Materiały źródłowe

• #1 Hypereosinophilic Syndrome | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/149474

  Hypereosinophilic syndrome (HES) encompasses a rare and complex group of heterogeneous disorders characterized by persistent and substantial elevations in eosinophil levels and mediators leading to tissue infiltration and damage. Eosinophilopoiesis plays a vital role in the pro-inflammatory processes of multiple diseases. […] As versatile leukocytes, eosinophils exhibit potent pro-inflammatory, prothrombotic, and pro-fibrotic properties. The multifunctional properties can cause organs to become infiltrated, resulting in end-organ dysfunction. Tissue infiltration by eosinophils, especially in conditions like eosinophilic pneumonia, is pathological. […] Fibroblast activation, proliferation, and secretion of transforming growth factor-beta (TGF-B) and interleukin-1B (IL-1B) play a crucial role. The toxic granule proteins stored within eosinophils, including eosinophil cationic protein (ECP), promote the release of TGF-B, initiating eosinophil-mediated tissue fibrosis. Numerous studies have substantiated the involvement of eosinophil infiltration in inflammatory fibrotic lesions.

• #2 Hypereosinophilic syndromes | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-2-37

  Hypereosinophilic syndromes (HES) constitute a rare and heterogeneous group of disorders, defined as persistent and marked blood eosinophilia ( 1.5 109/L for more than six consecutive months) associated with evidence of eosinophil-induced organ damage, where other causes of hypereosinophilia such as allergic, parasitic, and malignant disorders have been excluded. […] Recent advances in underlying pathogenesis have established that hypereosinophilia may be due either to primitive involvement of myeloid cells, essentially due to occurrence of an interstitial chromosomal deletion on 4q12 leading to creation of the FIP1L1-PDGFRA fusion gene (F/P+ variant), or to increased interleukin (IL)-5 production by a clonally expanded T cell population (lymphocytic variant), most frequently characterized by a CD3-CD4+ phenotype.

• #3 Molecular Pathogenesis and Treatment Perspectives for Hypereosinophilia and Hypereosinophilic Syndromes

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7825323/

  Hypereosinophilia (HE) is a heterogeneous condition with a persistent elevated eosinophil count of 350/mm3, which is reported in various (inflammatory, allergic, infectious, or neoplastic) diseases with distinct pathophysiological pathways. […] Different studies have allowed for the discovery of two major pathogenetic variants known as myeloid or lymphocytic HES. […] In this review, we highlight the molecular alterations that are involved in the pathogenesis of eosinophil disorders and revise possible therapeutic approaches, either implemented in clinical practice or currently under investigation in clinical trials. […] The aim of this review is to outline the molecular alterations that are involved in the pathogenesis of eosinophil disorders and provide an update on the therapeutic approaches that are available for the treatment of these disorders.

• #4 Molecular Pathogenesis and Treatment Perspectives for Hypereosinophilia and Hypereosinophilic Syndromes

  https://www.mdpi.com/1422-0067/22/2/486

  Hypereosinophilia (HE) is a heterogeneous condition with a persistent elevated eosinophil count of >350/mm³, which is reported in various (inflammatory, allergic, infectious, or neoplastic) diseases with distinct pathophysiological pathways. […] Different studies have allowed for the discovery of two major pathogenetic variants known as myeloid or lymphocytic HES. […] The aim of this review is to outline the molecular alterations that are involved in the pathogenesis of eosinophil disorders and provide an update on the therapeutic approaches that are available for the treatment of these disorders. […] The primary molecular defect that is responsible for this distinct phenotype is a gene fusion between FIP1-like 1 (FIPL1) and platelet-derived growth factor receptor alpha (PDGFRα), known as FIP1L1–PDGFRα fusion.

