Idiopathic hypereosinophilic syndrome in hemodialysis patients: Case reports.

RATIONALE: Herein, we report 3 hemodialysis patients with idiopathic hypereosinophilic syndrome who were successfully treated using corticosteroid therapy. PATIENT CONCERNS: Case 1 was a 63-year-old man who was undergoing hemodialysis because of bilateral nephrectomy and developed hypereosinophilia with digestive symptoms, myocardial injury, and intradialytic hypotension. Case 2 was an 83-year-old man who was undergoing hemodialysis because of nephrosclerosis and developed hypereosinophilia with pruritus, myocardial injury, and intradialytic hypotension. Case 3 was a 59-year-old man who was undergoing hemodialysis because of diabetic nephropathy and developed hypereosinophilia with pruritus, myocardial injury, and intradialytic hypotension. DIAGNOSES: All 3 patients presented with hypereosinophilia (eosinophil count ≥1500 /µL for more than 1 month) and multiple-organ involvement (intradialytic hypotension, cardiac injury, digestive symptoms, and allergic dermatitis). A specific cause for the hypereosinophilia was not identified by systemic computed tomography, electrocardiography, echocardiography, bone marrow examination, or blood tests. Furthermore, Case 2 and 3 had not recently started taking any new drugs and drug-induced lymphocyte stimulation tests were negative in Case 1. Therefore, they were diagnosed with idiopathic hypereosinophilic syndrome. INTERVENTIONS: All 3 patients received corticosteroid therapy with prednisolone at a dose of 40 mg/d, 30 mg/d, and 60 mg/d in Case 1, 2, and 3, respectively. OUTCOMES: Their digestive symptoms, pruritus, intradialytic hypotension, and serum troponin I concentrations were immediately improved alongside reductions in their eosinophil counts. LESSONS: There have been few case reports of idiopathic hypereosinophilic syndrome in patients undergoing hemodialysis. We believe that recording of the clinical findings and treatments of such patients is mandatory to establish the optimal management of idiopathic hypereosinophilic syndrome.

ATG5 promotes eosinopoiesis but inhibits eosinophil effector functions.

Eosinophils are white blood cells that contribute to the regulation of immunity and are involved in the pathogenesis of numerous inflammatory diseases. In contrast to other cells of the immune system, no information is available regarding the role of autophagy in eosinophil differentiation and functions. To study the autophagic pathway in eosinophils, we generated conditional knockout mice in which Atg5 is deleted within the eosinophil lineage only (designated Atg5eoΔ mice). Eosinophilia was provoked by crossbreeding Atg5eoΔ mice with Il5 (IL-5) overexpressing transgenic mice (designated Atg5eoΔIl5tg mice). Deletion of Atg5 in eosinophils resulted in a dramatic reduction in the number of mature eosinophils in blood and an increase of immature eosinophils in the bone marrow. Atg5-knockout eosinophil precursors exhibited reduced proliferation under both in vitro and in vivo conditions but no increased cell death. Moreover, reduced differentiation of eosinophils in the absence of Atg5 was also observed in mouse and human models of chronic eosinophilic leukemia. Atg5-knockout blood eosinophils exhibited augmented levels of degranulation and bacterial killing in vitro. Moreover, in an experimental in vivo model, we observed that Atg5eoΔ mice achieve better clearance of the local and systemic bacterial infection with Citrobacter rodentium. Evidence for increased degranulation of ATG5low-expressing human eosinophils was also obtained in both tissues and blood. Taken together, mouse and human eosinophil hematopoiesis and effector functions are regulated by ATG5, which controls the amplitude of overall antibacterial eosinophil immune responses.

Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial.

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.

Hypereosinophilia with Concurrent Venous Thromboembolism: Clinical Features, Potential Risk Factors, and Short-term Outcomes in a Chinese Cohort.

