Idiopathic Hypereosinophilia Research Articles

Exploring Cardiac Variability in Hypereosinophilia: Clinical Insights and Echocardiographic Findings

Introduction: The cardiac manifestations of hypereosinophilia include mainly endomyocardial fibrosis, which is the most frequently observed form. However, eosinophilic cardiopathy can manifest itself in different ways, affecting the various layers of the heart and presenting a variety of clinical and echocardiographic presentations. Aim: The aim of our study is to describe the various aspects of cardiac involvement observed in hypereosinophilia, based on our case series and data from the literature. Methods: This is a retrospective, descriptive study of five observations illustrating the diversity of eosinophilic cardiopathy, from the cardiology department of the Mohammed VI University Hospital in Marrakech, over a period of 12 months. Results: Over the period of the study, five patients presented with cardiac damage in the context of hypereosinophilia. The mean age was 53.8 years, with a predominance of women (sex ratio 0.66). In the majority of cases, the discovery of cardiac involvement was incidental to a cardiovascular check-up requested during the course of their medical condition. All cases had high levels of hypereosinophilia, with an average of 5681. These observations illustrate the wide variety of aetiologies of hypereosinophilia, all of which were represented: 3 cases of Churg-Strauss syndrome, 1 case of idiopathic hypereosinophilia syndrome, and 1 case of DRESS syndrome. The cardiac disorders observed were hypokinetic cardiomyopathy at the dilated stage in 60% of cases, acute eosinophilic myocarditis in 20%, and acute pericarditis in the remaining cases. The outcome was marked by an improvement in the FE in 60% of cases, stabilisation in 20%, and a fatal outcome in the remainder. Treatment is based on symptomatic therapy of the CHF and treatment of the underlying aetiology. Discussion and Conclusion: Eosinophils are cytotoxic through the release of granular proteins that initially attack the endocardium, leading to thrombosis and embolic events. Subsequently, this aggression contributes to fibrosis and valvular complications. Cardiac damage can also manifest itself as potentially serious acute myocarditis or pericarditis, which can progress to cardiac tamponade. These cardiac disorders and the diversity of possible aetiologies serve as a reminder that vital prognosis may be at stake in the acute phase, and to emphasise that functional prognosis depends on early echocardiographic screening and rapid initiation of treatment to limit the risk of thrombo-embolic and fibrosing complications.

Value and limitations of targeted next-generation sequencing in idiopathic hypereosinophilia: an integrative diagnostic tool in challenging cases

Here, we reviewed clinical-morphological data and investigated mutational profiles by NGS in a single-center series of 28 consecutive patients admitted to our hospital between September 2011 and November 2021 for idiopathic hypereosinophilia (HE).Bone marrow (BM) morphology was evaluated in 22 patients: while in six subjects BM was unremarkable, in the remaining cases an increase in BM eosinophils was observed, together with a slight increase in BM fibrosis (MF-1) in 5/22 patients.A total of 4/28 patients had at least one genetic lesion by targeted NGS. In particular, the genes involved were: two each of TET2 and DNMT3A; and one each of JAK2V617F, ASXL1, PPM1D, and ZBTB33. Notably, JAK2V617F and TET2 mutations co-occurred, with the JAK2V617F-mutated sample also carrying TET2 lesions. Median VAF was 21%, with the exception of the oncodriver JAK2V617F, which showed a VAF > 50% in the reported case. Of note, of the four cases bearing lesions, 2/4 had multiple hits in different genes.While in recent years mutational analysis using NGS has proven to be able to differentiate clonal hematopoietic neoplasms from reactive processes in diagnostically difficult cases, we found somatic mutations in only 14.3% of patients who acceded to our hospital for idiopathic HE. More importantly, excluding the JAK2V617F-mutated case with an underlying MPN-Eo diagnosis, NGS was able to identify somatic mutations in only three cases, all older than 70 years. Consequently, the detection of these mutations in idiopathic HE patients should be interpreted with caution and only in the context of other supportive clinical-pathological findings.