• #5

  https://www.haematologica.org/article/view/5338

  Hypereosinophilic syndromes (HES) are a group of disorders characterized by persistent and marked hypereosinophilia (1500 per microliter) not due to an underlying disease known to cause eosinophil expansion (such as an allergic drug reaction or parasitic infection), and which is directly implicated in damage or dysfunction of at least one target organ or tissue. […] Well-characterized pathogenic mechanisms leading to hypereosinophilia described so far in patients fulfilling classical HES diagnostic criteria involve: (i) stem cell mutations leading to expression of PDGFRA-containing fusion genes with constitutive tyrosine kinase (TK) activity (mainly the FIP1L1-PDGFRA fusion gene), and (ii) sustained overproduction of IL-5 by activated T-cell subsets with unusual phenotypes and/or clonal TCR gene rearrangement patterns.

• #6 Hypereosinophilic syndromes | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-2-37

  Two distinct underlying mechanisms may lead to chronic unexplained hypereosinophilia in HES patient subgroups: occurrence of a sporadic hematopoetic stem cell mutation, leading to primitive clonal expansion of cells belonging to the myeloid lineage with preferential eosinophilic differentiation (as such, hypereosinophilia belongs to the group of chronic myeloproliferative disorders), or overproduction of eosinophilopoietic cytokine(s) by an activated population of T cells (in the „lymphocytic variant” of HES, or L-HES). […] An interstitial deletion on chromosome 4q12 results in fusion of two genes, FIP1L1 and PDGFRA. The new fusion gene encodes a FIP1LI-PDGFRA (F/P) protein displaying constitutive tyrosine kinase activity, whose role in disease induction has been confirmed by its disappearance in patients successfully treated with the tyrosine kinase inhibitor, imatinib.

• #7

  https://omim.org/entry/607685

  A number sign (#) is used with this entry because some cases of hypereosinophilic syndrome are caused by fusion between the FIP1-like-1 (FIP1L1; 607686) and platelet-derived growth factor receptor-alpha (PDGFRA; 173490) genes. […] Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disorder in which persistent eosinophilia leads to tissue damage, caused by direct infiltration by eosinophils and cytokine release, which leads to progressive organ dysfunction that may be fatal (summary by Griffin et al., 2003). […] The clonality of hypereosinophilic syndrome has been demonstrated in some cases by clonal karyotypic abnormalities and X-inactivation assays (Luppi et al., 1994; Chang et al., 1999). […] In patients with hypereosinophilic syndrome who have clonal T cells and polymorphous skin lesions, interleukin-5 (147850) seems to play a critical pathogenic role (Cogan et al., 1994; Simon et al., 1999).

• #8 Molecular Pathogenesis and Treatment Perspectives for Hypereosinophilia and Hypereosinophilic Syndromes

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7825323/

  The laboratory screening performed to formulate a HES diagnosis allow for us to understand molecular events that cause gene driver alterations in myeloid and lymphoid disorders that are associated with eosinophilia. […] PDGFR and PDGFR fusions: PDGFR and PDGFR are a class of receptors with TK activity, which are characterized by an extracellular ligand-binding region and two intracellular TK domains. […] The most common PDGFR gene alterations reported in the eosinophilic syndrome are rearrangements with several partner genes, such as FIP1L1, BCR, and ETV6. […] The FIP1L1-PDGFR rearrangement represents the most frequently recurrent aberration in eosinophilia detected in different hematopoietic cells, including eosinophils, neutrophils, T-, or B-cells. […] The FIP1L1-PDGFR fusion protein is expressed in 10-20% of patients that are affected by HEN/HESN, with a higher prevalence in males.

• #9

  https://www.omim.org/entry/607685

  A number sign (#) is used with this entry because some cases of hypereosinophilic syndrome are caused by fusion between the FIP1-like-1 (FIP1L1; 607686) and platelet-derived growth factor receptor-alpha (PDGFRA; 173490) genes. […] Idiopathic hypereosinophilic syndrome (HES) is a myeloproliferative disorder in which persistent eosinophilia leads to tissue damage, caused by direct infiltration by eosinophils and cytokine release, which leads to progressive organ dysfunction that may be fatal (summary by Griffin et al., 2003). […] Cools et al. (2003) found that a hypereosinophilic syndrome patient being treated with imatinib had a complex chromosomal abnormality; this led to the identification of fusion of the FIP1L1 gene to the PDGFRA gene, which was caused by an interstitial deletion on chromosome 4q12. The resulting FIP1L1-PDGFRA gene was found to be a constitutively activated tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib.