Idiopathic hypereosinophilia (IHE) and hypereosinophilic syndrome (HES) are benign haematological disorders. Studies have suggested that venous thromboembolism (VTE) is a rare but sometimes fatal complication of hypereosinophilia; however, data are limited. We retrospectively analysed clinical features and short-term outcomes of 63 consecutive patients (82.5% men; mean age, 40.92 ± 10.89 years) with IHE or HES with concurrent VTE from January 1998 through December 2018. Risk factors for pulmonary embolism (PE) were explored by multivariate logistic analysis. DVT and/or PE was detected by imaging in all patients. Independent risk factors for PE were a body mass index of >24.1 kg/m2 (odds ratio [OR]: 5.62, 95% confidence interval [CI]: 1.21-26.13, P = 0.028), peak absolute eosinophil count of >6.3 × 109/L (OR: 5.55, 95% CI: 1.292-23.875, P = 0.021), and >13.9-month duration of hypereosinophilia (OR: 4.51, 95% CI: 1.123-18.09, P = 0.034). All patients were treated with corticosteroids and anticoagulants. The short-term hypereosinophilia remission rate was 100%; no recurrent VTE or major bleeding was observed. Hypereosinophilia is a potential risk factor for VTE. PE in patients with IHE/HES and DVT is associated with a higher body mass index, higher peak absolute eosinophil count, and longer duration of hypereosinophilia. Corticosteroids and anticoagulants provided effective short-term control of hypereosinophilia and VTE.

Causes of hypereosinophilia in 100 consecutive patients.

BACKGROUND: Hypereosinophilia (HE, persistent peripheral blood eosinophilia > 1.5 × 109 /L) and hypereosinophilic syndrome (HES, HE with end-organ damage) are classified as primary (due to a myeloid clone), secondary (due to a wide variety of reactive causes), or idiopathic. Diagnostic evaluation of eosinophilia is challenging, in part because secondary causes of HE/HES such as lymphocyte-variant HES (L-HES) and vasculitis are difficult to diagnose, and emerging causes such as immunoglobulin G4-related disease (IgG4-RD) have rarely been examined. OBJECTIVE AND METHODS: We reviewed 100 consecutive patients with HE/HES who underwent extensive evaluation for primary and secondary eosinophilia at a single tertiary care center to determine causes of HE/HES in a modern context. RESULTS: Six patients had primary HE/HES, 80 had a discrete secondary cause identified, and 14 had idiopathic HE/HES. The most common causes of secondary eosinophilia were L-HES/HES of unknown significance (L-HESus) (20), IgG4-RD (9), and eosinophilic granulomatosis with polyangiitis (EGPA) (8). CONCLUSIONS: In contrast to other large published series of HE/HES, most patients in this study were found to have a discrete secondary cause of eosinophilia and only 14 were deemed idiopathic. These findings highlight the importance of extensive evaluation for secondary causes of eosinophilia such as L-HES, IgG4-RD, and EGPA.

Systemic hypereosinophilic syndromes: when autoimmunity is Th2 mediated.

PURPOSE OF REVIEW: Clinical conditions associated with hypereosinophilia represent a field of particular interest, taking into account the epidemiological impact of the different primary and secondary forms. In addition to a classical Th1 response, also Th2 cells can be involved in the pathogenesis of autoimmune diseases, among them eosinophilic forms such as eosinophilic granulomatosis with polyangiitis. RECENT FINDINGS: In patients with severe asthma, recent evidence highlights the role of pathogenic autoantibodies against autologous eosinophil proteins (e.g. eosinophil peroxidase) suggest the role of autoimmune mechanisms, particularly in patients in which asthma is included in eosinophilic vasculitis with antineutrophilic autoantibody positivity. Is now evident that in addition to Th2 cells, also type 2 innate lymphoid cells and Th1/Th17 cells play a central role in the pathogenesis of hypereosinophilic syndrome. SUMMARY: The definition of cellular and molecular mechanisms and the critical role of specific cytokines involved in the pathogenesis of hypereosinophilic syndrome open the way to new therapeutic strategies by using biological agents targeting these specific factors.

Mechanisms of glucocorticoid resistance in hypereosinophilic syndromes.

BACKGROUND: Glucocorticoids (GC) are considered first-line therapy for most patients with hypereosinophilic syndrome (HES). Although response rates are generally high, many patients require moderate to high doses for control of eosinophilia and symptoms, and up to 15% of patients do not respond at all. Despite this, little is known about the mechanisms of GC resistance in patients with HES. OBJECTIVE: To explore the aetiology of GC resistance in HES. METHODS: Clinical data and samples from 26 patients with HES enrolled on a prospective study of GC responsiveness and 23 patients with HES enrolled on a natural history study of eosinophilia for whom response to GC was known were analysed retrospectively. Expression of GC receptor isoforms was assessed by quantitative RT-PCR in purified eosinophils. Serum cytokine levels were quantified by suspension array assay in multiplex. RESULTS: Despite an impaired eosinophil response to GC after 7 days of treatment, the expected rise in absolute neutrophil count was seen in 7/7 GC-resistant patients, suggesting that GC resistance in HES is not a global phenomenon. Eosinophil mRNA expression of glucocorticoid receptor (GR) isoforms (α, ß, and P) was similar between GC-sensitive (n = 20) and GC-resistant (n = 9) patients with HES. Whereas geometric mean serum levels were also comparable between GC-r (n = 11) and GC-s (n = 19) for all cytokines tested, serum IL-5 levels were >100 pg/mL only in GC-r patients. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that the mechanism of GC resistance in HES is not due to a global phenomenon affecting all lineages, but may be due, at least in some patients, to impairment of eosinophil apoptosis by increased levels of IL-5.

