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Mepolizumab, an anti-interleukin-5 antibody, has been proven a safe and effective glucocorticoid (GC)-sparing drug for many patients with nonclonal hypereosinophilic syndrome (HES) and is now approved in many countries. It remains unclear, however, which patients are most likely to benefit from therapy and whether the currently approved dosing regimen is appropriate for all. This observational retrospective study included all patients with HES who were enrolled in the MHE104317 compassionate use program (CUP) in our center. Patient and disease characteristics, mepolizumab dosing, and both clinical and hematological responses to treatment were collected from medical files. Treatment responses and mepolizumab dosing requirements were analyzed according to disease characteristics. Eighteen patients with HES were enrolled in the CUP, of whom nine are still on treatment. The median duration of exposure to mepolizumab was 45 mo (maximum 18 yr). A lower number of affected organs, requirement for GC dosing ≤10 mg prednisone-equivalent, and single-organ HES were associated with a higher likelihood of complete response. Lymphocytic variant HES (L-HES) was less treatment-responsive, leading to withdrawal and/or requiring higher mepolizumab dosing to achieve some degree of disease control. In contrast, all patients with single-organ disease had a complete response that could often be maintained despite increasing between-dose intervals. Few potentially treatment-related adverse events were observed despite prolonged exposure. This study confirms the efficacy and safety of mepolizumab in HES, although patients with L-HES rarely experience a complete response. In contrast, patients with single-organ disease affecting the lungs are often super-responders, and decreasing mepolizumab dosing may be attempted., Competing Interests: Conflict of interest statement. F.R. has received consultancy fees from Astra Zeneca, GlaxoSmithKline, Menarini, and Merck and Royalties from UpToDate., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Interleukin (IL)-5 is the key cytokine in the maturation, activation, proliferation, migration and survival of eosinophils, which are key effector cells in many upper and lower airway diseases. Through its effects on eosinophils, IL-5 indirectly contributes to various pathophysiological processes including tissue damage, repair and remodelling. Understanding the importance of IL-5 in eosinophil-associated diseases led to the development of anti-IL-5 therapies, which provide clinical benefits across a range of conditions. However, recent evidence suggests that eosinophil-depletion alone may not account for all of the therapeutic effects of anti-IL-5 therapy and that IL-5 may also contribute to disease independently of its effects on eosinophils. Indeed, evidence from ex vivo studies and targeted therapy in vivo demonstrates that IL-5 and its inhibition affects a much broader range of cells beyond eosinophils, including epithelial cells, plasma cells, mast cells, basophils, neutrophils, type 2 innate lymphoid cells, T regulatory cells and fibroblasts. This review will provide an update on the evidence supporting the breadth of IL-5 biology relevant to disease pathogenesis beyond eosinophil-associated inflammation, where there is a need for additional insight, and the clinical implications of a more central role of IL-5 in type 2 inflammation., (© 2024 GSK and The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Rare eosinophil-associated disorders (EADs), including hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis, and eosinophilic gastrointestinal disorders, are a heterogeneous group of conditions characterized by blood and/or tissue hypereosinophilia and eosinophil-related clinical manifestations. Although the recent availability of biologic therapies that directly and indirectly target eosinophils has the potential to dramatically improve treatment options for all EADs, clinical trials addressing their safety and efficacy in rare EADs have been relatively few. Consequently, patient access to therapy is limited for many biologics, and the establishment of evidence-based treatment guidelines has been extremely difficult. In this regard, multicenter retrospective collaborative studies focusing on disease manifestations and treatment responses in rare EADs have provided invaluable data for physicians managing patients with these conditions and helped identify important questions for future translational research. During the Clinical Pre-Meeting Workshop held in association with the July 2023 biennial meeting of the International Eosinophil Society in Hamilton, Ontario, Canada, the successes and limitations of pivotal multicenter retrospective studies in EADs were summarized and unmet needs regarding the establishment of guidelines for use of biologics in rare EADs were discussed. Key topics of interest included (1) clinical outcome measures, (2) minimally invasive biomarkers of disease activity, (3) predictors of response to biologic agents, and (4) long-term safety of eosinophil depletion. Herein, we report a summary of these discussions, presenting a state-of-the-art overview of data currently available for each of these topics, the limitations of the data, and avenues for future data generation through implementation of multidisciplinary and multicenter studies., Competing Interests: Conflict of interest statement. F.R. receives consultancy and/or speaker fees from GlaxoSmithKline, AstraZeneca, Menarini, and Merck. F.L.K. receives research funding from AstraZeneca and speaker fees from both AstraZeneca and GlaxoSmithKline. S.J.A. is the Chief Scientific Officer and an Executive Board member of EnteroTrack, LLC; a co-inventor and holds patents on the Esophageal String Test; and a consultant for Areteia Pharmaceuticals. P.A. has received consulting fees and research support from AstraZeneca, GlaxoSmithKline, and Sanofi and research support from Regeneron. B.S.B. receives remuneration for serving on the scientific advisory board of Allakos, Inc.; owns stock in Allakos; currently serves as a consultant for Third Harmonic Bio and Sanofi/Regeneron; receives publication-related royalty payments from Elsevier and UpToDate; is a co-inventor on existing Siglec-8–related patents and thus may be entitled to a share of royalties received by Johns Hopkins University during development and potential sales of such products; and is a co-founder of Allakos, which makes him subject to certain restrictions under university policy (the terms of this arrangement are being managed by Johns Hopkins University and Northwestern University in accordance with their conflict-of-interest policies). M.W.J. has received research funding from F. Hoffmann-La Roche. S.K.M. has received consulting, advisory, or speaking honoraria from AstraZeneca, Amgen, GlaxoSmithKline, Novartis, and Sanofi/Regeneron. P.O.B. receives research funding from GlaxoSmithKline, AstraZeneca, Blueprint, and DBV Technologies; and serves on advisory boards for AstraZeneca, Sanofi, Genentech, and Kalvista. M.E.W. has received consulting, advisory, or speaking honoraria from Amgen, Areteia Therapeutics, AstraZeneca, Avalo Therapeutics, Boehringer Ingelheim, Celldex, Cellergy Pharma, Cerecor, Cytoreason, Eli Lilly, Equillium, Glaxosmithkline, Incyte, Kinaset, Merck, Novartis, Om Pharma, Overtone Therapeutics/Foresite Labs, Phylaxis, Pulmatrix, Rapt Therapeutics, Regeneron, Roche/Genentech, Sanofi/Genzyme, Sentien, Sound Biologics, Tetherex Pharmaceuticals, Teva, Upstream Bio, and Verona Pharma. The other authors have no conflicts of interest to disclose., (Published by Oxford University Press on behalf of Society for Leukocyte Biology 2024.)