• #10 Molecular Pathogenesis and Treatment Perspectives for Hypereosinophilia and Hypereosinophilic Syndromes

  https://www.mdpi.com/1422-0067/22/2/486

  The activated catalytic domain promotes a cascade of signaling events via downstream pro-survival and anti-apoptotic effectors, such as SRC, STAT5, and the PI3K/RAS/MAP kinase pathway. […] The FIP1L1-PDGFRα rearrangement represents the most frequently recurrent aberration in eosinophilia detected in different hematopoietic cells, including eosinophils, neutrophils, T-, or B-cells. […] The FIP1L1-PDGFRα transcript is generated by juxtaposition of the 5′ and 3′ regions of FIP1L1 and PDGFRα, respectively. […] The extracellular PDGFRβ region contains the ligand binding site that is replaced by ETV6, which promotes an oligomerization process resulting in the activation of the PDGFRβ tyrosine kinase. […] Eosinophilia-associated neoplasm can be characterized by rare rearrangements involving FLT3 and ABL1.

• #11 Hypereosinophilic Syndrome – Hematology and Oncology – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hematology-and-oncology/eosinophilic-disorders/hypereosinophilic-syndrome

  The myeloproliferative variant is often associated with a small interstitial deletion in chromosome 4 at the CHIC2 site that causes the FIP1L1/PDGFRA-associated fusion gene (which has tyrosine kinase activity that can transform hematopoietic cells). […] A small proportion of patients with the myeloproliferative variant of hypereosinophilic syndrome have cytogenetic changes involving platelet-derived growth factor receptor beta (PDGFRB) and may also be responsive to tyrosine kinase inhibitors such as imatinib. […] Other cytogenetic abnormalities include rearrangement of the gene for fibroblast growth factor receptor 1 (FGFR1) or Janus kinase 2 (PCM1-JAK2). […] Recently, ETV6-ABL1 and various FLT3 fusions have been added to the gene rearrangements associated with hypereosinophilia. […] The lymphoproliferative variant is associated with a clonal population of T cells with aberrant phenotype.

• #12 Molecular Pathogenesis and Treatment Perspectives for Hypereosinophilia and Hypereosinophilic Syndromes

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7825323/

  Different researchers conducted several studies in human cell and in clonal HES mouse model in order to investigate the role of FIP1L1-PDGFR in the pathogenesis of the disease. […] The extracellular PDGFR region contains the ligand binding site that is replaced by ETV6, which promotes an oligomerization process resulting in the activation of the PDGFR tyrosine kinase. […] The JAK2-rearranged eosinophilia displays an unfavorable clinical course with a rapid progression from chronic to acute leukemia. […] Eosinophilia-associated neoplasm can be characterized by rare rearrangements involving FLT3 and ABL1. […] T-cell clonality is not detected in all patients with demonstrated aberrant lymphocyte cells.

• #13 Molecular Pathogenesis and Treatment Perspectives for Hypereosinophilia and Hypereosinophilic Syndromes

  https://www.mdpi.com/1422-0067/22/2/486

  The most common include ETV6-FLT3 and ETV6-ABL1, which are typically identified in chronic myeloid diseases, such as eosinophilic leukemia and/or in T-ALL leukemia/lymphoma. […] The detection of an aberrant T-cell immunophenotype by clonal TCR gene rearrangement is required for the diagnosis of most L-HES patients.

• #14 Hypereosinophilic syndromes | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-2-37

  In L-HES, overproduction of eosinophil growth factors by T cells leads to increased cycling, differentiation and maturation of eosinophil precursors, as well as prolonged survival of eosinophils in the periphery, resulting in non-clonal hypereosinophilia. […] Clonality of phenotypically aberrant T cells has been demonstrated in many cases, by analysis of TCR gene rearrangement patterns. […] A good half of patients with HES remain unclassified, and present truly „idiopathic” hypereosinophilia. Among these, some present features of myeloproliferative disease similar to those encountered in F/P+ individuals, whereas others appear to have more of an „immuno-allergic” disease suggesting possible involvement of T cells. Further investigation of eosinophils and T cells in these idiopathic cases, will very likely lead to identification of novel molecular mechanisms ultimately leading to hypereosinophilia.

