Hypereosinophilic syndrome: A multicenter, retrospective analysis of clinical characteristics and response to therapy

doi:10.1016/j.jaci.2009.09.022

Journal of Allergy and Clinical Immunology

Volume 124, Issue 6, December 2009, Pages 1319-1325.e3

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https://doi.org/10.1016/j.jaci.2009.09.022 Get rights and content

Background

Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by persistent blood eosinophilia ≥1.5 × 10⁹/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.

Objective

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.

Methods

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.

Results

Eighteen of 161 patients (11%) tested were Fip1-like 1–platelet-derived growth factor receptor α (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-α (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).

Conclusion

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.

Section snippets

Methods

Patients meeting diagnostic criteria for HES,⁶ evaluated between January 2001 and December 2006 at 11 participating institutions with expertise in the evaluation of eosinophilic disorders, were included in the study. Inclusion criteria were documentation of a peripheral eosinophil count of ≥1.5 × 10⁹/L and signs or symptoms of end organ involvement for which another etiology could not be found. Patients with neoplasms (other than Fip1-like 1–platelet-derived growth factor receptor α

Baseline characteristics

Of the 188 patients evaluated, 104 were male (55%), and 84 were female (45%). The median age at diagnosis was 45 years of age (range, 6-85 years). The peak recorded absolute eosinophil counts ranged from 1.5 to 400 × 10⁹/L with a geometric mean (GM) peak eosinophil count of 6.6 × 10⁹/L (Table I). Of the 161 patients tested for the FP mutation, 18 (11%), all of whom were male, were positive. Of the 168 patients who were evaluated for clonal or aberrant populations of T cells, 29 (17%; 15 male

Discussion

One of the major problems with previously reported series of patients with HES has been referral bias, with single centers more likely to see patients with end organ manifestations that fall within the area of expertise of a particular subspecialty interested in HES. This has been compounded by the tendency to publish cases of the most severely affected patients, a disproportionate number of whom, in retrospect, were likely FP-positive. Patients in the current series were referred to groups