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Benralizumab, a monoclonal antibody against the interleukin-5α receptor expressed on eosinophils, may be an option for treating EGPA., Methods: We conducted a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial to evaluate the efficacy and safety of benralizumab as compared with mepolizumab. Adults with relapsing or refractory EGPA who were receiving standard care were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecified noninferiority margin, -25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety., Results: A total of 140 patients underwent randomization (70 assigned to each group). The adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], -13 to 18; P = 0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per microliter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per microliter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively., Conclusions: Benralizumab was noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. (Funded by AstraZeneca; MANDARA ClinicalTrials.gov number, NCT04157348.)., (Copyright © 2024 Massachusetts Medical Society.)

Elevated eosinophil counts are implicated in multiple diseases, from relatively prevalent organ-specific disorders such as severe eosinophilic asthma, to rare multisystem disorders such as hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA). Patients with these multisystem diseases, often associated with markedly elevated eosinophil counts, have a substantial risk of morbidity and mortality due to delayed diagnosis or inadequate treatment. A thorough workup of symptomatic patients presenting with elevated eosinophil counts is essential, although in some cases the differential diagnosis may remain difficult because of overlapping presentations between HES and EGPA. Notably, first- and second-line treatment options and response to therapy may differ for specific HES and EGPA variants. Oral corticosteroids are the first line of treatment for HES and EGPA, except when HES is the result of specific mutations driving clonal eosinophilia that are amenable to targeted treatment with a kinase inhibitor. Cytotoxic or immunomodulatory agents may be required for those with severe disease. Novel eosinophil-depleting therapies, such as those targeting interleukin 5 or its receptor, have shown great promise in reducing blood eosinophil counts, and reducing disease flares and relapses in patients with HES and EGPA. Such therapies could reduce the side effects associated with long-term oral corticosteroids or immunosuppressant use. This review provides a pragmatic guide to approaching the diagnosis and clinical management of patients with systemic hypereosinophilic disorders. We highlight practical considerations for clinicians and present cases from real-world clinical practice to show the complexity and challenges associated with diagnosing and treating patients with HES and EGPA., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA) are rare systemic inflammatory disorders with overlapping symptoms, elevated eosinophil counts, and heterogenous clinical presentations. Although progress has been made in recent years, there are substantial gaps in our understanding of the pathologic mechanisms involved in these diseases, as well as numerous unmet needs relating to both diagnosis and patient management. For example, in most cases of HES, the underlying cause of hypereosinophilia is unknown, while in EGPA, although a polygenic genetic susceptibility has been found, understanding of the pathogenic mechanisms remains largely elusive. Delineating differences between certain disease variants may be challenging, and there are no reliable predictive markers of disease course. In addition, the current diagnostic criteria for HES and classification criteria for EGPA are not easy to implement in a nonspecialist setting, and specialist referral pathways need to be signposted more clearly. Furthermore, disease-specific activity scores need to be developed to aid the assessment of treatment effects, and improved biomarkers are needed to aid with treatment stratification. In this review, we outline the limitations of our current understanding of HES and EGPA and highlight areas for future work, which ultimately should help improve patient management and outcomes., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