T-cell chronic active EBV diagnosed in a 65-year-old male presenting as idiopathic hypereosinophilic syndrome

A 65-year-old male from Nigeria, admitted with dehydration and painful oral ulcers, is seen by allergy/immunology for hypereosinophilia.The patient had idiopathic eosinophilia (mean 5,000 cells/uL) ongoing for nine years. There were no evident drug or infectious causes. The eosinophilia peaked at 28,000 cells/µL, accompanied by parotid swelling, pustular skin rash, and elevated serum-IgG4 level (400 mg/dL). Rheumatology evaluated for IgG4-related disease and hypereosinophilic syndrome. This work-up demonstrated elevated IgE (39,000 IU/mL) and tryptase (40 ng/mL) levels. Bone marrow biopsy showed a hypercellular marrow with erythroid hyperplasia and eosinophilia. Submandibular gland, skin, and excisional lymph node biopsies demonstrated IgGsecreting plasma cells, lymphocytic/eosinophilic infiltrates, and lymphoid hyperplasia, respectively. All biopsies stained negative for IgG4. Treatment for idiopathic hypereosinophilia was initiated with corticosteroids, rituximab, and mycophenolate mofetil (MMF). Symptomatic improvement was attained on MMF (1000 mg twice daily) with the addition of mepolizumab (300 mg every 4 weeks).He unfortunately progressed to high fevers with elevated ferritin (7,286 ug/L) and soluble IL-2Ra (31,276.7 pg/mL) levels. He did not meet full criteria for hemophagocytic lymphohistiocytosis and improved after corticosteroids. EBV PCR from blood was >220,000 IU/mL.Dedicated immune work-up showed a non-specific population of lymphocyte-like cells without clear lineage markers (CD2dim/- surface CD3-CD4-CD8-CD7-CD56-CD49d-CD294dim) on peripheral blood flow cytometry, with otherwise normal T, B, and NK cell enumeration. There was reduced cytotoxic killing function of CD8+ T cells and NK cells by chromium-51 release assay. Sorted peripheral blood mononuclear cells demonstrated positive EBV viral load in B cells (1,018,239 IU/mL), T cells (857,418 IU/mL),NK cells (237,459), and myeloid cells (532,641 IU/mL). EBV-encoded RNA was positive within lymph node T cells, most consistent with a diagnosis of T-cell CA-EBV. The Invitae 407 gene immunodeficiency panel was sent; however, a pathogenic variant was not identified. The patient was seen by hematology/oncology with plans for hematopoietic stem cell transplant. Unfortunately, he succumbed to complications from CA-EBV and multiorgan failure.We describe a male with lymphocytic-variant hypereosinophilic syndrome and a longstanding constellation of inflammatory and lymphoproliferative symptoms due to CA-EBV. His course initially eluded his care team and only after careful multidisciplinary discussion was a diagnosis reached.

Idiopathic Hypereosinophilia: A Multicenter Retrospective Analysis.

Physicians can sometimes encounter idiopathic hypereosinophilia (HE), but little is known about it. In this multicenter study, we analyzed the clinical characteristics, treatment, and outcomes of patients with idiopathic HE. Patients diagnosed with idiopathic HE (idiopathic hypereosinophilic syndrome: iHES or hypereosinophilia with undetermined significance: HEus) at six tertiary hospitals between January 2010 and June 2021 were included in this retrospective observational study. Demographics, clinical and laboratory data, and treatment responses were obtained from the electronic medical records of the study subjects. A total of 73 patients with idiopathic HE (45 with iHES and 28 with HEus) were included in the present study. Overall, 12 (26.7%) and 5 (17.9%) were women, and mean age of patients at diagnosis was 51.84 ± 17.29 years and 60.21 ± 18.01 years in iHES and HEus groups, respectively. Forty-three (95.6%) patients of iHES and 15 (53.6%) patients of HEus received corticosteroids as 1st-line treatment. Treatment response to corticosteroids in patients with iHES was generally good: complete response (n=25, 58.1%), partial response (n=12, 27.9%), no response (n=6, 14.0%). Treatment response to corticosteroids in HEus was complete response (n=7, 46.7%), partial response (n=6, 40.0%), and no response (n=2, 13.3%). There were 13 patients (46.4%) with HEus who were not treated. Corticosteroid treatment is generally effective and well tolerated by patients with iHES. Some patients with HEus are treated with corticosteroids in clinical practice. Extensive research is needed to establish a standardized management guidelines for iHES and determine whether treatment for HEus is required.

