac magnetic resonance (CMR) and clinical judgment in establishing the diagnosis of EM irrespective of the histopathologic result.

Hypereosinophilic syndromes - An enigmatic group of disorders with an intriguing clinical spectrum and challenging treatment.

Hypereosinophilic syndromes (HES) comprises a group of rare disorders characterized by blood hypereosinophilia (>1.5 × 109/l) accompanied by eosinophil-associated organ damage. The 2016 World Health Organization classification recognizes a category of myeloid/lymphoid neoplasms with prominent eosinophilia (M/Leo) and well-characterized gene rearrangements of PDGFRA/B, FGFR1 or JAK2. PDGFRA/B-rearranged patients usually manifest as imatinib-sensitive myeloproliferative neoplasms (MPNs). FGFR1- and JAK2- rearranged cases may manifest as MPNs or aggressive lymphomas/leukemias and historically have had a dismal prognosis, although clinical trials with targeted treatment are promising. A negative screen for M/Leo in a patient with myeloid features should prompt consideration of a diagnosis of chronic eosinophilic leukemia-not otherwise specified. If these are excluded and a secondary cause is not identified, a diagnosis of idiopathic HES and/or other rare variants of HES should be considered. This review, through an illustrative case, summarizes current knowledge on HES pointing at new directions in diagnosis and treatment.

Eosinophils and eosinophil-associated disorders: immunological, clinical, and molecular complexity.

Eosinophils and their mediators play a crucial role in various reactive states such as bacterial and viral infections, chronic inflammatory disorders, and certain hematologic malignancies. Depending on the underlying pathology, molecular defect(s), and the cytokine- and mediator-cascades involved, peripheral blood and tissue hypereosinophilia (HE) may develop and may lead to organ dysfunction or even organ damage which usually leads to the diagnosis of a HE syndrome (HES). In some of these patients, the etiology and impact of HE remain unclear. These patients are diagnosed with idiopathic HE. In other patients, HES is diagnosed but the etiology remains unknown - these patients are classified as idiopathic HES. For patients with HES, early therapeutic application of agents reducing eosinophil counts is usually effective in avoiding irreversible organ damage. Therefore, it is important to systematically explore various diagnostic markers and to correctly identify the disease elicitors and etiology. Depending on the presence and type of underlying disease, HES are classified into primary (clonal) HES, reactive HES, and idiopathic HES. In most of these patients, effective therapies can be administered. The current article provides an overview of the pathogenesis of eosinophil-associated disorders, with special emphasis on the molecular, immunological, and clinical complexity of HE and HES. In addition, diagnostic criteria and the classification of eosinophil disorders are reviewed in light of new developments in the field.

Successful Long-Term Control of the Syndrome of Episodic Angioedema With Eosinophilia (Gleich Syndrome) With Low-Dose Imatinib Mesylate and Prednisone.

The syndrome of episodic angioedema with eosinophilia, first reported over 40 years ago, is a hypereosinophilic disorder that, uniquely, is not associated with end-organ pathology. However, patients develop a constellation of symptoms that include angioedema, urticaria, fatigue, and fever. Episodes are accompanied by massive hypereosinophilia and weight gain. Type II serum cytokine levels (IL-5, IL-13, IL-9, and IL-10) show cyclic variations peaking at or just prior to the peak of eosinophilia and an abnormal Th2 cell phenotype has been reported. Attacks may occur with predictable regularity and have been described in both adults and children. Glucocorticoid therapy reliably reverses symptoms with accompanying diuresis, defervesce, and normalization of the eosinophil count. In this report, a patient who had the syndrome of episodic angioedema with eosinophilia exceeding 20 years is reported. He has had no end-organ damage to date. Testing for the CHIC2 deletion, a surrogate for the FIP1L1-PDGFRA fusion, was negative. Use of imatinib mesylate, initially as a steroid-sparing agent, and subsequently as a maintenance medication, plus low-dose prednisone has provided long-term control of hypereosinophilia and all clinical manifestations.

What does elevated TARC/CCL17 expression tell us about eosinophilic disorders?

Eosinophilic disorders encompass a large spectrum of heterogeneous diseases sharing the presence of elevated numbers of eosinophils in blood and/or tissues. Among these disorders, the role of eosinophils can vary widely, ranging from a modest participation in the disease process to the predominant perpetrator of tissue damage. In many cases, eosinophilic expansion is polyclonal, driven by enhanced production of interleukin-5, mainly by type 2 helper cells (Th2 cells) with a possible contribution of type 2 innate lymphoid cells (ILC2s). Among the key steps implicated in the establishment of type 2 immune responses, leukocyte recruitment toward inflamed tissues is particularly relevant. Herein, the contribution of the chemo-attractant molecule thymus and activation-regulated chemokine (TARC/CCL17) to type 2 immunity will be reviewed. The clinical relevance of this chemokine and its target, C-C chemokine receptor 4 (CCR4), will be illustrated in the setting of various eosinophilic disorders. Special emphasis will be put on the potential diagnostic, prognostic, and therapeutic implications related to activation of the TARC/CCL17-CCR4 axis.