What Is This Summary About?: Eosinophil-associated diseases (EADs) are a group of conditions in which eosinophils (a type of white blood cell) are thought to play a key role in the disease and how it develops. Some EADs are common, such as atopic dermatitis (also called eczema) and a subtype of asthma called eosinophilic asthma, while others are rare, such as hypereosinophilic syndrome (a condition in which a person has a very high number of eosinophils in both the blood and one or more organs). People with EADs face many problems related to their conditions. Symptoms such as severe abdominal pain, itch, or shortness of breath impact both the patient as well as their friends and family. Patients with EADs also experience delays to diagnosis and treatment as well as financial barriers. Healthcare professionals sometimes fail to recognize the complex set of symptoms that characterize an EAD, and this may cause delays in reaching a correct diagnosis. As a result, it may take longer for a patient to get the best care and the most effective treatments, which may contribute to poor health. The goal of this charter is to describe the key elements of good quality care, which all people with EADs deserve, as well as to present an action plan to improve health and overall well-being for people with EADs. Proposed use of this patient charter: The principles described in this charter (a written guide to achieve an outcome) show the core elements of quality care that people with EADs must receive. They also describe clear steps to reduce the burden on patients and their caregivers and to improve patient health outcomes. We urge healthcare professionals, hospitals, and policymakers around the world to adopt these principles quickly. By doing this, people with EADs will be more likely to receive an accurate and timely diagnosis and have access to quality care and treatment in the right setting.

Background: Hypereosinophilic syndrome (HES) is characterized by persistent elevated blood and/or tissue eosinophil levels and eosinophil-mediated organ damage. Presentation is highly heterogenous; patients may experience symptoms affecting multiple organ systems., Objectives: To assess the effects of mepolizumab, which targets interleukin-5, on HES-related symptom burden, based on HES daily symptoms (HES-DS) questionnaire data collected during the Phase III (ClinicalTrials.gov ID: NCT02836496) study of mepolizumab in patients with HES., Methods: Each of the six HES-related symptoms were rated (0-10) daily by patients, recalling worst symptom experience in the prior 24 hours; change from baseline at Week 32 was also calculated for mepolizumab versus placebo., Results: Mepolizumab versus placebo reduced HES-related symptom burden severity in patients with HES at Week 32. Improvements in the median change from baseline scores were seen across all symptom groups except skin for patients treated with mepolizumab; greatest improvement from baseline was observed for breathing symptoms., Conclusion: These data highlight the considerable symptom burden associated with HES and further support the clinical benefits of mepolizumab treatment for these patients., Competing Interests: The authors declare that this study and the post hoc analysis received funding from GSK (GSK study ID: 200622; NCT02836496). The funder had the following involvement in the study: input in the study design, data collection/analysis and interpretation. The funder did not place any restrictions on access to data or statements made in the manuscript. Authors had full access to all study data and had final responsibility to submit the manuscript for publication. Editorial support in the form of writing assistance, including development of the initial draft based on author direction was funded by GSK. FR reports consulting fees and personal fees from AstraZeneca and GSK and royalty payments from UpToDate. JB reports royalty payments for the licensing of a cell line developed in his laboratory. JS, NK, JHB, RM, and LN were employed by GSK and own stocks/shares., (Copyright © 2023 Roufosse, Butterfield, Steinfeld, Bentley, von Maltzahn, Kwon and Nelsen.)

Eosinophilia and eosinophil activation are recurrent features in various reactive states and certain hematologic malignancies. In patients with hypereosinophilia (HE), HE-induced organ damage is often encountered and may lead to the diagnosis of a hypereosinophilic syndrome (HES). A number of known mechanisms and etiologies contribute to the development of HE and HES. Based on these etiologies and the origin of eosinophils, HE and HES are divided into primary forms where eosinophils are clonal cells, reactive forms where an underlying reactive or neoplastic condition is detected and eosinophils are considered to be "non-clonal" cells, and idiopathic HE and HES in which neither a clonal nor a reactive underlying pathology is detected. Since 2012, this classification and the related criteria have been widely accepted and regarded as standard. However, during the past few years, new developments in the field and an increasing number of markers and targets have created a need to update these criteria and the classification of HE and HES. To address this challenge, a Working Conference on eosinophil disorders was organized in 2021. In this conference, a panel of experts representing the relevant fields, including allergy, dermatology, hematology, immunology, laboratory medicine, and pathology, met and discussed new markers and concepts as well as refinements in definitions, criteria and classifications of HE and HES. The outcomes of this conference are presented in this article and should assist in the diagnosis and management of patients with HE and HES in daily practice and in the preparation and conduct of clinical trials., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES) are driven by persistently high eosinophil numbers, causing damage to tissues and organs. As rare diseases, they are often underappreciated by healthcare professionals. Using a social listening analysis, we collected patient and caregiver comments relating to EGPA and HES made on online social platforms between 1 January 2019 and 31 May 2020, in English, French, and German. Results were classified into key areas of interest. In total, 746 comments with consent to publish were collected mentioning EGPA, and 39 were identified mentioning HES. The most common theme was sharing of personal experiences (EGPA: 77%; HES: 100%). Diagnosis, including diagnosis delays and misdiagnosis, was mentioned in 33% of comments for EGPA, and 82% for HES. Other common themes included seeking and giving advice, symptoms, and treatments. These insights highlight the views and unmet needs of people living with EGPA and HES. Further work should improve disease awareness and effective communications among healthcare professionals and patients with these conditions., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MJS and DA have no competing interests. FR has received consultancy fees from AstraZeneca, and GSK. ZA, NK, and LB are employees of and shareholders in GSK. MW has received research grants from the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute, and has acted as a consultant for AstraZeneca, Boehringer Ingelheim, Equillium, Genentech, GSK, Novartis, Regeneron, Sanofi, Sentien, and Teva., (© The Author(s) 2022.)