• #15

  https://www.haematologica.org/article/view/5338

  The other major mechanism involved in HES pathogenesis described so far is polyclonal eosinophil expansion in response to IL-5 in the setting of a primitive T-cell disorder. […] A number of similar observations have been reported in the literature, and a tentative definition of lymphocyte-variant HES (L-HES), or T-cell mediated HES, has been proposed, wherein hypereosinophilia is secondary to IL-5 overproduction by an expanded population of T cells which can generally be detected on the basis of an aberrant phenotype. […] The pathogenic role of the CD8 T-cell subset reported by Helbig in this issue is more debatable, as there is no evidence here for Th2 cytokine production. […] Thus, in contrast to FIP1L1-PDGFRA associated disease, development of targeted therapy for T-cell driven HES remains hindered by our incomplete understanding of primary molecular mechanisms, and specific pathways involved in survival, growth, and persistent activation of the abnormal T-cell subsets.

• #16 Orphanet: Hypereosinophilic syndrome

  https://www.orpha.net/en/disease/detail/168956

  Hypereosinophilic syndrome (HES) constitutes a rare and heterogeneous group of disorders, defined as persistent and marked blood eosinophilia and/or tissue eosinophilia associated with a wide range of clinical manifestations reflecting eosinophil-induced tissue/organ damage. […] Recent advances in underlying pathogenesis have established that what was once thought to be ”idiopathic” HES may in some cases be due to either primitive involvement of myeloid cells (primary HES), essentially due to occurrence of an interstitial chromosomal deletion on 4q12 leading to creation of the F/P fusion gene (CEL), or to increased interleukin (IL)-5 production by a clonally expanded T cell population (lymphocytic variant HES), most frequently characterized by a CD3-CD4+ phenotype, or due to other reactive causes (secondary HES) such as helminthic infection. […] However, in roughly 3/4 of cases, pathogenesis remains unknown, now defining idiopathic HES. […] A small subgroup of patients have HES that shows familial clustering (familial HES), presumably due to an as of yet unknown inherited gene.

• #17 Hypereosinophilic Syndrome | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/149474

  Allergic reactions contribute to the inflammatory process. Th2 cells, fostering an interleukin-5 (IL-5) rich environment, facilitate eosinophil migration, infiltration, and heightened inflammation in the affected organ. […] Lastly, eosinophil-mediated disorders are associated with an elevated thrombotic risk, potentially attributed to eosinophil tissue factor (TF) expression. The prothrombotic quality induces a hypercoagulable state influenced by the platelet-activating effects of eosinophilic granules.

• #18 How I Diagnose Hypereosinophilic Syndromes – European Medical Journal

  https://www.emjreviews.com/hematology/article/how-i-diagnose-hypereosinophilic-syndromes/

  Secondary (reactive) HES, in contrast, generally result from increased eosinophil production and may occur in a variety of disease conditions. […] The eosinophils are not clonally related and the eosinophilia is generally considered to be driven by cytokine/growth factor production. […] Persistent eosinophilia is commonly found in allergic and atopic disease. […] Its development is driven by activated Type 2 T helper cells that produce eosinophil-stimulating cytokines. […] This variant of HES results from the abnormal proliferation of T helper cells. […] While eosinophils play a role in the pathogenesis of organ dysfunction, the mechanisms by which this damage occurs are poorly understood. […] Further research may clarify the extent of eosinophil-mediated cytotoxicity compared to the consequences of cell recruitment.