A Noncoding Germline Variant Creates a Gain-of-Function De Novo Enhancer That up-Regulates IL5 Transcription to Cause Familial Hypereosinophilia, Revealing a Previously Undescribed Mechanism for Human Disease

Introduction: Familial eosinophilia (FE) is a rare inherited condition characterized by lifelong idiopathic hypereosinophilia (absolute eosinophil count >1.5 x 109/L) in multiple family members with or without clinical manifestations. Although the gene underlying FE in one large kindred was mapped to chromosome 5q31-33 using genomewide linkage analysis, targeted sequencing of genes in this region, including interleukin 5 (IL5), was unrevealing. Despite more recent studies demonstrating selective dysregulation of IL5 transcription, the underlying genetic abnormality in FE has remained elusive to date. Methods: Whole genome sequencing (WGS) was performed using peripheral blood mononuclear cell (PBMC) DNA from 5 affected and 1 unaffected family members of the above-described kindred followed by targeted Sanger sequencing of candidate variants. After identifying a single nucleotide variant common to all affected family members in a noncoding region upstream of IL5, RNA sequencing (RNAseq), including long-read PacBio sequencing, was performed to examine IL5 gene expression and to identify IL5 isoforms. To predict potential transcription factor binding sites, we applied motif analyses around the variant and performed chromatin immunoprecipitation (ChIP)-PCR to assess chromatin occupancy of the predicted transcriptional regulators (HMGA1, FOXO3) and of RNA Polymerase II (Poll II). The variant of interest was introduced into a B-lymphoblast cell line (NCI-BL1184) via CRISPR/Cas9, after which clones derived from single cells were compared with respect to IL5 transcription (via quantitative PCR) and chromatin occupancy of HMGA1, FOXO3, and Pol II (by ChIP-PCR). Chromatin marks associated with active gene expression at enhancers (H3K4me1, H3K27Ac) and promoters (H3K4me3) were assessed by ChIP-PCR. Integration of genomewide ChIP-Seq, ATAC-Seq and gene expression analyses are underway to further assess the role of the variant as the primary driver of aberrant IL5 expression. Results: WGS revealed a novel single nucleotide variant in all 5 affected family members located 13.19 kb from the transcription start site (TSS) of the IL5 gene and 250 bp from the TSS of the RAD50 gene. Targeted Sanger sequencing confirmed the presence of this variant in 4/4 affected and 0/4 unaffected family members. Bulk RNA-seq revealed abnormally long transcripts spanning the entire intergenic region between the variant and the IL5 TSS in affected PBMCs, while long-read RNA-seq identified novel full-length IL5 isoforms, including one containing all 5 exons of the IL5 gene. By contrast, RAD50 transcription was unaffected by the variant. In silico motif analysis predicted that the variant generates potential binding sites for transcriptional regulators, including the High Mobility Group A1 (HMGA1) chromatin regulator and the forkhead transcription factor, FOXO3. ChIP-PCR confirmed robust chromatin binding of both HMGA1 and FOXO3 at the variant site in PBMCs from affected family members, but not in PBMCs lacking the variant. Introduction of the single nucleotide variant into B-lymphoblast cells via CRISPR/Cas9 recapitulates the findings in affected family members, with up-regulation of IL5 expression and protein levels and no effects on IL4, IL13, or RAD50 gene expression. In edited lymphoblasts with the variant, HMGA1 chromatin binding and that of H3K4me3/H3K27Ac are enriched in the 200 bp region encompassing the variant, although FOXO3 occupancy was not enriched in this setting nor were there changes in occupancy of control histone H3 in that region. Conclusions: We describe a previously unknown mechanism of human disease: a non-coding single nucleotide germline variant that results in a de novo enhancer and up-regulation of IL5 production in a family with autosomal dominant hypereosinophilia. Orthogonal methods indicate that this variant enables HMGA1 to bind DNA, recruit active histone marks, and induce IL5 expression from a de novo TSS. This finding was validated by CRISPR/Cas9-mediated introduction of the variant into a B cell lymphoblast cell line that does not normally produce IL-5. This mechanism highlights the importance of assessing non-coding regions in the study of Mendelian disorders and may be relevant to other human diseases. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