Background: Mepolizumab, an anti-interleukin-5 (IL-5) antibody, reduces disease flares in patients with hypereosinophilic syndrome (HES). Factors predicting treatment response are unknown., Objective: To assess mepolizumab efficacy by baseline blood eosinophil count (BEC) and serum IL-5 level in patients with HES., Methods: This post hoc analysis used data from the phase III study assessing mepolizumab in patients with HES (NCT02836496). Patients 12 years old or older, with HES for 6 or more months, 2 or more flares in the previous year, and BEC ≥1,000 cells/μL at screening were randomized (1:1) to 4-weekly subcutaneous mepolizumab (300 mg) or placebo, plus baseline HES therapy, for 32 weeks. The proportion of patients experiencing 1 or more flares (wk 32), annualized flare rate, and proportion of patients with change from baseline in Brief Fatigue Inventory (BFI) item 3 (wk 32), were analyzed by baseline BEC (<1500/≥1500 to <2500/≥2500 cells/μL). Flare outcomes were assessed by baseline serum IL-5 (<7.81/≥7.81 pg/mL)., Results: Across baseline BEC subgroups, mepolizumab reduced the proportion of patients experiencing 1 or more flares by 63% to 90% and flare rate by 58% to 84% (treatment-by-eosinophil interaction P = .76 and P = .90, respectively); patients had improved BFI item 3 score with mepolizumab versus placebo (cells/μL: <1,500: 54% vs 37%; ≥1,500 to <2,500: 47% vs 31%; ≥2,500: 61% vs 0%; treatment-by-eosinophil interaction P = .42). Most patients had undetectable baseline serum IL-5 levels; among these, mepolizumab versus placebo reduced the proportion of patients with 1 or more flares (77%) and flare rate (67%)., Conclusions: Mepolizumab was efficacious in the patients with HES studied, irrespective of baseline BEC. Undetectable IL-5 levels should not preclude mepolizumab treatment., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Eosinophil-associated diseases (EADs) are a range of heterogeneous conditions in which eosinophils are believed to play a critical pathological role. EADs include common illnesses such as eosinophilic asthma and chronic rhinosinusitis and rare conditions such as hypereosinophilic syndromes (HES) and eosinophilic gastrointestinal disorders (EGIDs). EADs are associated with substantial burdens for the patient, including chronic, debilitating symptoms, increased financial burden, decreased health-related quality of life, and the need for repeated visits to multiple different healthcare professionals (HCPs), emergency departments, and/or hospitals. Poor EAD recognition by HCPs often contributes to delayed diagnoses, which further delays patient access to appropriate care and effective treatments, contributing to poor health outcomes. The objective of this charter is to outline key patient rights and expectations with respect to the management of their condition(s) and to set forth an ambitious action plan to improve health outcomes for patients with EADs: (1) people with EADs, their caretakers, HCPs, and the public must have greater awareness and education about EADs; (2) people with EADs must receive a timely, accurate diagnosis; (3) all people with EADs must have access to an appropriate multidisciplinary team, when necessary; and (4) people with EADs must have access to safe and effective treatment options without unnecessary regulatory delays. The principles described in this charter demonstrate the core elements of quality care that people with EADs must receive, and they represent clear steps by which to reduce patient and caregiver burden and improve patient outcomes. We urge HCPs, healthcare systems, and policymakers worldwide to swiftly adopt these principles to ensure patients with EADs have an accurate diagnosis in a timely manner and access to high-level care and treatment in an appropriate setting., (© 2022. The Author(s).)