Serum cytokine and chemokine levels in patients with eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, or eosinophilic asthma.

OBJECTIVES: The pathogenesis of eosinophilic granulomatosis with polyangiitis (EGPA) remains poorly understood, and may overlap with eosinophilic asthma and primary hypereosinophilic syndrome (HES). The aim of this study was to analyse a panel of serum cytokines and chemokines as markers of disease activity in patients with these conditions. METHODS: The levels of 54 cytokines and chemokines were measured in the sera of 40 patients with active EGPA, 10 of these patients during inactive disease, 6 patients with HES, 8 with asthma, and 10 healthy controls. Serum cytokine/chemokines measured included interleukin (IL)-1α, 1ß, 3, 4, 5, 6, 8, 13, 15, 17A, 17E(25), 18, 23 and 33, soluble IL-2 receptor alpha, eotaxin-1 (CCL11), -2 (CCL24) and -3 (CCL26), macrophage-derived chemokine (MDC/CCL22), macrophage inflammatory protein (MIP)-1a and -1b, and tumour necrosis factor (TNF)-α. Results were compared between disease and control groups using regression analysis, with Bonferroni correction for multiple comparisons (significant p value ≤0.00093). RESULTS: Significant differences were observed only in serum levels of MDC, IL-8, MIP-1a and -1b, TNF-α, each of which were lower in patients with active EGPA than in healthy controls (p<0.0001). Differences between patients with active disease and other disease groups did not reach significance. Paired comparisons between sera from patients with active or inactive EGPA showed no significant difference for any of the studied cytokines or chemokines. CONCLUSIONS: No clear difference in the serum levels of measured cytokines and chemokines helped distinguish between active EGPA or inactive EGPA, or other disease or control groups.

A man with abdominal pain and eosinophilia : tissue is the issue.

A 24-year-old male presented with abdominal pain, postprandial vomiting and weight loss. Lab results showed an elevated serum eosinophil count and CT-scan demonstrated a thickened antral, duodenal and jejunal wall. Repetitive endoscopic mucosal biopsies were normal. Work-up of eosinophilia-associated gastro-intestinal disorders excluded secondary causes. Bone marrow showed an elevated eosinophil count without arguments for a primary hypereosinophilic syndrome. Endoscopic ultrasound-guided fine needle biopsy detected a strongly elevated number of eosinophils in the muscularis layer of the duodenum. The diagnosis of muscularispredominant eosinophilic gastroenteritis together with a secondary hypereosinophilic syndrome was made. The patient was started on steroids and all symptoms vanished within a few days.

An Approach to the Evaluation of Persistent Hypereosinophilia in Pediatric Patients.

Hypereosinophilia (HE) is currently defined by a peripheral blood absolute eosinophil count (AEC) of ≥1,500 cells/microL. Although mild blood eosinophilia (AEC 500-1,500 cells/microL) is observed relatively frequently within the pediatric population, persistent HE is uncommon and should prompt additional clinical evaluation. While the clinical manifestations and underlying etiologies of HE in adults have been well-characterized, there is a paucity of data on HE in children. Limited evidence suggests that many similarities between adult and pediatric HE likely exist, but some important differences remain between these populations. The evaluation of HE in children can be challenging given the broad differential diagnosis, which includes primary hematologic disorders and secondary eosinophilia in which the increased eosinophil levels are propagated by disease states that promote eosinophil production and survival. On the basis of the underlying etiology, clinical manifestations can range from benign, self-resolving elevations in the AEC to life-threatening disorders with the potential for significant end-organ damage. Given the broad differential diagnosis of HE, it remains essential to systematically approach the evaluation of unexplained HE in children. This review will discuss the differential diagnosis for pediatric HE, highlighting etiologies that are more prevalent within the pediatric population. Additionally, a summary of the epidemiology of pediatric HE will be presented, with focus on some of the differences that exist between pediatric and adult HE. Finally, a directed approach to the diagnostic evaluation of children with HE will be discussed.

Efficacy and Safety of Mepolizumab (Anti-Interleukin-5) Treatment in Gleich's Syndrome.