• #19 Hypereosinophilic Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/202030-overview

  Eosinophil production is governed by several cytokines, including interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). IL-5 appears to be the most important cytokine responsible for differentiation of the eosinophil line. […] Several mechanisms have been proposed for the pathogenesis of hypereosinophilic syndrome, including overproduction of eosinophilopoietic cytokines, their enhanced activity, and defects in the normal suppressive regulation of eosinophilopoiesis. Organ damage induced by hypereosinophilic syndrome is due to the eosinophilic infiltration of the tissues accompanied by the mediator release from the eosinophil granules. Hence, the level of eosinophilia is not a true reflection of organ damage. […] The most serious complication of hypereosinophilic syndrome is cardiac involvement, which can result in myocardial fibrosis, chronic heart failure (CHF), and death. The mechanisms of cardiac damage are not entirely understood, but the damage is marked by severe endocardial fibrotic thickening of either or both ventricles, resulting in restrictive cardiomyopathy due to inflow obstruction.

• #20 (PDF) Mechanisms of Eosinophilia in the Pathogenesis of Hypereosinophilic Disorders

  https://www.academia.edu/92908083/Mechanisms_of_Eosinophilia_in_the_Pathogenesis_of_Hypereosinophilic_Disorders?uc-sb-sw=927363

  Although the pathophysiology of HES is poorly defined, dysregulation of cytokines (interleukin 5 [IL-5], IL-3, granulocyte-macrophage colony-stimulating factor [GM-CSF]) responsible for the maturation of eosinophils is a primary feature. […] Of these cytokines, IL-5 appears to have the greatest role in the regulation of eosinophil maturation. […] Recent advances in molecular biology allowed a better understanding which led to a new classification of the hypereosinophilic syndromes corresponding to molecular abnormalities, offering the possibility of new therapeutic approaches. […] The higher TF expression in patients with hypereosinophilic disorders may contribute to increase the thrombotic risk. […] Eosinophilic injury to the mucosa of the airways is suggestive of pathogenesis of bronchial asthma, based on histologic observation of the deposition of major basic protein.

• #21 Hypereosinophilic Syndrome | 5-Minute Clinical Consult

  https://www.unboundmedicine.com/5minute/view/5-Minute-Clinical-Consult/1688726/all/Hypereosinophilic_Syndrome?q=Chronic+Leukemia%2C+Myelogenous

  Hypereosinophilic syndrome (HES): a group of disorders characterized by an overproduction of eosinophils that subsequently infiltrate and damage multiple organs. […] Primary molecular defect resulting in clonal eosinophilic proliferation and/or overproduction or functional abnormalities of eosinophilopoietic cytokines and/or defects in normal suppressive regulation of eosinophilopoiesis. […] Three hematopoietic cytokines: IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulate bone marrow myeloid progenitors to overproduce eosinophils; IL-5 is most specific for eosinophil differentiation. […] Pathogenesis: HES: Eosinophils infiltrate organs and release toxic granules containing major basic protein, eosinophil peroxidase, eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), Charcot-Leyden crystals, VIP, and substance P; neurotoxic, cytotoxic, and prothrombotic; creates oxidative burst, reactive oxygen species. […] EDN and ECP activate fibroblasts: fibrosis and organ dysfunction.

• #22 Hypereosinophilic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Hypereosinophilic_syndrome

  Hypereosinophilic syndrome is a disease characterized by a persistently elevated eosinophil count ( 1500 eosinophils/mm) in the blood for at least six months without any recognizable cause, with involvement of either the heart, nervous system, or bone marrow. […] Despite the lack of knowledge regarding the precise mechanism underlying eosinophil-induced tissue damage, eosinophil accumulation seems to have pathological outcomes. Eosinophils cause direct cytotoxicity by releasing harmful substances locally, such as enzymes, pro-inflammatory cytokines, reactive oxygen species, cationic proteins, and factors derived from arachidonic acid. The extent of end-organ damage varies, and the severity of organ damage is frequently unrelated to the degree or duration of eosinophilia.

