Hypereosinophilic syndrome response to mepolizumab in the setting of a compassionate use program.

Mepolizumab, an anti-interleukin-5 antibody, has been proven a safe and effective glucocorticoid-sparing drug for many patients with non-clonal 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 HES patients 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 HES patients were enrolled in the CUP, of which 9 are still on treatment. The median duration of exposure to mepolizumab was 45 months (maximum 18 years). A lower number of affected organs, requirement for glucocorticoid dosing ≤10 mg prednisone-equivalent, and single-organ HES were associated with a higher likelihood of complete response. Lymphocytic variant (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.

An Unusual Case of Immune Complex-Mediated Membranoproliferative Glomerulonephritis as Renal Manifestation of Idiopathic Hypereosinophilic Syndrome: A Case Report and Literature Review.

BACKGROUND: Idiopathic hypereosinophilic syndrome (IHES) is a disorder characterized by abnormal and persistent peripheral blood hypereosinophilia (eosinophil count ≥ 1.5 × 109/L and ≥10% eosinophils) with duration ≥ 6 months, associated organ damage, and/or dysfunction attributable to tissue eosinophilic infiltrate of unknown cause. IHES affects different organs such as the heart, lungs, nervous system, and skin, with renal involvement being rare in this condition. CASE PRESENTATION: We present a case of a young patient with IHES and immune complex-mediated membranoproliferative glomerulonephritis with nephrotic syndrome, as a rare renal manifestation. We discuss the clinical, analytical, and histopathologic renal and hematologic features, comparing them with other reported cases in the literature.

The challenge of diagnosing and classifying eosinophilia and eosinophil disorders: A review.

Eosinophilia is a feature of multiple conditions, both hematologic and non-hematologic, and may be associated with organ damage. The pathogenesis of eosinophilia can follow two distinct pathways. Primary eosinophilia is caused by a cell-intrinsic mechanism originating from clonal expansion of eosinophils through acquisition of a somatic mutation, such as FIP1L1-PDGFRA. In recent years, great progress has been made in the field of pathogenesis and molecularly targeted therapy of neoplastic eosinophilia. The diagnostic procedure should include, among other things, morphologic analysis of blood and bone marrow samples, cytogenetics and fluorescence in situ-hybridization tests to detect evidence of an acute or chronic myeloid or lymphoid disorder. Secondary eosinophilia follows a cell-extrinsic mechanism as a response to exogenous cytokines. In most clinical cases, peripheral blood eosinophilia is reactive and typically associated with non-hematological disorders such as infections, allergic conditions, connective tissue disorders, vasculitis, malignancy, or endocrinopathies. Nonetheless, the cause of most cases of hypereosinophilic syndrome remains unknown. In this article, we present a short review focused on differential diagnosis of eosinophilia and eosinophilic disorders. The diagnosis of eosinophilia is a challenge for physicians; thus this review may be useful in clinical practice.

A case report of refractory multivessel coronary spasm associated with hypereosinophilic syndrome: one cell, one disease?

Background: Hypereosinophilic syndrome (HES) is characterized by moderate to severe eosinophilia, exclusion of neoplastic or secondary origins of eosinophilia, and systemic involvement with end-organ damage. Coronary arteries can be affected to cause vasospastic angina (VSA); however, the association of the two diseases is not well recognized. Case summary: A 55-year-old woman who had a history of multiple allergic disease such as bronchial asthma and chronic sinusitis with nasal polyps was hospitalized due to attacks of chest pain at rest. During a spontaneous attack of chest pain, ECG revealed ST-segment elevation in the inferior leads and emergency coronary angiography showed focal spasms of the right and left anterior descending coronary arteries, both of which were relieved after intracoronary administration of nitroglycerine. She was diagnosed with VSA according to the Japanese Circulation Society guidelines. Despite conventional vasodilator therapies, her resting angina remained refractory. Laboratory findings were notable for moderate eosinophilia. A comprehensive evaluation to uncover the underlying cause of refractory VSA led to the diagnosis of HES, concomitant with eosinophilic pneumonia and eosinophilic chronic rhinosinusitis. Pericoronary inflammation by fat attenuation index (FAI) was increased in the proximal segment of the right coronary artery. Treatment was initiated with oral prednisolone at a starting dose of 30 mg/day. The response to treatment was rapid, with her symptoms disappearing and a regression of eosinophilia observed the following day. Discussion: Hypereosinophilic syndrome manifests with refractory VSA, and eosinophil-suppressing corticosteroid therapy proves effective in improving both conditions along with reduction of the pericoronary inflammation by FAI.