Gleich's syndrome (GS) is characterized by recurrent episodes of angioedema, increase in body weight, fever, hypereosinophilia, and elevated serum IgM. The exact etiology remains unclear. Currently, the only treatment strategy is the administration of high dose of steroids during the acute phases. We report the case of a 37-year-old man suffering from GS with recurrent episodes of angioedema, fever, hypereosinophilia [6,000/mm3 (45%)], and high eosinophil cationic protein (ECP) (>200 µg/l), treated with oral steroids during the acute phase (prednisone 50-75 mg/day), the dose of maintenance being 25 mg/day. No monoclonal components were identified, and genetic tests exclude mutations including Bcr/Abl, JAK2 V617F, c-KIT D816V, and FIP1L1-PDGFRA. Using Luminex technology, we observed higher serum levels of interleukin (IL)-5, CCL2, and CCL11 during the acute exacerbations in comparison with the clinical remission phases though CCL11 did not achieve statistical significance. The flow-cytometric analysis identified a CD3+ CD8- lymphocyte population with high frequency of IL-4-, IL-5-, and IL-13-producing cells. No clinical benefit was observed after therapeutic strategies with imatinib, interferon-α, cyclosporine-A, and azathioprine. Due to high IL-5 serum levels, an intravenous treatment with anti-IL-5 monoclonal antibody mepolizumab (750 mg every 4 weeks) was started. A reduction in the rate of exacerbation phases/year (10 ± 3 vs 2 ± 1; p < 0.005), in the eosinophils count both in percentage (28.8 ± 12.8 vs 9.8 ± 3.9; p < 0.001) and absolute value (2,737 ± 1,946 vs 782 ± 333; p < 0.001) were observed as well as the ECP serum levels (132.7 ± 62.7 vs 21 ± 14.2 µg/l; p < 0.05). The daily dose of prednisone was significantly reduced (25 vs 7.5 mg). Any adverse effects were recorded. To the best of our knowledge, this case is the first report of the disease successfully treated with mepolizumab, and it could represent a novel therapeutic strategy in GS.

A Case of Pulmonary Hypertension Associated with Idiopathic Hypereosinophilic Syndrome.

Hypereosinophilic syndrome (HES) is characterized by multi-organ damage that is associated with tissue hypereosinophilia. A persistently elevated eosinophilic count is also required for the diagnosis of HES. Although HES affects various organs, damage to pulmonary artery is rarely reported. We present a case of a 39-year-old man who was diagnosed with pulmonary hypertension (PH) associated with idiopathic HES. Although the pulmonary arterial hypertension specific drugs including intravenous epoprostenol could not control his PH, corticosteroid was effective for both hypereosinophilia and PH. Our case suggests the importance of steroid therapy as well as specific drugs for pulmonary arterial hypertension in the treatment of PH associated with HES.

Diagnosis and Novel Approaches to the Treatment of Hypereosinophilic Syndromes.

PURPOSE OF REVIEW: Hypereosinophilic syndrome (HES) is characterized by persistent hypereosinophilia associated with end-organ damage. As our understanding of the pathogenesis of various forms of HES broadens, so does our ability to tailor steroid-sparing therapies for each subtype. The purpose of this review is to summarize recent literature related to the etiology, diagnosis, and management of HES. RECENT FINDINGS: Mutations involved in subsets of HES can guide the choice of tyrosine kinase inhibitors beyond just imatinib. Several biologics that target interleukin-5 or its receptor have shown beneficial and selective eosinophil-reducing effects in clinical trials for asthma and other disorders including HES. Early clinical data with emerging therapies such as dexpramipexole and anti-Siglec-8 antibody show promise, but need to be confirmed in randomized trials. Several new biologics and tyrosine kinase inhibitors have been shown to lower eosinophil numbers, but more randomized trials are needed to confirm efficacy in HES.

Reversible bioprosthetic valve thrombosis from eosinophilia.

A 31-year-old man with a mitral bioprosthetic valve presented with recent worsening of exertional dyspnoea 7 years after the mitral valve replacement. Evaluation revealed an increased gradient across the thickened mitral bioprosthetic valve leaflets. Marked eosinophilia was present and was considered as a putative cause for bioprosthetic valve thrombosis. The treatment with systemic corticosteroids and oral anticoagulation led to complete resolution of symptoms with significant decrease in mitral bioprosthetic valve gradient and leaflet thinning. The case is reported to highlight the fact that eosinophilia may cause reversible bioprosthetic valve thrombosis.