Background: Treatment of hypereosinophilic syndrome (HES) often requires the use of immunomodulators with substantial side effect profiles. The emergence of biologics offers an alternative treatment modality., Objective: To examine real-world practice data to describe the safety and consequences of various biologics suspected to directly or indirectly affect eosinophilic inflammation for the treatment of HES., Methods: Retrospective data from 13 centers were collected via an online Research Electronic Data Capture repository. Inclusion criteria included (1) peripheral eosinophil count of 1,500/mm 3 or greater without a secondary cause; (2) clinical manifestations attributable to the eosinophilia; and (3) having received mepolizumab (anti-IL-5), benralizumab (afucosylated anti-IL-5 receptor α), omalizumab (anti-IgE), alemtuzumab (anti-CD52), dupilumab (anti-IL-4 receptor α), or reslizumab (anti-IL-5) outside a placebo-controlled clinical trial., Results: Of the 151 courses of biologics prescribed for 121 patients with HES, 59% resulted in improved HES symptoms and 77% enabled tapering of other HES medications. Overall, 105 patients were receiving daily systemic glucocorticoids at the time of a biologic initiation and were able to reduce the glucocorticoid dose by a median reduction of 10 mg of daily prednisone equivalents. Biologics were generally safe and well-tolerated other than infusion reactions with alemtuzumab. Thirteen of 24 patients had clinical improvement after switching biologics and nine patients responded to increasing the dose of mepolizumab after a lack of response to a lower dose., Conclusions: Biologics may offer a safer treatment alternative to existing therapies for HES, although the optimal dosing and choice for each subtype of HES remain to be determined. Limitations of this study include its retrospective nature and intersite differences in data collection and availability of each biologic., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Effective treatment of inflammatory diseases is often challenging owing to their heterogeneous pathophysiology. Understanding of the underlying disease mechanisms is improving and it is now clear that eosinophils play a complex pathophysiological role in a broad range of type 2 inflammatory diseases. Standard of care for these conditions often still includes oral corticosteroids (OCS) and/or cytotoxic immune therapies, which are associated with debilitating side effects. Selective, biological eosinophil-reducing agents provide treatment options that improve clinical symptoms associated with eosinophilic inflammation and reduce OCS use. Mepolizumab is a humanized monoclonal antibody that binds to and neutralizes interleukin-5, the major cytokine involved in eosinophil proliferation, activation, and survival. Mepolizumab is approved for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Additionally, the efficacy of add-on mepolizumab has been observed in patients with severe chronic rhinosinusitis with nasal polyposis and chronic obstructive pulmonary disease with an eosinophilic phenotype. Here, we review the development, approval, and real-world effectiveness of mepolizumab for the treatment of patients with severe eosinophilic asthma, from the DREAM to REALITI-A studies, and describe how knowledge from this journey extended to the use of mepolizumab and other biologics across a broad spectrum of eosinophilic diseases., (© 2021 GlaxoSmithKline. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Eosinophil-mediated endomyocardial damage is a well-known complication in patients with hypereosinophilic syndromes (HES). Although management and survival have improved significantly, some patients continue to develop severe cardiomyopathy as a direct consequence of uncontrolled hypereosinophilia. Cardiologists play a key role in early detection and treatment. At the early generally asymptomatic stage, related to subendocardial eosinophilic infiltrates, elevation of the biomarker of cardiac damage (serum troponin) and cardiac MRI are the best tools for diagnosis. As disease progresses, patients typically develop intracardiac mural thrombi and may experience variable degrees of heart failure due to valve damage and/or subendocardial fibrosis, all of which are more readily detectable with traditional echocardiographic investigation. New imaging modalities such as strain imaging and specific sequences in MRI offer the perspective of detecting subtle perturbations and distinguishing inflammatory versus fibrotic stages. Endomyocardial biopsy may help in difficult settings, namely, when blood eosinophilia is not prominent, but may be non-contributive due to sampling issues or eosinophil degranulation or replacement by fibrosis, and must always be performed after careful consideration of the risk:benefit ratio. Although treatment of the HES itself should be managed by clinicians with expertise in this rare disorder with the aim of lowering eosinophil counts to prevent and treat eosinophil-mediated organ damage and dysfunction, cardiologists play a key role in managing the associated cardiopathy. There are no consensual disease-specific guidelines for treating eosinophil-mediated thrombotic complications and cardiopathy, which should be managed according to classical international recommendations., Competing Interests: Competing interests: AB has received consultancy fees from Amicus, Baeyer, Boehringer Ingelheim, Sanofi, Pfizer, Novartis and Alnylam; speaker fees from Pfizer, Sanofi and Alnylam. FR has received consultancy fees from GlaxoSmithKline and AstraZeneca for expertise in hypereosinophilic syndromes and royalties from UpToDate., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

The functions ascribed to eosinophils have classically been limited to host defence against certain parasitic infections and potentially deleterious effects in the setting of specific diseases that are associated with elevated eosinophil counts in blood and/or tissue. The ability to induce eosinophil depletion either experimentally in animal models or through targeted therapies in humans has extended our understanding of the roles played by eosinophils in health and homeostasis as well as in disease pathogenesis. When associated with human disease aetiology, the eosinophil takes on a pathogenic rather than a protective role. This maladaptive response, called "eosinophilic immune dysfunction" herein, appears central to exacerbation pathogenesis and disease control in severe asthma and may be involved in the aetiology of other eosinophil-related conditions ranging from organ-system-limited diseases such as phenotypic subsets of chronic obstructive pulmonary disease and chronic rhinosinusitis with nasal polyposis to more broadly systemic diseases such as eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. In this review, we describe the evidence supporting eosinophilic functions related to health and homeostasis and explore the contribution of eosinophilic immune dysfunction to human disease., Competing Interests: Conflict of interest: D.J. Jackson has received consulting, speaker fees, and support to attend international congresses from AstraZeneca, GSK, Sanofi, Teva, BI, Novartis, Chiesi, and Napp. Conflict of interest: P. Akuthota has received consulting fees and research support from AstraZeneca, GlaxoSmithKline, and Regeneron; consulting fees from Advance Medical; grant support from the National Institutes of Health (US); royalties from UpToDate; and honoraria from Medscape/WebMD, AKH, Prime CME, Rockpointe, and Vindico. Conflict of interest: F. Roufosse has received consulting fees from AstraZeneca, GlaxoSmithKline, and Knopp Biosciences for drug development in hypereosinophilic syndromes and royalties from UpToDate., (Copyright ©The authors 2022.)