• #23 Hypereosinophilic Syndrome | 5-Minute Clinical Consult

  https://www.unboundmedicine.com/5minute/view/5-Minute-Clinical-Consult/1688726/all/Hypereosinophilic_Syndrome?q=Headache

  Hypereosinophilic syndrome (HES): a group of disorders characterized by an overproduction of eosinophils that subsequently infiltrate and damage multiple organs. […] Primary molecular defect resulting in clonal eosinophilic proliferation and/or overproduction or functional abnormalities of eosinophilopoietic cytokines and/or defects in normal suppressive regulation of eosinophilopoiesis. […] Three hematopoietic cytokines: IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulate bone marrow myeloid progenitors to overproduce eosinophils; IL-5 is most specific for eosinophil differentiation. […] HES: Eosinophils infiltrate organs and release toxic granules containing major basic protein, eosinophil peroxidase, eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), Charcot-Leyden crystals, VIP, and substance P; neurotoxic, cytotoxic, and prothrombotic; creates oxidative burst, reactive oxygen species. […] EDN and ECP activate fibroblasts: fibrosis and organ dysfunction.

• #24 Hypereosinophilia in Summary | IntechOpen

  https://www.intechopen.com/chapters/1186317

  Eosinophils play a role in the fight against many parasitic infections. Eosinophilic asthma, nasal polyps, eosinophilic gastrointestinal disorders, polyangiitis, and eosinophilic granulomatosis are diseases referring hypereosinophilic syndrome. Eosinophil granules participate in tissue healing, damage, repair and restructuring processes thanks to proteins and chemical mediators. Interleukin (IL)-5, IL-4, and IL-13 play a role in the proliferation, maturation, activation, and recruitment of eosinophils. Eosinophils have receptors for various cytokines, chemokines, and adhesion molecules that allow them to participate in inflammatory activities. In response to stimuli, eosinophils may release a range of granule proteins, including major basic proteins (MBPs) 12, eosinophil cationic protein (ECP), eosinophil peroxidase (EPX), eosinophil-derived neurotoxin (EDN), cytokines, and cytosolic Charcot-Leyden crystal protein/ galectin-10 (CLC/Gal-10). Improvements can be made in understanding the pathophysiological mechanisms of these diseases. It has led to the development of new therapeutics for eosinophilic inflammatory diseases.

• #25 Hypereosinophilia in Summary | IntechOpen

  https://www.intechopen.com/chapters/1186317

  HES is a heterogeneous hematological disorder. In patient groups with different clinical findings, malignancies belonging to the myeloid or lymphoid series may develop. The development of these disorders suggests that there may be different underlying pathologies. HES can affect both myeloid and lymphoid series. Eosinophils belong to the myeloid series. Clonal eosinophilic differentiation may occur from the myeloid early differentiation stage or from the T-cell series that undergo abnormal differentiation in the T-cell stage. […] Eosinophils develop and differentiate in the bone marrow under the influence of interleukin (IL) 5, IL-3, and GM-CSF. There may be different subsets of eosinophils that play different roles in inflammation and homeostasis. […] Eosinophilic myocarditis in cardiac involvement is the main cause of mortality and morbidity. Heart damage develops in three stages. The early necrotic stage is rarely symptomatic. This stage is followed by the thrombotic stage with thrombus formation in the damaged endocardium and emboli emanating from it. In the final fibrotic stage, endomyocardial fibrosis and damage to the atrioventricular valves lead to congestive heart failure.

• #26 Hypereosinophilic syndrome presenting as coagulopathy | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-022-00666-2

  With the patients significant eosinophilia, it is not completely clear why he presented with thromboses in his gastrointestinal tract as opposed to developing cardiac complications, as is often seen with idiopathic HES. Based on previous studies, he was at risk of developing cardiac complications, given his thrombocytopenia and elevated vitamin B12. However, it is thought that eosinophil-mediated cardiac disease evolves in three stages. The first stage involves acute necrosis and damage to the endocardium and myocardium. The second is a thrombotic stage, which is then followed by a third fibrotic stage. On average, the thrombotic stage can be found in patients who have had 10-months of eosinophilia. Prior to his hospitalization, it is unclear how long he had eosinophilia. It could be postulated that his disease may not have been present long enough to progress to this stage. In the near future, we may better understand why cardiac involvement is seen in certain HES patients, as models are being developed to investigate this phenomenon.