HYPEREOSINOPHILIA LEADS TO PRIMARY IMMUNODEFICIENCY DIAGNOSIS

<h3>Introduction</h3> In the absence of prior infections, idiopathic hypereosinophilia should prompt consideration of a primary immunodeficiency (PID). <h3>Case Description</h3> We present an 8-month-old previously healthy male admitted for persistent hypoxia and suspected bronchiolitis. This patient did not present with fever, weight loss, adenopathy, chronic rash, GI symptoms, or medication use. There was no travel history, sick contacts, or pertinent family history. Laboratory results were significant for negative viral panel and absolute eosinophil count > 34,000. Chest CT showed scattered ground glass opacities without cavitation or bronchiectasis. Bone marrow biopsy was negative for malignancy. T cell (beta) and B cell gene rearrangement studies were negative, as well as FIP1L1-PDFGFRA, FISH studies, and myelodysplastic panels. Cardiac workup, infectious/parasitic tests, tryptase, and B12 levels were normal. The patient was started on systemic steroids with dramatically improved hypereosinophilia. Workup revealed low IgG/IgA levels, with normal IgM. Vaccine titers to tetanus, diphtheria and Hib were absent, despite up-to-date immunizations. Genetic testing revealed a pathogenic mutation in the CD40L gene, indicating X-linked hyper IgM syndrome (HIGM). Pneumocystic jirovecii was confirmed with bronchoscopy. TMP-SMX treatment allowed for weaning off steroids. The patient was started on IVIG and is awaiting bone marrow transplant. <h3>Discussion</h3> HIGM often presents in infancy with increased susceptibility to sinopulmonary infections. Unlike other PIDs with clinical manifestations of atopy, HIGM does not often present with eosinophilia. Opportunistic infections, including PJP, may drive eosinophil production through antigenic stimulation of TH2 cells. This case illustrates the importance of immunologic considerations in patients with unexplained hypereosinophilia, even without a significant infectious history.

Proposed refined diagnostic criteria and classification of eosinophil disorders and related syndromes.

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.

Mechanisms and Neuroimaging Patterns of Hypereosinophilia-Related Ischemic Stroke: A Narrative Review through Three Cases.

Background: Hypereosinophilic syndromes (HES) are a group of relatively rare disorders in which neurological manifestations, including ischemic stroke, are common. The hypothesized pathophysiological mechanisms are hypercoagulability, cardioembolism (mainly mediated by myocardial involvement) and damage to the endothelium. A variable ischemic pattern has been described, including an association of territorial and border zone ischemic stroke. Methods: Three patients who presented to our department with acute stroke were selected aiming to show these three different mechanisms inferred from the stroke pattern on brain Magnetic Resonance Imaging (MRI) and to simultaneously illustrate the three main causes of HES. Results and Discussion: The first patient is a 55-year-old man with an abrupt onset of aphasia due to an acute ischemic stroke involving the left parietal lobule and the angular gyrus; recent lab test had shown hypereosinophilia. An extensive workup excluded primary and secondary causes of hypereosinophilia so a diagnosis of idiopathic hypereosinophilia was done and he was treated with high doses of steroids. The second patient had severe hypereosinophilia and developed multiple small, scattered ischemic lesions, mainly in border zone zones. The history of severe asthma and recurrent sinusitis supported the diagnosis of EGPA (Eosinophilic Granulomatosis with Polyangiitis); considering the severe clinical conditions and the presumptive role of hypereosinophilia in determining her symptoms, steroid treatment was promptly started, with good clinical response. The third patient also presented with multiple metachronous ischemic lesions, both in cortical and border zone distribution and marked eosinophilia; the diagnostic work-up found an ovarian cancer. She was treated with steroids and then underwent surgery and adjuvant chemotherapy. Conclusions: HES should be considered in stroke etiological evaluation, although it is a rare disorder, and border zones pattern without large artery steno-occlusion on neuroimaging may help to raise the suspicion in the neurovascular diagnostic pathway. A thorough research of the sources of hypereosinophilia should be performed to select the appropriate therapy.

A Four-Year Old with Severe Idiopathic Hypereosinophilia

Abstract&#x0D; Background:&#x0D; Background: Eosinophils are granulocytes that have a role in allergy and immune defense reactions. They represent a small percentage of circulating WBCs, and marked increases in their numbers can cause significant detrimental effects. Hypereosinophilia can be allergic, inflammatory, infectious, or malignant in origin. Hypereosinophilic syndrome is an uncommon disorder of eosinophils that can cause significant end-organ damage (Chen YY, Khoury P, Ware JM, et al.)&#x0D; Case presentation: A 4-year-old female presented with fever and abdominal pain and was found to have cervical and axillary lymphadenopathy spontaneously resolved and with an incidental finding of hypereosinophilia. The patient had an extensive workup, which was negative for common allergic, infectious, inflammatory, and neoplastic etiologies. She continued to show clinical and laboratory improvement and was discharged with the diagnosis of the idiopathic hypereosinophilic syndrome after the exclusion of other etiologies. Her follow-up after discharge showed improvement in eosinophil counts, and she is still being monitored. Given the lack of clear etiology and end-organ damage, she meets the definition of hypereosinophilia of undetermined significance. However, a gastroenterology workup is still considered as future symptoms evolve.&#x0D; Conclusion: Hypereosinophilia is a relatively uncommon disorder in the pediatric population that could be asymptomatic and discovered incidentally through laboratory workup; however, if it goes unrecognized, it can cause significant morbidity secondary to end-organ damage.&#x0D; &#x0D; Keywords: absolute eosinophil count, eosinophilia, hypereosinophilic syndrome.&#x0D;

Carotid Occlusion Associated With Eosinophilia and Proteinuria: Potential Diagnostic Clues or Red Herrings?