Background: A double-blind, placebo-controlled, phase III study (200622) showed that mepolizumab reduces disease flares for patients with uncontrolled FIP1-like-1-platelet-derived growth factor receptor α-negative hypereosinophilic syndrome (HES) and two or more flares in the previous year., Objective: To further characterize the safety, clinical benefit, and pharmacodynamics of mepolizumab., Methods: Eligible patients from both treatment arms of the double-blind study could enter an open-label extension study (205203; NCT03306043) to receive 4-weekly mepolizumab (300 mg subcutaneously) plus background therapy for 20 weeks. Primary end points were safety-based; other end points included flare rates and changes from baseline in mean daily oral corticosteroid (OCS) dose and blood eosinophil count., Results: Of 104 patients who completed the double-blind study, 98% (previous placebo, n = 52; previous mepolizumab, n = 50) enrolled in the open-label extension. Overall, 66 of patients reported adverse events (AEs) (65%), 15 reported treatment-related AEs (15%), and nine reported serious AEs (9%). No events were fatal. The annualized flare rate (95% confidence interval) in the previous placebo and previous mepolizumab groups was 0.37 (0.16-0.86) and 0.14 (0.04-0.49) events/y, respectively. Of 72 patients receiving OCS during weeks 0 to 4, 20 (28%; previous placebo, n = 14; previous mepolizumab, n = 6) achieved 50% or greater reductions in mean daily dose during weeks 16 to 20. At week 20, blood eosinophil count was reduced by 89% in patients previously receiving placebo and remained reduced for those previously receiving mepolizumab., Conclusions: Extended mepolizumab treatment was associated with a positive benefit-risk profile. Continued control of disease flares and blood eosinophil counts, plus reductions in OCS use, were observed with mepolizumab in patients with FIP1-like-1-platelet-derived growth factor receptor α-negative HES., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Identification of patients with lymphocytic variant hypereosinophilic syndrome (L-HES) is challenging, and has important prognostic and therapeutic implications., Objective: This study was undertaken to assess diagnostic tools for L-HES and to develop evidence-based diagnostic recommendations., Methods: Biomarkers of T-cell-driven disease were compared between patients with L-HES versus idiopathic HES (I-HES) variants. Those performed routinely (serum immunoglobulin levels, T-cell phenotyping, T-cell receptor [TCR] gene rearrangement patterns) were collected from medical files, whereas others were prospectively assessed on stored blood samples (serum CCL17/thymus and activation regulated chemokine [TARC] levels, in vitro cytokine production)., Results: This study included 48 patients with I-HES and 20 with L-HES associated with a CD3 - CD4 + T-cell subset, including 7 with less than 5% aberrant cells. Neither increased serum immunoglobulin levels nor clonal TCR gene rearrangements were sufficiently sensitive or specific for L-HES. In contrast, systematically enhanced expression of the T-cell surface antigens CD2, CD5, CD45RO, and CD95 by these cells allowed for accurate detection by flow cytometry. Serum CCL17/TARC levels were significantly higher in patients with L-HES compared with those with I-HES, and a threshold of 3000 pg/mL allowed for detection of all subjects with L-HES with 75% specificity. Quantification of intracytoplasmic cytokine production by flow cytometry is the most reliable method for detection of enhanced type 2 cytokine expression, most notably for IL-4 and IL-13., Conclusion: Adapting the standard of procedure for T-cell phenotyping in patients with unexplained hypereosinophilia is currently the most reliable means of identifying those with CD3 - CD4 + L-HES., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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.

The enigmatic eosinophil has emerged as an exciting component of the immune system, involved in a plethora of homeostatic and inflammatory responses. Substantial progress has been achieved through experimental systems manipulating eosinophils in vivo, initially in mice and more recently in humans. Researchers using eosinophil knockout mice have identified a contributory role for eosinophils in basal and inflammatory processes and protective immunity. Primarily fueled by the purported proinflammatory role of eosinophils in eosinophil-associated diseases, a series of anti-eosinophil therapeutics have emerged as a new class of drugs. These agents, which dramatically deplete eosinophils, provide a valuable opportunity to characterize the consequences of eosinophil knockout humans. Herein, we comparatively describe mouse and human eosinophil knockouts. We put forth the view that human eosinophils negatively contribute to a variety of diseases and, unlike mouse eosinophils, do not yet have an identified role in physiological health; thus, clarifying all roles of eosinophils remains an ongoing pursuit.