• #27 Hypereosinophilic syndrome presenting as coagulopathy | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-022-00666-2

  Hypereosinophilic syndrome (HES) is a group of disorders defined as elevated peripheral blood eosinophil count1500 eosinophils per microliter (eos/L) on two occasions1 month apart with organ dysfunction attributable to eosinophilia. These disorders are rare, thought to have a prevalence rate between 0.315 and 6.3 per 100,000 in the United States. Types of HES include primary (clonal/neoplastic), secondary (reactive), or undetermined significance, also known as idiopathic HES. Idiopathic HES is a diagnosis of exclusion following workup for primary or secondary causes. […] Eosinophils have been shown to play a direct role in atherosclerotic plaque formation and thrombosis. Recent studies have shown that eosinophils are activated in atherosclerosis and support plaque formation by increasing von Willebrand factor exposure and platelet adhesion to the endothelium. They are also recruited during arterial thrombosis via integrins and serve to stabilize thrombi through platelet interaction. Eosinophils are stimulated by platelets to form eosinophil extracellular traps which then activate platelets through major basic protein. A similar, well-studied mechanism results in recruitment of neutrophils and monocytes during plaque rupture which contribute to thrombosis via neutrophil extracellular traps.

• #28 Idiopathic Hypereosinophilic Syndrome as a Rare Cause of Stroke: A Case Report | 2021, Volume 27 – Issue 4 | Turkish Journal of Neurology

  https://tjn.org.tr/full-text/144/eng

  Hypereosinophilic syndrome (HES) is a rare hematological disease that causes organ damage by eosinophil infiltration in the tissue with increased eosinophil production in the bone marrow. HES is a rare but important cause of stroke. Central nervous system involvement findings can be serious and life-threatening. Eosinophil values should be examined as the cause of stroke, and hypereosinophilia should be suspected, especially in young patients with no etiology. […] HES, is a rare but highly specific neurovascular syndrome and is a fast-progressing disease that can cause heterogeneous and multiple organ damage with various symptoms. The granular proteins in active eosinophils cause clotting and fibrinolysis, which results in thrombosis after endothelial injury. Neurological involvement may be in the form of encephalopathy, brain infarction, and sensory polyneuropathy. Cerebral infarction develops with endomyocardial thromboembolism due to vascular endothelium toxicity after the release of mediators by eosinophils.

• #29 Idiopathic Hypereosinophilic Syndrome as a Rare Cause of Stroke: A Case Report | 2021, Volume 27 – Issue 4 | Turkish Journal of Neurology

  https://tjn.org.tr/full-text/144/eng

  The exact pathogenesis of encephalopathy is unknown, but encephalopathic changes are associated with significantly higher eosinophil rates and infarctions in the cerebral-arterial border zone areas. […] Hypereosinophilia should be suspected to be a cause of cerebrovascular disease especially in patients with ischemic lesions at a young age with borderline zones and multiple locations. […] The characteristic features of a stroke due to HES are the emergence of multiple ischemiae in different vascular areas. HES is a syndrome that should be kept in mind that can change the treatment options in patients with bilateral, multiple localization, and border area infarction with unknown etiology. This case report aimed to emphasize that HES can cause multiple embolic infarcts.

• #30 Idiopathic Hypereosinophilic Syndrome with Skull Base Involvement | American Journal of Neuroradiology

  https://www.ajnr.org/content/28/5/971

  Idiopathic hypereosinophilic syndrome (HES) is a heterogeneous disorder characterized by prolonged eosinophilia without an identifiable cause, ultimately resulting in organ dysfunction. […] The pathogenesis of both the encephalopathy and peripheral neuropathy of HES remains unknown. Possible mechanisms include direct damage from the infiltration of eosinophils and other inflammatory cells and injury from a toxin originating within eosinophils. […] The pathologic mechanism for IPT remains obscure. The histology is similar in all cases with variable amounts of plasma cells, lymphocytes, histiocytes, and fibroblasts. In several reported cases, patients had elevated levels of serum immunoglobulins and erythrocyte sedimentation rates, leading to the hypothesis that the lesion may have resulted from an exaggerated immunologic or inflammatory process occurring at sites of injury or infection. […] The case presented here suggests that a similar process may occur in HES and result in IPT.