Nephrotic syndrome and hypereosinophilic syndrome both are uncommon causes of arterial stroke. We had a young patient with internal carotid artery occlusion, who had both these rare associations and was found to have membranous nephropathy. Idiopathic hypereosinophilia was treated with corticosteroids and conventional parasiticidal therapy with the intention of bringing down the eosinophil count. Nephrotic syndrome was also treated with corticosteroids and immunosuppression with cyclophosphamide. Hematologic abnormalities are an important cause of arterial thrombosis with effective secondary prevention strategies. Similarly, nephrotic syndrome is not to be missed as early treatment may prevent vascular complications. While cause-effect associations remained presumptive and a single diagnostic label elusive, the patient was recognized and treated early and had a good prognosis. However, other common causes of stroke should always be worked up for, and vigilant follow-up mandatory for prevention and treatment of recurrences which can have devastating sequelae such as total blindness and other vascular outcomes.

Idiopathic Hypereosinophilia in an Elderly Male with Contraindications to Glucocorticoids and Good Response to Omalizumab.

Idiopathic Hypereosinophilia in an Elderly Male with Contraindications to Glucocorticoids and Good Response to Omalizumab.

Unusual concomitant small‐ and large‐fiber neuropathy related to hypereosinophilic syndrome

AbstractBackgroundSmall‐fiber neuropathy is a disorder clinically dominated by neuropathic pain and autonomic symptoms. In &gt;50% of patients, no etiology can be identified. and some evidence suggests a possible role of the immune system. Among the most common manifestations of hypereosinophilic syndrome, neurological lesions have been described in the central and peripheral nervous systems. No correlation between idiopathic hypereosinophilia with systemic involvement and small‐fiber neuropathy has been described before.Case presentationWe present the case of a 21‐year‐old woman with large‐ and small‐fiber neuropathy associated with systemic idiopathic hypereosinophilic syndrome. The patient manifested a subacute itchy rash to the limbs and trunk with painless lymphadenopathy of the neck and groin, persistent lack of appetite, vomiting, and subsequent painful dysesthesia on the feet. At blood test, eosinophilic leukocytosis was detected, electrophysiological studies showed axonal sensory neuropathy on the sural nerve bilaterally, cerebrospinal fluid analysis showed a cytological–albumin dissociation, and skin biopsy was decisive in confirming a severe picture of the small fibers pathology and lymphocytic infiltrates with eosinophils in the dermis. The in‐depth diagnostic investigations excluded other significant alterations and pathologies. After steroid and immunoglobulin therapies, the patient progressively improved with resolution of the rash and vomiting episodes, resuming regular nutrition and obtaining important reduction of painful dysesthesia.ConclusionsIn the present case, we hypothesized that idiopathic hypereosinophilic syndrome was the likely cause of the atopic dermatitis and small‐fiber neuropathy, consistent with pain and dysautonomic symptoms.

Rates of Thrombotic Events in Hypereosinophilic Syndrome and the Effect of Molecular Aberrations in Thrombotic Risk