Eosinophilic Granulomatosis With Polyangiitis: Dissecting the Pathophysiology.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare multisystemic disease classified both amongst hypereosinophilic disorders and ANCA-associated vasculitis. Vessel inflammation and eosinophilic proliferation are the hallmarks of the disease and main effectors of organ damage. Two distinct disease phenotypes have classically been described according to ANCA-status: the ANCA-negative subset with eosinophil-driven manifestation and the ANCA-positive one with vasculitic manifestations. An analogous dichotomization has also been backed by histological findings and a distinct genetic background. EGPA is typically consider a Th2-mediated disease and blood and tissue eosinophilia represent the cornerstone of diagnosis. Besides, ANCA are known for inducing endothelial injury and vascular inflammation by activating the circulating neutrophils. Thus, the pathogenesis of EGPA seems to be mediated by two coexisting mechanisms. However, the verbatim application of this strict dualism cannot always be translated into routine clinical practice. In the present review we describe the current knowledge on the eosinophilic and ANCA-mediated aspects of EGPA pathogenesis. Finally, we review the rationale of the currently proposed EGPA dichotomy and future research perspectives.

Hypereosinophilic syndromes in the precision medicine era: clinical, molecular aspects and therapeutic approaches (targeted therapies).

Introduction: Hypereosinophilic syndromes are a heterogeneous group of disorders that may be associated with life-threatening organ injury as a result of tissues infiltration by eosinophils. The main goal of therapy is to mitigate eosinophil-mediated organ damage. When possible, therapy should be directed at the underlying etiology. However, even in the absence of any known cause, when organ damage is present, hypereosinophilia must be treated promptly and aggressively to reduce potential morbidity and mortality.Areas covered: Conventional therapies, including corticosteroids, hydroxyurea (hydroxycarbamide) and interferon-alpha, have shown variable efficacy and a non-negligible toxicity emphasizing the need of new therapeutic strategies based on drugs with different mechanisms of action.Expert opinion: Tyrosine kinase inhibitors have a central role among targeted therapies of hypereosinophilic syndromes. Imatinib, initially empirically used based on its activity in chronic myeloid leukemia, achieved preliminary excellent results further confirmed in large series of patients. Third-generation tyrosine kinase inhibitors such as ponatinib, while active in vitro and in vivo in animals, still deserve confirmation in properly designed clinical trials. In addition, clinical investigation on monoclonal antibodies against interleukin-5, interleukin-5Rα, IgE, and CD52 represents a promising area of research.

Consultation for Elevated Blood Eosinophils: Clinical Presentations, High Value Diagnostic Tests, and Treatment Options.

The workup of a patient found to have eosinophilia should follow a thorough path with a detailed history and physical examination aimed at eliciting eosinophilic organ involvement, followed by histological confirmation whenever possible. The differential diagnosis of hypereosinophilia is extensive, but a rational approach beyond the history and physical examination including serologic, blood, and bone marrow cell analyses, genetic testing, and radiologic imaging can distinguish many of the causes. Often input from specialists (eg, hematology, dermatology, pulmonary, gastroenterology, and neurology) can help narrow down the possibilities and eventually result in a specific diagnosis. An accurate diagnosis is key to choosing the optimal treatment for a particular condition, and this is certainly true for eosinophilic disorders. Myeloid neoplasms that present with eosinophilia, for example, may respond to medicines that the allergist may be less accustomed to using, such as immunosuppressive agents and kinase inhibitors. Similarly, newly approved biologics that target IL-5 and eosinophils may provide new options for management. What follows is a case-based approach that helps to underscore key features of diagnosis, management, and follow-up when faced with a patient with a potential eosinophil-related disorder.

Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD).