• #31 Hypereosinophilic syndrome presenting as coagulopathy | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-022-00666-2

  While corticosteroid therapy is first line for idiopathic HES, newer biologic medications have shown promise in reducing eosinophilia and clinical symptoms of HES. Mepolizumab, an anti-IL-5 agent, was approved by the FDA in September 2020. In a phase III trial, Mepolizumab reduced flares in treatment-refractory FIP1L1-PDGFRAnegative HES by 50% in comparison to placebo group. Reslizumab, another anti-IL-5 agent, has shown some promise in treating HES; however, its use has been limited to a pilot study and case reports. Benralizumab is an anti-IL-5 receptor agent approved for severe eosinophilic asthma. In a recent phase II trial, it was found to be effective in reducing eosinophilia in treatment-refractory, PDGFRAnegative HES. Benralizumab was used to take advantage of its dosing regimen, opportunity for self administration, as the patient lives farther away from specialty care.

• #32 Hypereosinophilia in Summary | IntechOpen

  https://www.intechopen.com/chapters/1186317

  The aim of treatment is the control of organ damage rather than the elimination of eosinophilia. […] The success of the tyrosine kinase inhibitor imatinib in HES led to a search for its target in HES. As a result, the FIP1L1/PDGFR fusion on chromosome 4 and its product tyrosine kinase were identified. The activity of this mutation can be suppressed with imatinib.

• #33 Idiopathic hypereosinophilic syndrome presenting with severe vasculitis successfully treated with imatinib

  https://www.wjgnet.com/2307-8960/full/v4/i10/328.htm

  Idiopathic hypereosinophilic syndrome (HES) is a rare disorder characterized by peripheral eosinophilia exceeding 1500/mm3, a chronic course, absence of secondary causes, and signs and symptoms of eosinophil-mediated tissue injury. […] One of the best-characterized forms of HES is the one associated with FIP1L1-PDGFRA gene rearrangement, which was recently demonstrated as responsive to treatment with the small molecule kinase inhibitor drug, imatinib mesylate. […] Imatinib mesilate is the mainstay therapy of hypereosinophilic syndrome (HES) associated with molecular rearrangement of the PDGFR gene. […] The current literature reports more than 50 different fusion genes resulting from various chromosomal and molecular abnormalities, the dysregulated functions of which have highlighted the fundamental role of constitutively activated tyrosine kinases in the pathogenesis of hypereosinophilic disorders.

• #34 Hypereosinophilic syndrome presenting as coagulopathy | Allergy, Asthma & Clinical Immunology | Full Text

  https://aacijournal.biomedcentral.com/articles/10.1186/s13223-022-00666-2

  Given evidence that eosinophils play a direct role in thrombosis, targeting eosinophils may prevent further thrombotic complications. Once eosinophil levels have normalized, discontinuation of anticoagulation could be considered if thrombi have resolved, and no other indication exists based on patient risk factors. […] Rapid diagnosis of HES and utilization of steroid-sparing agents such as anti-IL-5 therapies could help prevent further end-organ damage, treat an underlying mechanism for associated coagulopathy, and avoid long-term side effects of corticosteroid use.

• #35 (PDF) Mechanisms of Eosinophilia in the Pathogenesis of Hypereosinophilic Disorders

  https://www.academia.edu/92908083/Mechanisms_of_Eosinophilia_in_the_Pathogenesis_of_Hypereosinophilic_Disorders?uc-sb-sw=927363

  Increased numbers of activated eosinophils in the blood and tissues that typically accompany hypereosinophilic disorders result from a variety of mechanisms. […] Accumulation alone is insufficient to lead to eosinophil-associated pathology, hence the importance of additional means for activation and release of eosinophil-derived mediators. […] Common themes in these events include participation of subsets of transcription factors, cytokines, chemokines, adhesion molecules and survival regulatory pathways. […] Different studies have allowed for the discovery of two major pathogenetic variants known as myeloid or lymphocytic HES. […] The etiopathogenic diagnosis is difficult and delayed in many cases and clinical evolution may be severe, with multiorgan involvement and poor prognosis.

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