Background: Idiopathic hypereosinophilia and hypereosinophilic syndrome (HES) comprise a rare, heterogeneous group of hematologic disorders characterized by the overproduction of eosinophils leading to tissue eosinophilic infiltration and damage. Hypereosinophilia can be primary - due to a clonal or malignant process - or secondary to a non-clonal process. Primary eosinophilia can be accompanied by clonal markers, such as in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA/B, FGFR1 or PCM1-JAK2, genetic mutations or chromosomal abnormalities leading to a diagnosis of chronic eosinophilic leukemia. Without easily identifiable clonal markers, a diagnosis of idiopathic HES is made after secondary causes are excluded. Thrombotic complications in clonal eosinophilic disorders have been described in case reports but the prevalence of thrombosis has not been extensively studied. We hypothesized that HES is associated with an increased thrombotic risk compared to the general population. Additionally, given the known increased thrombotic risk in patients with clonal hematopoiesis of indeterminate potential, we also hypothesized that the risk of thrombosis is greatest in HES patients with evidence of an underlying clonal process. Methods: Using an institutional database, we retrospectively analyzed 44 patients with HES who had undergone molecular testing with a DNA based next generation sequencing (NGS) assay (Heme SnapShot) and an RNA based NGS assay (Heme fusion) as part of their work up for HES at Massachusetts General Hospital from 2016 to 2020. Patients with secondary eosinophilia were excluded. We used Fisher's exact test to compare rates of thrombotic events or death between patients with and without molecular aberration. Relative risk and corresponding 95% CI was estimated by fitting a log-binomial regression model. Results: Among the 44 patients analyzed, 16 (36.4%) had a molecular aberration detected on NGS. Of the patients with molecular aberrations detected, 4 (25%) had PGFRA, PGFRB, or FGFR1 fusions. Other pathogenic mutations were as follows - 1 (6.3%) JAK2 mutation, 3 (18.8%) TET2, 1 (6.3%) DNMT3A and 9 (56.4%) had mutations in other genes. White blood cell count, absolute eosinophil count, hematocrit, platelet count, tryptase and vitamin B12 levels at diagnosis of HES were similar between the two groups. After a median follow-up time of 29 months (IQR 19.3, 52), 9 (20.5%) of all HES patients had a thrombotic event after diagnosis of HES (4 venous and 5 arterial) with a median time to first thrombotic event of 14.0 months (IQR 3.5, 28.0). HES patients with a molecular aberration had increased number of thrombotic events compared to HES patients with no molecular aberrations, 37.5% versus 10.7% respectively (p = 0.053, risk ratio 3.5, 95% CI 1.01 - 12.12). Three patients with molecular aberrations died versus 1 patient with no molecular aberrations (p = 0.129, risk ratio 5.25, 95% CI 0.59 - 46.36). Among patients with at least 12 months of follow-up (n = 40, 14 with and 26 without molecular aberrations), the one-year cumulative incidence of thrombotic events was 42.9% in patients with molecular aberrations vs 11.5% without (p = 0.044, RR 3.7 95% CI 1.2-12.0). HES patients who had thrombotic events had an increased risk of death compared to those without thrombotic events (p = 0.0226, RR 11.7, 95% CI 1.8 - 75.2). Conclusions: Thrombotic complications are common in the current study of patients with HES and are associated with an increased risk of death. Although our patient cohort was small, presence of molecular aberrations had increased rates of thrombotic events and mortality, suggesting an area of further study including possible therapeutic trials. Figure 1 Disclosures Brunner: Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Al-Samkari:Argenx: Consultancy; Amgen: Research Funding; Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Rigel: Consultancy. Rosovsky:Bristol-Myers Squibb, Janssen: Research Funding; Bristol-Myers Squibb, Dova, Janssen, Portola: Consultancy. Fathi:PTC Therapeutics: Consultancy; Takeda: Consultancy; TrovaGene: Consultancy; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Astellas: Consultancy; Novartis: Consultancy; NewLink Genetics: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Trillium: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Kura: Consultancy; Boston Biomedical: Consultancy; Blue Print Oncology: Consultancy; AbbVie: Consultancy; Agios: Consultancy, Research Funding; Amphivena: Consultancy, Honoraria. Weitzman:Abbvie: Consultancy. Hobbs:Incyte: Research Funding; Bayer: Research Funding; Novartis: Honoraria; Celgene/BMS: Honoraria; Merck: Research Funding; Constellation: Honoraria, Research Funding; Jazz: Honoraria.

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.

Budd-Chiari Syndrome Associated With Hypereosinophilic Syndrome Treated by Deceased-Donor Liver Transplantation: A Case Report

IntroductionBudd-Chiari syndrome (BCS) associated with hypereosinophilic syndrome (HES) is very rare, and only a few reports have described its treatment. Furthermore, no report to date has described the performance of liver transplantation for the treatment of BCS associated with HES. We herein describe a 54-year-old man who underwent deceased-donor liver transplantation (DDLT) for treatment of BCS associated with HES. CaseA 54-year-old man was found to have an increased eosinophil count during a medical check-up. After exclusion of hematopoietic neoplastic diseases and secondary eosinophilia, idiopathic hypereosinophilia was diagnosed. Oral prednisolone was administered to the patient, and his eosinophil count immediately decreased to a normal level. He had an uneventful course without complications for 11 months but then presented with bloating and malaise. Imaging studies including ultrasonography, enhanced computed tomography, and angiography revealed BCS associated with HES. Transjugular intrahepatic portosystemic shunt failed because of complete obstruction of the hepatic veins. Therefore, the patient was introduced to our hospital for liver transplantation. DDLT was performed with venovenous bypass 1 month after the patient was placed on the DDLT waiting list. The explanted hepatic veins were completely occluded and organized. The patient’s eosinophil count was maintained at a normal level with prednisolone treatment after DDLT. ConclusionsLiver transplantation can be a treatment option for BCS associated with HES if neoplastic diseases and secondary eosinophilia have been excluded. Life-long oral steroid therapy is required to control HES even after liver transplantation.