Background: Anti-IL-5 therapy is a potential treatment for patients with hypereosinophilic syndrome (HES), although its clinical efficacy is unclear., Objective: We sought to investigate the clinical efficacy and safety of mepolizumab versus placebo in patients with HES., Methods: This randomized, multicenter, double-blind, placebo-controlled, phase III trial was conducted across 39 centers in 13 countries. Eligible patients had FIP1L1-PDGFRA-negative HES, experienced 2 or more flares (worsening of HES-related symptoms or blood eosinophil count requiring therapeutic escalation) in the previous 12 months, and had a screening blood eosinophil count greater than or equal to 1000 cells/μL. Patients were randomized (1:1) to subcutaneous mepolizumab (300 mg) or placebo every 4 weeks for 32 weeks, plus existing HES therapy. The primary outcome was the proportion of patients with 1 or more flares (worsening of HES-related symptoms necessitating therapy escalation or ≥2 courses of blinded rescue oral corticosteroids) during the study; in addition, patients who withdrew early from the study were counted as having a flare. Safety end points were also assessed., Results: The proportion of patients experiencing 1 or more flares/withdrawing from the study was 50% lower with mepolizumab versus placebo (15 of 54 [28%] vs 30 of 54 [56%]; P = .002). Logistic regression analysis was consistent with the primary analysis (odds ratio, 0.28; 95% CI, 0.12-0.64; P = .003). Similar proportions of patients in the mepolizumab and placebo groups experienced on-treatment adverse events (48 of 54 [89%] vs 47 of 54 [87%])., Conclusions: Compared with placebo, mepolizumab significantly reduced the occurrence of flares in patients with HES, with no new safety signals identified., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

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

Introduction: Idiopathic chronic eosinophilic pneumonia (ICEP) is an orphan lung disease characterized by concomitant systemic and local eosinophilia, along with bilateral lung infiltrates. Symptoms include dyspnea of subacute/chronic onset, cough, and general systemic signs. Although all patients do respond to oral corticosteroids, relapse rate is very high, which highlights the need for alternative therapies in case of relapsing ICEP. Mepolizumab is a fully humanized antibody directed against interleukin 5, a key growth factor of eosinophils. In the present study, we retrospectively studied the effect of off-label use of mepolizumab for relapsing ICEP., Materials and Methods: All data from patients treated with mepolizumab for relapsing ICEP were included in our database and diagnoses were reviewed. We analyzed the effect of treatment on relapse rate, oral corticosteroids (OCS) use, and lung lesions on high-resolution computed tomography (HRCT)., Results: We included ten patients in the final analysis, with a median follow-up of 9 months after initiation of mepolizumab. Beside its expected effect on circulating eosinophils, treatment with mepolizumab was associated with a significant reduction of annual rate of exacerbations and a reduced consumption of corticosteroids. We also observed a remission of lung lesions on follow-up HRCT., Conclusions: In this open-label retrospective study, treatment of ICEP with mepolizumab was associated with a reduction of relapses, OCS use, and the disappearance of lung infiltrates.

This article, coauthored by a patient with eosinophilic granulomatosis with polyangiitis (EGPA) initially presenting as severe eosinophilic asthma and his physician-specialist, discusses the use and management of oral corticosteroid (OCS) treatment. It also considers the importance of early diagnosis of a rare disease and patient education. The patient describes his journey from progressive worsening of asthma and eventual diagnosis of EGPA to long-term OCS treatment and then participation in a clinical trial for this rare disease, involving the introduction of targeted biologic therapy with OCS tapering. The physician describes the importance of patient referral to obtain a correct diagnosis and optimal maintenance treatment, the balance between risk of adverse events associated with long-term OCS use and benefits of disease control, and various aspects of patient participation in clinical trials. Finally, the patient describes the role of continual patient education in the management of disease and OCS treatment. These considerations can apply to all chronic inflammatory diseases requiring maintenance OCS treatment.Funding: AstraZeneca.

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., (©2018 Society for Leukocyte Biology.)

Improved understanding of the contribution of eosinophils to various chronic inflammatory conditions, most notably allergic asthma, has encouraged development of monoclonal antibodies specifically targeting mediators and surface receptors involved in eosinophil expansion and activation. The pivotal role of interleukin-5 (IL-5) in eosinophil biology, its high specificity for this leukocyte subset, and its involvement in the majority of eosinophilic conditions make it a very enticing target for treatment of eosinophil-mediated disorders. Two types of antibodies have been developed to target eosinophils: antibodies against IL-5 (mepolizumab and reslizumab), and an antibody against the IL-5-receptor-alpha-chain (IL-5Rα) (benralizumab). Both types of antibodies prevent IL-5 from engaging its receptor and in addition, anti-IL-5Rα antibodies induce target-cell lysis. They have been shown to reduce circulating eosinophil counts rapidly in humans with various disorders. Herein, a brief overview of the role of IL-5 in eosinophil biology will be presented, followed by a description of the development and characteristics of antibodies targeting IL-5 or its receptor. Results of clinical trials evaluating the efficacy and safety of these new antibodies in diseases (other than eosinophilic asthma) with prominent tissue eosinophilia are reviewed, followed by safety considerations and potential future applications.