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Hypereosinophilic syndrome is a rare systemic condition characterized by eosinophil-mediated organ damage. Cardiac involvement is common and typically occurs in sequential stages. We present two cases that demonstrate these different stages and presentations of eosinophilia-mediated myocardial disease, where multimodality imaging was essential for the diagnosis. More importantly, they demonstrate, for the first time, the dissociation between the eosinophil count and patients' clinical evolution, suggesting the need for close follow up even after the eosinophilia has been controlled.
Cardiac involvement in hypereosinophilic syndrome typically occurs in three stages – necrotic, thrombotic, and fibrotic. Although cardiac damage is mediated by eosinophils, the blood eosinophil count and patients' clinical evolution are dissociated. Therefore, eosinophil count on its own is not an adequate marker of clinical evolution, and cardiac follow up should be continued even after the eosinophilia has been controlled.
GEMA 5.3. Spanish Guideline on the Management of Asthma
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The Spanish Guideline on the Management of Asthma, better known by its acronym in Spanish GEMA, has been available for more than 20 years. Twenty-one scientific societies or related groups both from Spain and internationally have participated in the preparation and development of the updated edition of GEMA, which in fact has been currently positioned as the reference guide on asthma in the Spanish language worldwide.
Its objective is to prevent and improve the clinical situation of people with asthma by increasing the knowledge of healthcare professionals involved in their care. Its purpose is to convert scientific evidence into simple and easy-to-follow practical recommendations. Therefore, it is not a monograph that brings together all the scientific knowledge about the disease, but rather a brief document with the essentials, designed to be applied quickly in routine clinical practice. The guidelines are necessarily multidisciplinary, developed to be useful and an indispensable tool for physicians of different specialties, as well as nurses and pharmacists.
Probably the most outstanding aspects of the guide are the recommendations to: establish the diagnosis of asthma using a sequential algorithm based on objective diagnostic tests; the follow-up of patients, preferably based on the strategy of achieving and maintaining control of the disease; treatment according to the level of severity of asthma, using six steps from least to greatest need of pharmaceutical drugs, and the treatment algorithm for the indication of biologics in patients with severe uncontrolled asthma based on phenotypes. And now, in addition to that, there is a novelty for easy use and follow-up through a computer application based on the chatbot-type conversational artificial intelligence (ia-GEMA).
La Guía Española para el Manejo del Asma, mejor conocida por su acrónimo en español, GEMA, está a nuestra disposición desde hace más de veinte años. Veintiuna sociedades científicas o grupos relacionados, tanto de España como de otros países, han participado en la preparación y desarrollo de la edición actualizada de GEMA que, de hecho, se ha posicionado en la actualidad a nivel mundial como la guía de referencia sobre asma en lengua española.
Su objetivo es prevenir y mejorar la situación clínica de las personas con asma, aumentando el conocimiento de los profesionales sanitarios involucrados en su cuidado. Su propósito es convertir la evidencia científica en recomendaciones prácticas sencillas y fáciles de seguir. Por lo tanto, no se trata de una monografía que reúna todo el conocimiento científico sobre la enfermedad, sino más bien de un documento conciso con lo esencial, diseñado para ser aplicado rápidamente en la práctica clínica de rutina. Las recomendaciones son necesariamente multidisciplinares, están desarrolladas para ser útiles y una herramienta indispensable para médicos de diferentes especialidades, así como para profesionales de enfermería y farmacia.
Seguramente, los aspectos más destacados de la guía son las recomendaciones para: establecer el diagnóstico del asma utilizando un algoritmo secuencial basado en pruebas diagnósticas objetivas; el seguimiento de los pacientes, preferentemente basado en la estrategia de lograr y mantener el control de la enfermedad; el tratamiento según el nivel de gravedad del asma utilizando seis escalones, desde la menor hasta la mayor necesidad de medicamentos, y el algoritmo de tratamiento basado en fenotipos para la indicación de biológicos en pacientes con asma grave no controlada. A esto se suma ahora una novedad para su fácil uso y seguimiento a través de una aplicación informática basada en la inteligencia artificial conversacional de tipo chatbot (ia-GEMA).
The dermatologic and histologic spectrum of hypereosinophilic syndrome
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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.
Unmet needs and evidence gaps in hypereosinophilic syndrome and eosinophilic granulomatosis with polyangiitis
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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.
Hypereosinophilic syndrome in Europe: Retrospective study of treatment patterns, clinical manifestations, and healthcare resource utilization
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The burden of hypereosinophilic syndrome (HES) in Europe is not well characterized.
To evaluate real-world patient characteristics, treatment patterns, clinical manifestations, and healthcare resource utilization for patients with HES from France, Germany, Italy, Spain, and the United Kingdom.
In this retrospective, noninterventional study, data for patients with a physician-confirmed diagnosis of HES were abstracted from medical chart reviews. Patients were aged 6 years or older at the time of HES diagnosis and had 1 or more years of follow-up from the index date (first clinic visit between January 2015 and December 2019). Data on treatment patterns, comorbidities, clinical manifestations, clinical outcomes, and healthcare resource utilization were collected from diagnosis or index date to end of follow-up.
Data for 280 patients were abstracted from medical charts by 121 physicians treating HES, with multiple specialties. Most patients (55%) had idiopathic HES, and 24% had myeloid HES; the median number (interquartile range [IQR]) of diagnostic tests per patient was 10 (6-12). The most common comorbidities were asthma (45%) and anxiety or depression (36%). Most patients (89%) used oral corticosteroids; 64% used immunosuppressants or cytotoxic agents, and 44% used biologics. Patients had a median (IQR) of 3 clinical manifestations (1-5), most commonly constitutional (63%), lung (49%), and skin (48%). Twenty-three percent of patients experienced a flare, and 40% had a complete treatment response. Some patients (30%) were hospitalized with a median (IQR) stay of 9 days (5-15) for HES-related issues.
Patients with HES across 5 European countries had a substantial disease burden despite extensive oral corticosteroids treatment, highlighting the need for additional targeted therapies.

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: Supported by the Division of Intramural Research of the NIAID/NIH (A.D.K., P.U.O., T.B.N.), grants AI41472 and AI72265 from the NIH (B.S.B.), grant AI061097 from the NIH (G.J.G.), the Human Immunology grant program of the Dana Foundation (B.S.B.), the Swiss National Science Foundation (H.-U.S.), the Belgian National Fund for Scientific Research (F.R.), and the Campaign Urging Research for Eosinophilic Disorders (M.E.R.). B.S.B. is a Cosner Scholar in Translational Research from Johns Hopkins University. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation or review of the manuscript. The manuscript was approved by the Division of Intramural Research, NIAID/NIH.