195 An Evidence-Based Approach to the Diagnostic Workup of Eosinophilia in Morphologically Normal Bone Marrow

The differential diagnosis of eosinophilia in otherwise morphologically normal bone marrow (BM) is broad with many ancillary testing options. Given that some ancillary studies may be unnecessary, we evaluated the diagnostic utility of these studies to develop an evidence-based testing approach. We identified BM cases with a final diagnosis including eosinophilia. Pathology reports and ancillary testing results were reviewed: cytogenetics, immunohistochemistry (IHC) for tryptase/CD25/CD117, flow cytometry (T-cells, mast cells), FISH (BCR/ABL1, PDGFRA/CHIC2, PDGFRB), and molecular testing (JAK2V617F, KITD816V, T-cell receptor gene rearrangement [TCRG]). Of 305 cases, 208 (68%) had isolated BM eosinophilia. Four (of 176) cases had a cytogenetic abnormality (+8, +8, Del20q (1) and t(5;12)/PDGFRB positive). Three (of 151) cases were positive for aberrant (CD25-positive) mast cells (tryptase/CD25/CD117 IHC) with two harboring PDGFRA-rearrangement and one KITD816V positive. Four (of 163) cases had an aberrant T-cell population by flow cytometry; two clonal, one negative, and one equivocal by TCRG. Seven cases showed equivocal TCRG and one case with clonal TCRG; all with normal T-cell flow. Four (of 175) cases were positive for PDGFRA rearrangement. No cases (of 107) were cytogenetically normal/PDGFRB positive, JAK2 (0/104) or BCR/ABL1 (0/92) positive. Ancillary tests, with clinical findings, resulted in diagnoses of idiopathic hypereosinophilia (197), chronic eosinophilic leukemia (2), PDGFRA-rearranged myeloid neoplasm (4), PDGFRB-rearranged myeloid neoplasm (1), mastocytosis (1) and lymphocyte variant of hypereosinophilic syndrome (4). Our findings support an evidence-based testing approach for the workup of isolated BM eosinophilia. Testing should include FISH for PDGFRA rearrangement, KIT D816V, tryptase/CD25 IHC, cytogenetics, T-cell flow cytometry, and TCRG. Our data would not support routine testing of BCR/ABL1, JAK2 V617F, PDGFRB FISH or flow cytometry for mast cells. These findings are incorporated into our testing algorithm for eosinophilia and help achieve test utilization efficiency in our clinical practice.

Idiopathic hypereosinophilia is clonal disorder? Clonality identified by targeted sequencing.

Idiopathic hypereosinophilia (IHE)/idiopathic hypereosinophilic syndrome (IHES) has been defined by a persistent elevation of the blood eosinophil count exceeding 1.5×103/μL, without evidence of reactive or clonal causes. While T-cell clonality assessment has been recommended for unexplained hypereosinophilia, this approach is not often applied to routine practice in the clinic. We hypothesized that the clonality would exist in a subset of IHE/IHES patients. We aimed to investigate the candidate mutations and T-cell clonality in IHE/IHES and to explore the role of mutations in eosinophil proliferation. We performed targeted capture sequencing for 88 genes using next-generation sequencing, T-cell receptor (TCR) gene rearrangement assays, and pathway network analysis in relation to eosinophil proliferation. By targeted sequencing, 140 variants in 59 genes were identified. Sixteen out of 30 patients (53.3%) harbored at least one candidate mutation. The most frequently affected genes were NOTCH1 (26.7%), SCRIB and STAG2 (16.7%), and SH2B3 (13.3%). Network analysis revealed that our 21 candidate genes (BIRC3, BRD4, CSF3R, DNMT3A, EGR2, EZH2, FAT4, FLT3, GATA2, IKZF, JAK2, MAPK1, MPL, NF1, NOTCH1, PTEN, RB1, RUNX1, TET2, TP53 and WT1) are functionally linked to the eosinophilopoietic pathway. Among the 21 candidate genes, five genes (MAPK1, RUNX1, GATA2, NOTCH1 and TP53) with the highest number of linkages were considered major genes. A TCR assay revealed that four patients (13.3%) had a clonal TCR rearrangement. NOTCH1 was the most frequently mutated gene and was shown to be a common node for eosinophilopoiesis in our network analysis, while the possibility of hidden T cell malignancy was indwelling in the presence of NOTCH1 mutation, though not revealed by aberrant T cell study. Collectively, these results provide new evidence that mutations affecting eosinophilopoiesis underlie a subset of IHE/IHES, and the candidate genes are inferred to act their potential roles in the eosinophilopoietic pathway.