Eosinophil-associated diseases (EADs) are rare, heterogeneous disorders characterized by the presence of eosinophils in tissues and/or peripheral blood resulting in immunopathology. The heterogeneity of tissue involvement, lack of sufficient animal models, technical challenges in working with eosinophils, and lack of standardized histopathologic approaches have hampered progress in basic research. Additionally, clinical trials and drug development for rare EADs are limited by the lack of primary and surrogate endpoints, biomarkers, and validated patient-reported outcomes. Researchers with expertise in eosinophil biology and eosinophil-related diseases reviewed the state of current eosinophil research, resources, progress, and unmet needs in the field since the 2012 meeting of the NIH Taskforce on the Research of Eosinophil-Associated Diseases (TREAD). RE-TREAD focused on gaps in basic science, translational, and clinical research on eosinophils and eosinophil-related pathogenesis. Improved recapitulation of human eosinophil biology and pathogenesis in murine models was felt to be of importance. Characterization of eosinophil phenotypes, the role of eosinophil subsets in tissues, identification of biomarkers of eosinophil activation and tissue load, and a better understanding of the role of eosinophils in human disease were prioritized. Finally, an unmet need for tools for use in clinical trials was emphasized. Histopathologic scoring, patient- and clinician-reported outcomes, and appropriate coding were deemed of paramount importance for research collaborations, drug development, and approval by regulatory agencies. Further exploration of the eosinophil genome, epigenome, and proteome was also encouraged. Although progress has been made since 2012, unmet needs in eosinophil research remain a priority.

The Spectrum of Hypereosinophilia and Associated Clonal Disorders - A Real-World Data Based on Combined Retrospective and Prospective Analysis from a Tropical Setting.

OBJECTIVE: To determine the frequency, etiological spectrum and treatment outcome of hypereosinophilia (HE) and hypereosinophilic syndromes (HES) in a tropical setting. METHODS: A retrospective analysis of hospital data of five years (January 2009 to December 2013) and a comprehensive prospective evaluation of patients presenting with HE/HES over a period of 33 months (January 2014 to September 2016) was performed. RESULTS: HE/HES was diagnosed in a total of 125 patients during the study period with an estimated prevalence of 0.5-1 case per 100,000 population in our hospital settings. 41 patients were excluded from the final analysis due to lack of sufficient data. Infections, especially helminths were the commonest cause (34%) followed by primary/clonal HE/HES (24%) and reactive HE/HES secondary to various clonal disorders (14.3%). A lymphocytic variant of HES and FIP1L1-PDGFRA positive HES were diagnosed in 3.6% each. Imatinib-responsive BCR-ABL1 negative HE/HES constitute 7.1% in our patients. None of the clinical or routine laboratory features including the age of patients, duration of HE, presence or absence of organomegaly, hemoglobin levels, eosinophil %, absolute eosinophil count, total leukocyte count, platelet counts, serum IgE levels or presence of myelofibrosis could predict or exclude malignancy in patients with HE/HES. The absence of blasts in peripheral blood or the absence of >5% blasts in bone marrow does not exclude primary/clonal HES. CONCLUSIONS: An underlying malignancy (Primary HE/HES and neoplasms leading to reactive HES; 35.7%) is diagnosed with nearly equal frequency compared to infections (34.5%) in tropical settings. There are no hematological or serological parameters, which can reliably be used to exclude an underlying malignancy, necessitating a thorough follow-up and comprehensive work-up in patients with HE/HES.

Imatinib for the treatment of hypereosinophilic syndromes.

INTRODUCTION: Hypereosinophilic syndromes (HES) encompass a group of disorders defined by sustained peripheral blood hypereosinophilia >1500/mm3 and evidence of eosinophilia-associated organ impairment. Approximately 10% of HES patients may harbor a cryptic deletion on chromosome 4 leading to formation of the FIP1L1-PDGFRA (F/P) fusion gene; these patients are diagnosed as F/P-mutated myeloid/lymphoid neoplasms with eosinophilia (MLN-eo). Areas covered: This review discusses the results of IM treatment in HES depending on mutation status. The literature on IM therapy in HES by searching PubMed for the terms 'imatinib mesylate', 'hypereosinophilic syndromes' and 'FIP1L1-PDGFRA' has been reviewed. The author's publications as well as his own experience in the field of HES treatment remain a significant contribution to this work. Expert commentary: Imatinib mesylate, a first generation tyrosine kinase inhibitor, has revolutionized the therapeutic approach to patients with hypereosinophilic syndromes and detectable F/P fusion gene. The response to IM in F/P-mutated MLN-eo is universal with minimal side effects. IM at 100mg per day induces complete molecular remission and even lower doses can be efficient to maintain durable response. Some patients may remain in continued remission after IM discontinuation. Resistance to IM is associated with dismal prognosis. IM is less effective in F/P-unmutated HES with short-lived response.

Eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome) as a differential diagnosis of hypereosinophilic syndromes.

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome, is a rare systemic disease situated between primary small vessel vasculitides associated with antineutrophil cytoplasmic antibodies (ANCAs) and hypereosinophilic syndromes (HES). Here, we present a case of EGPA in a 38-year-old male, with a previous diagnosis of asthma, who presented with fever, migratory lung infiltrates and systemic eosinophilia that was refractory to previous courses of antibiotics. This case highlights the importance of the primary care physician understanding the differential diagnosis of pulmonary eosinophilic syndromes.