: Disclosure of potential conflict of interest: G. J. Gleich and K. M. Leiferman have equity in Ception, have received research support from GlaxoSmithKline, and are on the advisory board for APFE. J. E. Kahn has received consulting fees and research support from GlaxoSmithKline. T. B. Nutman is a stockholder in Johnson & Johnson and is employed by the National Institutes of Health. J. Ring has received research support from Novartis, Schering-Plough, Fujisawa, GlaxoSmithKline, Bencard, Stallergenes, ALK-Abelló, Allergopharma, Pharmacia, DPC Biermann, Aventis, Almirall, Leo, Galderma, and Switch Biotech. M. E. Rothenberg is a speaker and consultant for Merck; is a consultant for Ception Therapeutics, Novartis, Nycomed, and Centocor; has received research support from the National Institutes of Health, FAAN, and the Dana Foundation; is on the Medical Advisory Board for APFED; and is on the Executive Council for the International Eosinophil Society. F. Roufosse has received consulting fees from GlaxoSmithKline. J. Sheikh is on the speakers' bureau for Alcon, Meda, Sanofi-Aventis, and UBC; is a consultant for and is on the Advisory Board for Zeer.com; has received research support from GlaxoSmithKline; has been a legal consultant on the topics of allergy/immunology medical malpractice and latex allergy; is a member of the ACAAI; and is on the Executive Board of the Massachusetts Allergy Society (Secretary) and the New England Society of Allergy (CME Director). H.-U. Simon has received consulting fees from Pfizer, has received honoraria from Merck, and has received research support from the Swiss National Science Foundation, GlaxoSmithKline, and AstraZeneca. A. Wardlaw has received honoraria and research support from GlaxoSmithKline. P. F. Weller has served as a consultant for GlaxoSmithKline and has received research support from Merck. The rest of the authors have declared that they have no conflict of interest.

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Journal of Allergy and Clinical Immunology

Background

Objective

Methods

Results

Conclusion

Section snippets

Methods

Baseline characteristics

Discussion

References (17)

The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature

Medicine (Baltimore)

The idiopathic hypereosinophilic syndrome

Blood

Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia

N Engl J Med

A novel tyrosine kinase created by the fusion of the PDGFRA and FIP1L1 genes is a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome

N Engl J Med

Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis and imatinib-responsiveness

Blood

Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report

J Allergy Clin Immunol

Treatment of patients with the hypereosinophilic syndrome with mepolizumab

N Engl J Med

Lymphocytic variant hypereosinophilic syndromes

Immunol Allergy Clin North Am

Cited by (458)

The three stages of eosinophilic cardiac damage: A series of case reports

GEMA 5.3. Spanish Guideline on the Management of Asthma

The dermatologic and histologic spectrum of hypereosinophilic syndrome

HES and EGPA: Two Sides of the Same Coin

Unmet needs and evidence gaps in hypereosinophilic syndrome and eosinophilic granulomatosis with polyangiitis

Hypereosinophilic syndrome in Europe: Retrospective study of treatment patterns, clinical manifestations, and healthcare resource utilization

Mechanisms of allergy and clinical immunologyHypereosinophilic syndrome: A multicenter, retrospective analysis of clinical characteristics and response to therapy

Background

Objective

Methods

Results

Conclusion

Section snippets

Methods

Baseline characteristics

Discussion

The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature

Medicine (Baltimore)

The idiopathic hypereosinophilic syndrome

Blood

Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia

N Engl J Med

A novel tyrosine kinase created by the fusion of the PDGFRA and FIP1L1 genes is a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome

N Engl J Med

Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis and imatinib-responsiveness

Blood

Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report

J Allergy Clin Immunol

Treatment of patients with the hypereosinophilic syndrome with mepolizumab

N Engl J Med

Lymphocytic variant hypereosinophilic syndromes

Immunol Allergy Clin North Am

Mechanisms of allergy and clinical immunology
Hypereosinophilic syndrome: A multicenter, retrospective analysis of clinical characteristics and response to therapy