INTRODUCTION — The hypereosinophilic syndromes (HES) are a group of disorders marked by the sustained overproduction of eosinophils, in which eosinophilic infiltration and mediator release cause damage to multiple organs. Although these disorders had long been considered idiopathic (eg, as in the "idiopathic hypereosinophilic syndrome," IHES), etiologies for some forms of HES have been described.
The clinical features, pathophysiology, and diagnosis of HES will be reviewed here. The treatment of these disorders is discussed separately, as is the initial approach to the patient with unexplained eosinophilia. (See "Hypereosinophilic syndromes: Treatment" and "Approach to the patient with unexplained eosinophilia".)
DEFINITIONS — A panel of experts reached consensus on terminology pertaining to hypereosinophilic conditions and published recommendations in 2012 [1]:
Hypereosinophilia — Hypereosinophilia (HE) is defined as an absolute eosinophil count (AEC) >1.5 x 109/L (or >1500 cells/microL) in the peripheral blood on two examinations separated in time by at least one month and/or pathologic confirmation of tissue HE.
For these purposes, tissue HE is defined by:
●On bone marrow section, a percentage of eosinophils that exceeds 20 percent of all nucleated cells, and/or
●Tissue infiltration that is extensive in the opinion of a pathologist (hematoxylin-eosin, May-Grunwald-Giemsa and Wright-Giemsa are the recommended stains for visualizing eosinophils in tissue section) and/or
●Marked deposition of eosinophil granule proteins in tissue (in the absence or presence of major tissue infiltration by eosinophils). This is demonstrated by immunofluorescence and usually performed in expert centers. There is also a novel monoclonal antibody that recognizes eosinophil peroxidase, which can detect both tissue eosinophils and eosinophil degranulation [2,3].
Hypereosinophilic syndrome — A hypereosinophilic syndrome (HES) is defined by the association of HE (as defined above), with eosinophil-mediated organ damage and/or dysfunction, provided other potential causes for the damage have been excluded.
●The term "HES" can therefore be used to qualify any condition characterized by eosinophilic infiltrates and associated complications, including situations where the cause of HE is identified (eg, restrictive cardiac disease occurring in the setting of parasitic infections [Löffler's endocarditis]).
●In contrast, the term "HES" should not be used when the clinical manifestations and underlying organ damage found in a hypereosinophilic patient can be explained by a mechanism other than HE. As an example, a patient with cardiovascular risk factors presenting with persistent HE and thoracic pain that is shown to be secondary to coronary artery occlusion, should not be diagnosed as HES, unless another clinical manifestation can be attributed to eosinophilic tissue infiltration.
Categories of HES — HES are further subclassified according to the pathogenic mechanisms resulting in eosinophil expansion: primary, secondary, or idiopathic. (See 'Pathophysiology' below.)
●Primary (or neoplastic) HES – In primary HES, eosinophilic expansion occurs in the setting of an underlying stem cell, myeloid, or eosinophilic neoplasm, and is considered (or proven) clonal.
●Secondary (or reactive) HES – In secondary HES, eosinophilic expansion is driven by overproduction of eosinophilopoietic cytokines by other cell types and is polyclonal. This is typically the situation encountered in parasitic infections, certain solid tumors, and T cell lymphoma, wherein marked secondary HE may be responsible for organ damage and dysfunction. Lymphocytic variant HES (L-HES) is a subvariant in this category. (See 'Diagnosis of L-HES' below.)
●Idiopathic HES – In idiopathic hypereosinophilic syndrome (IHES), the underlying cause of HE remains unknown despite thorough etiologic work-up. The associated organ damage generally warrants therapeutic intervention.
In addition to HES, several other clinical situations associated with HE can be defined as follows:
●Specific syndromes associated with HE, in which the relative contribution of eosinophils to the clinical presentation and disease complications has not been fully elucidated, such as eosinophilic granulomatosis and polyangiitis (EGPA) and certain immunodeficiencies. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)" and "Autosomal dominant hyperimmunoglobulin E syndrome" and "Primary disorders of phagocyte number and/or function: An overview".)
●"Hypereosinophilia of undetermined significance" (HEUS), which describes patients with persistent unexplained HE, but without apparent complications related to tissue eosinophilia. This terminology highlights both the lack of an explanation for HE and the inability to predict whether the patient will eventually develop clinical manifestations related to eosinophilic organ infiltration, and thus progress to HES.
EPIDEMIOLOGY — Hypereosinophilic syndrome (HES) is rare, and the true prevalence is unknown. In one study that used clinician coding of eosinophilia to identify patients with HES in the Surveillance, Epidemiology, and End Results (SEER) database, the estimated prevalence was between 0.36 to 6.3 per 100,000 [4].
Most patients are between 20 and 50 years of age at the time of diagnosis, although HES can develop in children [5-7]. One study suggested that the frequencies of clinical HES variants (including myeloproliferative variants) were similar in children and adults, although immunodeficiency presenting with HE was more common in children; children were also more likely to present with gastrointestinal complaints and had higher peak eosinophil counts than adults [8]. (See 'Differential diagnosis' below.)