Prognostic factors of idiopathic hypereosinophilic syndrome: A nationwide survey in Japan.

Idiopathic hypereosinophilic syndrome (iHES) is a condition wherein persistent hypereosinophilia associated with end-organ damage occurs without any known causes. Due to the rarity of the disease, insufficient knowledge has been accumulated. We therefore conducted a retrospective, multicentre, nationwide survey on iHES in Japan. A total of 57 patients were identified. For 43 patients who received any treatment, all cases were first treated with corticosteroids. An eosinophil percentage of less than 30% in the bone marrow and the absence of oedema were identified as factors associated with steroid dependency. The 5-year overall survival was 88.2%, and five patients died during follow-up; factors associated with worse overall survival were age >50, haemoglobin <12 g/dL, activated partial thromboplastin time >34 s, the presence of dyspnoea, the presence of thrombotic tendency and the presence of renal failure. Given the rarity of fatalities in our cohort, time-to-next-treatment (TTNT) was further analysed; the presence of renal failure, splenomegaly and lung abnormalities were associated with worse TTNT. Our nationwide study not only demonstrated clinical characteristics and the outcome of patients with iHES but also for the first time revealed clinical factors associated with steroid dependency and duration of first-line corticosteroid efficacy.

Ophthalmic vascular manifestations in eosinophil-associated diseases: a comprehensive analysis of 57 patients from the CEREO and EESG networks and a literature review.

Introduction: Eosinophils have widespread procoagulant effects. In daily practice, eosinophil-related cardiovascular toxicity consists of endomyocardial damage, eosinophilic vasculitis and arterial or venous thrombosis. Here we aim to report on the clinical features and treatment outcomes of patients with unexplained ophthalmic vascular manifestations and eosinophilia. Methods: We conducted a retrospective, multicenter, observational study and a literature review of patients with eosinophilia (≥0.5 x109/L) and concomitant ophthalmic vascular manifestations independent of the underlying eosinophilic disease but with no alternative cause for ophthalmic manifestations. Results: Fifty-seven patients were included (20 from the observational study and 37 from the literature review). Ophthalmic vascular features were the initial manifestation of eosinophil-related disease in 34 (59%) patients and consisted of 29 central retinal artery occlusions, six branch retinal artery occlusions, five central retinal vein occlusions, two branch retinal vein occlusions, seven retinal vasculitides, two retinal vasospasms, 12 Purtscher's retinopathies, 13 anterior ischemic optic neuropathies and two posterior ischemic optic neuropathies. The median [IQR] absolute eosinophil count at onset of ophthalmic vascular manifestations was 3.5 [1.7-7.8] x109/L. Underlying eosinophil-related diseases included eosinophilic granulomatosis with polyangiitis (n=32), clonal hypereosinophilic syndrome (HES) (n=1), idiopathic HES (n=13), lymphocytic HES (n=2), adverse drug reactions (n=3), parasitosis (n=2), polyarteritis nodosa (n=1), IgG4-related disease (n=1), eosinophilic fasciitis (n=1) and primary sclerosing cholangitis (n=1). Other extra-ophthalmologic arterial or venous thromboses related to eosinophilia were reported in four (7%) and nine (16%) patients, respectively. Visual prognosis was poor: only eight (10%) patients achieved full recovery of ophthalmologic symptoms. After a median follow-up of 10.5 [1-18] months, one patient (3%) had a recurrence of an ophthalmic vascular manifestation, and three patients (10%) had a recurrence of other vascular symptoms (deep vein thrombosis in two and pulmonary embolism in one patient). At the time of recurrence, absolute eosinophil counts were above 0.5 x109/L in all cases (n=4). Discussion: This study broadens the spectrum of vascular manifestations associated with hypereosinophilia by adding ophthalmic vascular manifestations. In patients with ophthalmological vascular manifestations and hypereosinophilia, aggressive treatment of the underlying pathology (and normalization of blood count) should be implemented.