The forkhead box P1 (FOXP1) transcription factor has been shown to regulate the generation and maintenance of quiescent naïve murine T cells. In humans, FOXP1 expression has been correlated with overall survival in patients with peripheral T-cell lymphoma (PTCL), although its regulatory role in T-cell function is currently unknown. We found that FOXP1 is normally expressed in all human leukocyte subpopulations. Focusing on primary human CD4 + T cells, we show that nuclear expression of FOXP1 predominates in naïve cells with significant downregulation detected in memory cells from blood and tonsils. FOXP1 is repressed following in vitro T-cell activation of naïve T cells, and later re-established in memory CD4 + T cells, albeit at lower levels. DNA methylation analysis revealed that epigenetic mechanisms participate in regulating the human FOXP1 gene. ShRNA-mediated FOXP1 repression induces CD4 + T cells to enter the cell cycle, acquire memory-like markers and upregulate helper T-cell differentiation genes. In patients with lymphoproliferative disorders, FOXP1 expression is constitutionally repressed in the clonal T cells in parallel with overexpression of helper T-cell differentiation genes. Collectively, these data identify FOXP1 as an essential transcriptional regulator for primary human CD4 + T cells and suggest its potential important role in the development of PTCL., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Transient acute reversible lymphopenia occurring within hours after glucocorticoid administration is a well-known phenomenon. The objective of this study was to establish the impact of chronic methylprednisolone (mPDN) administration on lymphocyte counts in patients with immune-mediated inflammatory disorders., Methods: The charts of 44 women and 17 men (median age, 59 years) with several immune-mediated inflammatory disorders receiving oral mPDN for at least 4 months were reviewed. Morning lymphocyte counts measured during treatment (LP) were compared with pretreatment values (LA). In addition, the acute effect of mPDN on lymphocyte counts was evaluated in 43 of these patients by quantifying lymphocyte subpopulations before and 8 hours after mPDN administration. Values are expressed as median with 25%-75% interquartile range., Results: The initial daily oral mPDN dose was 28 mg (12-32 mg). An increase in morning lymphocyte counts was detected 13 days (8.5-16 days) after initiation of mPDN treatment (LP: 2130/μL vs LA: 1650/μL; P = .0121) and persisted over time. Morning lymphocytosis (LP ≥4000/μL) was observed in 15 patients, including 7 with hyperlymphocytosis (LP ≥5000/μL). The increase in morning lymphocyte counts during treatment was most marked for CD4 T cells. In the subset of patients who agreed to a second blood test after mPDN absorption, a 49% decrease in the lymphocyte count (P <.0001) was transiently observed at the 8-hour time point., Conclusions: A significant increase of the morning lymphocyte count is frequently observed in patients with immune-mediated inflammatory disorders chronically treated with oral mPDN. Heightened awareness that the timing of blood sampling in corticosteroid-treated patients affects lymphocyte counts, with possible hyperlymphocytosis before absorption, should help avoid unnecessary investigations and worry., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Chronic eosinophilic leukaemia associated with the FIP1L1-PDGFRA fusion gene (F/P+ CEL) is a rare cause of marked persistent hypereosinophilia, arising almost exclusively in male patients. Clinical presentations are heterogeneous with a higher incidence of eosinophil-mediated cardiomyopathy than in other hypereosinophilic syndrome variants. Features of chronic myeloproliferative disease are often present, including splenomegaly and elevated serum vitamin B12 levels. The diagnosis is made by fluorescence in situ hybridization (FISH) showing the deletion of the CHIC2 locus and/or RT-PCR showing the FIP1L1-PDGFRA fusion transcript. Treatment with imatinib mesylate, a tyrosine kinase inhibitor, results in rapid and complete resolution of hypereosinophilia and associated symptoms, except for those related to sub-endocardial fibrosis that may be irreversible. We report the case of a male patient in whom isolated intractable cough remained the only clinical manifestation of F/P+ CEL for 4 years. Furthermore, eosinophil autofluorescence, an as yet unreported artefact in this setting, precluded the detection of the CHIC2 deletion and further delayed diagnosis, underlining that both FISH and RT-PCR should be performed when this disease is suspected., (© 2016 S. Karger AG, Basel.)

The symptomatic hypereosinophilic patient must be approached in a stepwise manner, with thorough assessment to determine whether the hypereosinophilia itself is contributing to damage and disease manifestations (thereby defining a hypereosinophilic syndrome), and to identify an eventual cause of hypereosinophilia, followed by initiation of treatment directed against the underlying condition or deleterious hypereosinophilic state. Situations encountered in the clinic are extremely heterogeneous because of the numerous potential causes of hypereosinophilia and the variable spectrum of eosinophil-mediated organ damage. A practical approach to many of these situations is presented in this review., (Copyright © 2015 Elsevier Inc. All rights reserved.)