A neoplasm with FIP1L1-PDGFRA fusion presenting as pediatric T-cell lymphoblastic leukemia/lymphoma without eosinophilia

The 2016 World Health Organization (2016 WHO) classification of hematopoietic malignancies classifies neoplasms with a fusion between the FIP1L1 and PDGFRA genes in 4q12 into a group called "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2". Neoplasms characterized by this fusion are pluripotent stem cell disorders that can show both myeloid and lymphoid differentiation. They typically occur in adult patients and most are characterized by eosinophilia. We describe identification of a FIP1L1-PDGFRA fusion in a 13-year-old boy who presented with T-lymphoblastic leukemia/lymphoma without eosinophilia. Detection of FIP1L1-PDGFRA driven neoplasms at diagnosis is usually critical for proper treatment, since almost all reported cases responded to tyrosine kinase inhibitors. However, our patient's leukemia was refractory to standard chemotherapy, and did not show a meaningful response to tyrosine kinase inhibitor therapy. Testing for a FIP1L1-PDGFRA rearrangement is at present limited to patients with idiopathic hypereosinophilia, and we hypothesize that this abnormality may be under-diagnosed in children with acute leukemias.

Staring inside of Idiopathic Hypereosinophilia: Identification of Clonality Using Targeted Exome Sequencing

Idiopathic hypereosinophilia (IHE) has been a disorder of uncertain etiology, characterized by persistent elevation of blood eosinophil count exceeding 1.5x103/μL without evidence of reactive and clonal causes. When end-organ damage due to eosinophilic infiltration is present, idiopathic hypereosinophilic syndrome (IHES) is diagnosed. As the name 'idiopathic' implies the uncertain etiology, the nature of eosinophilic proliferation is unclear whether benign or clonal. While T cell clonality assessment has been recommended for unexplained hypereosinophilia, this approach is not often applied to the routine practice in clinic. We hypothesized that the clonality would exist in patients classified into IHE/IHES. The bone marrow cells of 30 IHE patients were retrospectively evaluated.The T cell receptor (TCR) assay and the targeted sequencing for 88 genes related to hematologic malignancies were performed. After being analyzed, the candidate mutations were subjected to pathway analysis.Through the targeted sequencing, 140 variants in 59 genes were identified. Sixteen out of 30 patients (53.3%) harbored at least 1 candidate mutation. The most frequently affected genes were NOTCH (n=8); SCRIB and STAG2 (n=5); SH2B3 (n=4). Remarkably, we identified recurrent somatic mutations in 4 genes with 5 patients (16.7%); MPLY521X (n=2), SCRIBE795X (n=2), ASXL1G646f (n=3) and STAG2E249X (n=2). A known mutation TP53V216M was confirmed in an IHE patient. Interestingly, the TCR assay revealed that 4 of 30 patients (13.3%) had a clonal TCR rearrangement. Skin involvement was described in patients with clonal T cell population. Through the pathway analysis, the role of these genes in eosinophilia was identified. These results highly suggest that these genes are likely related to clonality of hypereosinophilia.This study revealed that somatic mutations affecting hematopoiesis and monoclonal T cell clones underlie idiopathic hypereosinophilia. It would be valuable to extend our findings on the molecular profiling of hypereosinophilia to the further study discovering the clonality of IHE. DisclosuresNo relevant conflicts of interest to declare.

Chronic eosinophilic leukemia with a FIP1L1-PDGFRA rearrangement: Two case reports and a review of Korean cases.

TO THE EDITOR: According to the 2008 World Health Organization (WHO) guidelines, eosinophilia is associated with hematologic diseases such as chronic eosinophilic leukemia-not otherwise specified (CEL-NOS); idiopathic hypereosinophilic syndrome (HES) or idiopathic hypereosinophilia; and myeloid and lymphoid neoplasms with eosinophilia, and abnormalities of PDGFRA, PDGFRB or FGFR1 [1]. CEL is diagnosed in cases with increased blasts or cytogenetic/clonal abnormalities. We report 2 cases of myeloid and lymphoid neoplasms (CEL) with the FIP1L1-PDGFRA rearrangement.