Eosinophilic Myocarditis Resulting in Ventricular Tachycardia Storm.

Eosinophilic myocarditis (EM) is a rare but potentially fatal complication of sustained eosinophilia that is characterized by eosinophilic infiltration into myocardial tissue. There are various etiologies of EM that can be classified into general categories: reactive, clonal, and idiopathic. We present a case of EM caused by chronic eosinophilic leukemia, a rare myeloproliferative neoplasm that frequently presents with sustained peripheral eosinophilia. This case displays several serious complications of EM, including recurrent ventricular tachycardia storm, cardiogenic shock, and mural thrombus formation despite anticoagulation. Diagnosis of EM can be difficult as formal diagnosis requires an endomyocardial biopsy. Once EM is suspected, identifying the underlying etiology of eosinophilia is critical for timely implementation of disease-specific therapy.

Concurrent Challenges in Idiopathic Hypereosinophilic Syndrome Complicating Beta-Thalassemia Major: A Case Report.

This case report highlights the uncommon idiopathic hypereosinophilic syndrome (HES) complicating beta-thalassemia major, presenting a diagnostic and management challenge. Beta-thalassemia major, characterized by impaired beta-globin synthesis, necessitates regular blood transfusions and iron chelation therapy. HES, a rare disorder marked by persistent eosinophilia, adds complexity to the clinical course. We present the case of a 27-year-old male with beta-thalassemia major who developed fever, weakness, and weight loss and was subsequently diagnosed with HES. Treatment involved antibiotics, blood transfusions, and corticosteroids, leading to clinical improvement. This case underscores the need to further understand the relationship between thalassemia and eosinophilia and the importance of comprehensive evaluation in patients with overlapping hematological disorders.

Clinical and Therapeutic Intervention of Hypereosinophilia in the Era of Molecular Diagnosis.

Hypereosinophilia (HE) presents with an elevated peripheral eosinophilic count of >1.5 × 109/L and is composed of a broad spectrum of secondary non-hematologic disorders and a minority of primary hematologic processes with heterogenous clinical presentations, ranging from mild symptoms to potentially lethal outcome secondary to end-organ damage. Following the introduction of advanced molecular diagnostics (genomic studies, RNA sequencing, and targeted gene mutation profile, etc.) in the last 1-2 decades, there have been deep insights into the etiology and molecular mechanisms involved in the development of HE. The classification of HE has been updated and refined following to the discovery of clinically novel markers and targets in the 2022 WHO classification and ICOG-EO 2021 Working Conference on Eosinophil Disorder and Syndromes. However, the diagnosis and management of HE is challenging given its heterogeneity and variable clinical outcome. It is critical to have a diagnostic algorithm for accurate subclassification of HE and hypereosinophilic syndrome (HES) (e.g., reactive, familial, idiopathic, myeloid/lymphoid neoplasm, organ restricted, or with unknown significance) and to follow established treatment guidelines for patients based on its clinical findings and risk stratification.

Cardiac Magnetic Resonance Imaging Used to Determine a Rare Etiology of a Layered Left Ventricular Apical Thrombus.

Eosinophilic myocarditis (EM) is a rare disease, often associated with hypereosinophilic syndrome (HES). Historically, the diagnostic gold standard was endomyocardial biopsy (EMB). We present a unique case of a 58-year-old female who presents after a syncopal episode and was found to have a layered left ventricular (LV) thrombus. Using laboratory studies and cardiac magnetic resonance imaging (MRI), we were able to delineate the etiology, avoiding any invasive testing.

Not just for lymphoid cells: The role of the noncanonical NF-κB signaling pathway in early and late myelopoiesis with a focus on hypereosinophilic disorders.

The noncanonical NF-κB pathway is involved in lymphoid organ development, B cell maturation, and cytokine production. However, new research has demonstrated that this pathway is also key for the orderly and sequential maturation of myeloid cells, including neutrophils and eosinophils. When this pathway is disrupted or constitutively activated, aberrations in hematopoietic stem and progenitor cell (HSPC) survival and proliferation, as well as subsequent granulopoiesis and eosinophilopoiesis are affected. Disturbance of such a coordinated and delicate process can manifest in devastating clinical disease including acute and chronic myeloid leukemias (AML and CML, respectively), pre-leukemic processes such as myelodysplastic syndrome (MDS) or hyperinflammatory conditions like Hypereosinophilic Syndrome (HES). In this review, we will discuss the molecular machinery within the noncanonical NF-κB pathway, crosstalk with the canonical NF-κB pathway, murine models of noncanonical signaling, as well as how aberrations in this pathway manifest in leukemic or hyperinflammatory disease with a focus on HES. Potential and promising drug therapies will also be discussed, emphasizing the noncanonical NF-κB pathway as a potential target for improved treatment for patients suffering from leukemia or idiopathic HES. The hope is that review of such mechanisms and treatments may eventually result in findings that aid physicians in rapidly diagnosing and more accurately classifying patients suffering from such complex and overlapping hematopoietic diseases.

Biologic Therapy in Rare Eosinophil-Associated Disorders: Remaining Questions and Translational Research Opportunities.

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.

A rare case of eosinophilic jejunitis: diagnosis and management strategies.

Eosinophilic gastroenteritis is a rare disease with an unknown cause, which can manifest independently or as part of a hyper-eosinophilic syndrome. The severity of the condition depends on the extent of eosinophilic infiltration and damage to the digestive tract. Diagnosis relies on histological examination, which reveals a significant presence of eosinophilic polymorphonuclear leukocytes in the digestive wall. The authors present a new case of eosinophilic gastroenteritis in a 28-year-old patient who exhibited obstructive symptoms but lacked peripheral eosinophilia. Esophagogastroduodenoscopy showed no abnormalities, but barium transit imaging revealed gastro-duodeno-jejunal dilation upstream of a tight jejunal stenosis. Surgical examination of the affected area confirmed a diffuse and transparietal eosinophilic infiltrate, with no evidence of parasitic or granulomatous lesions. Fortunately, the patient had a swift recovery following surgery. Biopsies conducted at other locations, including the gastric, hepatic, and medullary levels, produced negative results, indicating the localized nature of the condition.

Eosinophil-associated diseases: the allergist's and clinical immunologist's perspective.

Summary: Eosinophil-associated diseases (EADs) refer to heterogeneous conditions in which eosinophils are believed to play critical pathological roles. They encompass common respiratory conditions, such as asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), less common primary eosinophilic disorders of gastrointestinal tract, and rare conditions including eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES). A literature search was carried out in January 2024 in the MEDLINE and Scopus databases using the PubMed search engine (PubMed, National Library of Medicine, Bethesda, MD). We focused on blood eosinophilia and hypereosinophilia. A diagnostic workup is proposed. From allergist's point of view, we focused the review on 4 groups of eosinophilic disorders of specific interest. Our increased understanding of type 2 inflammation and biology has recently led to development of highly effective precision targeted therapies that are now approved for a growing number of eosinophilic disorders. Novel targeted biologics have a major impact on treatment strategies and have resulted in major advances in our understanding of the pathogenesis of these disorders. In the context of EADs, according to the heterogeneity of eosinophilic disorders a multidisciplinary approach should be adopted. Allergists and Clinical Immunologists play an important role as they have a clear understanding of the eosinophilic inflammation and the role of cytokines and are trained to recognize and characterize type 2 (T2) inflammation and its associated pathologies.

Eosinophilic enterocolitis in duodenum, ileum, and colon: A case report.

Eosinophilic gastroenteritis (EGE) is a rare disease which mainly consists of an abnormal eosinophile infiltration of the gastrointestinal tract. It's classified according to its location: eosinophilic esophagitis, eosinophilic gastritis, eosinophilic enteritis (including duodenum, jejunum and/or ileum) and eosinophilic colitis and degree of infiltration (mucosal, muscular, serosal). Depending on eosinophile concentration, type of EGE and the patient's condition it may manifest with different clinical presentations such as functional dyspepsia, abdominal pain, irritability, hypoproteinemia, diarrhea, anemia, among others. Few research has been done on such an uncommon pathology to the extent that treatment evidence is mostly limited to small case series. This case study reports an infrequent presentation of EGE in the small and large intestine as an undifferentiated gastrointestinal disease and successful corticoid management given to the patient in order to further broaden knowledge on this subject and facilitate an established clinical conduct for the treating physician.

Co-occurrence of Idiopathic Hypereosinophilic Syndrome in End-Stage Renal Disease Patients Undergoing Maintenance Hemodialysis.

Hypereosinophilic syndrome (HES) is defined as the presence of (1) peripheral blood eosinophilia >1.5 x 109/L for at least one month, (2) evidence of eosinophil-mediated organ damage and/or dysfunction, and (3) exclusion of other potential causes of eosinophilia. In hemodialysis patients, HES has been associated with manifestations because of low blood pressure or gastrointestinal symptoms that result in dialysis intolerance. Very few cases of HES co-occurrence in dialysis patients have been reported in the literature, and their clinical characteristics are not fully understood. Here, we report two end-stage renal disease patients diagnosed with idiopathic HES while undergoing maintenance hemodialysis. The first patient presented with unexplained persistent pruritus and intradialytic hypotension, which started 10 minutes after the dialysis session initiation. Hematologic studies revealed hypereosinophilia which remarkably improved on steroid therapy. The second patient was accidentally discovered with asymptomatic persistent hypereosinophilia. His blood counts improved initially on interferon treatment before achieving full remission on steroid therapy. Neither of the two patients reported any history of allergy or atopic manifestations. Our case report sheds light on the possible occurrence of HES in hemodialysis patients which may be confused with other dialysis-related complications. Although steroids remain the mainstay of treatment, the optimal dose and duration of treatment remain unknown.

A rare manifestation of IgG4-related disease and secondary hypereosinophilic syndrome: A case report.

We report a case of IgG4-related disease (IgG4-RD) with marked eosinophilia. A 79-year-old woman was admitted due to diarrhoea and weight loss. Cervical lymphadenopathy, bilateral submandibular glands swelling, anaemia (Hb8.5 g/dl), hypereosinophilia (9750/µl), elevated serum creatinine (1.57 mg/dl), pancreatic amylase (191 IU/l), and IgG4 (3380 mg/dl) were found. Diffusion-weighted image on magnetic resonance imaging showed high-intensity signals inside both the pancreas and the kidneys. The echogram of submandibular glands revealed cobblestone pattern. Kidney biopsy revealed acute tubulointerstitial nephritis. Biopsies of lip, gastrointestinal tract, and bone marrow showed infiltration of lymphoplasmacytic cells and IgG4-positive plasma cells (30-67/HPF). Gastrointestinal and bone marrow biopsies also showed eosinophilic infiltration. Adrenal insufficiency, rheumatic disease, tuberculosis, parasite infection, drug-induced eosinophilia, and eosinophilic leukaemia were all ruled out. We started treatment with 40 mg of prednisolone (PSL) and her general condition rapidly improved. The eosinophil count, serum IgG4, and serum creatinine decreased. We gradually tapered PSL and maintained 5 mg/day. During the 5 years of treatment, she had no recurrence of the symptom. According to the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-RD, eosinophils >3000/µl is one of the exclusion criteria. If we comply with this criterion, the diagnosis of IgG4-RD should be avoided. However, our case fit the diagnostic criteria of type I autoimmune pancreatitis, IgG4-related sialadenitis, and global diagnosis of IgG4-RD. We finally diagnosed our case as IgG4-RD with secondary hypereosinophilic syndrome. This case suggests that IgG4-RD with eosinophils >3000/µl does exist in the real world.

B-cell acute lymphoblastic leukemia associated with hypereosinophilia: a case report and brief literature review.

Few cases of B-cell acute lymphoblastic leukemia (B-ALL)-eosinophilia (ALL-eo) association have been reported. The lack or absence of blasts in the peripheral blood smear (PBS) along with urticarial rash, fever, arthralgia, myalgia, sweating, and dyspnea are common features of this condition. Herein, we report a 16-year-old male patient admitted to the emergency department with urticaria and generalized itching. PBS was examined, and eosinophils (90%) were seen in different fields. However, blast cells were not seen in PBS. In a bone marrow examination, terminal deoxynucleotidyl transferase-positive and CD20-positive lymphoid blasts were reported along with eosinophilia. Eventually, the B-ALL diagnosis was confirmed for the patient, and he was started on the Berlin-Frankfurt-Münster chemotherapy regimen. The association of B-ALL with hypereosinophilia is a rare condition. We hope this case report and literature review can help clinicians to manage this rare condition properly.