Certain variants of HES (ie, those associated with aberrations in the gene for tyrosine kinase receptor platelet-derived growth factor receptor alpha [PDGFRA] and platelet-derived growth factor beta [PDGFRB]) occur almost exclusively in males, whereas others (lymphocytic variant HES [L-HES] and HES of unknown etiology) appear to be equally distributed between the sexes [9,10]. (See 'HES variants' below.)
PATHOPHYSIOLOGY — In hypereosinophilic syndrome (HES), eosinophils damage the tissues that they infiltrate. Common target organs include the skin, lung, and gastrointestinal tract. Less commonly, patients can have potentially life-threatening damage to the cardiovascular system and brain. Activated eosinophils may damage tissues in a number of mechanisms, which are described in more detail separately. (See "Eosinophil biology and causes of eosinophilia".)
Eosinophils are derived from myeloid progenitors in the bone marrow, through the action of three hematopoietic cytokines: granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5). Of these three, only IL-5 is specific for eosinophil differentiation.
Mechanisms of eosinophil overproduction — There is evidence that at least two distinct mechanisms can lead to dysregulated overproduction of eosinophils in patients with HES [11,12]:
●Clonal eosinophilic proliferation as a result of a primary molecular defect involving hematopoietic stem cells and/or defects in signal transduction from the receptors that mediate eosinophilopoiesis
●Overproduction of eosinophilopoietic cytokines, such as IL-5
In theory, HES could also result from defects in the normal suppressive regulation of eosinophil survival and activation, abnormalities in chemotaxis, or from functional abnormalities of the eosinophilopoietic cytokines, related to enhanced or prolonged biologic activity. However, these mechanisms have not been conclusively demonstrated.
Since the initial description of HES, progress has been made in identifying specific etiologic abnormalities that underlie hypereosinophilia (HE) in some patients with an HES occurring in the absence of an obvious cause (such as parasitic infection or drug allergy). These involve both of the above mentioned mechanisms: clonal eosinophil production (eg most significantly Fip1-like1-platelet-derived growth factor receptor alpha [FIP1LI-PDGFRA]) and reactive IL-5-driven eosinophil expansion (eg lymphocytic variant HES [L-HES]). In practice, once classical causes of HE have been ruled out (parasitic infection, etc), the underlying mechanism resulting in HE remains unknown despite thorough investigations in 70 to 80 percent of patients [9,13-16]. However, the true proportion of all patients with unexplained HE and identified abnormalities remains unknown, since the techniques used for identification have not been uniformly applied across series. Moreover, it is probable that each of the major investigative groups is affected by referral biases favoring HES patients with certain clinical presentations. Thus, while a specific center may observe a particular etiology to be common in its own patients with HES, this does not provide much information about prevalence in the broader population.
HES variants — HES has been subdivided into several clinically relevant variants (table 1) [17]:
●Myeloproliferative variants of HES (M-HES).
●T lymphocytic variants of HES (L-HES).
●Familial HES.
●Idiopathic HES (IHES).
●Organ-restricted hypereosinophilic conditions – This term is applied to disorders with blood eosinophilia ≥1500/microliter in the setting of single organ involvement.
●Specific/defined syndromes associated with HE — This term is applied to disorders with blood eosinophilia ≥1500/microliter in association with a distinct diagnosis, wherein the role of eosinophils in disease complications and clinical manifestations remains inconclusive.
Myeloproliferative HES variants — A subgroup of patients with HES display features more typical of myeloproliferative disorders, including increased serum vitamin B12 levels, chromosomal abnormalities, anemia and/or thrombocytopenia, hepatomegaly, splenomegaly, and circulating leukocyte precursors [5,18,19]. These patients tend to be more refractory to glucocorticoid therapy. (See "Hypereosinophilic syndromes: Treatment", section on 'Myeloid variants'.)
Myeloproliferative neoplasms — Some HES patients with myeloproliferative features have responded to treatment with tyrosine kinase inhibitors. Clonal chromosomal aberrations not recognizable by conventional cytogenetics have been demonstrated in the majority of these patients, leading to reclassification of this subset as having myeloproliferative neoplasms (MPN) [19,20]. Such patients fall into the category "primary/neoplastic hypereosinophilic syndromes" in the 2012 consensus classification proposal for eosinophilic conditions [1].
The World Health Organization (WHO) classification system of hematopoietic and lymphoid tissues includes a special category for myeloid and lymphoid disorders with eosinophilia and one of the following abnormalities [21]:
●PDGFRA – The gene encoding the tyrosine kinase receptor, platelet-derived growth factor receptor alpha, is located on chromosome 4 and may be involved in translocations with various fusion partners, most commonly due to an interstitial deletion on chromosome 4q12 resulting in a FIP1L1-PDGFRA fusion.
●PDGFRB – The gene for the tyrosine kinase receptor, platelet-derived growth factor receptor beta [10,22].
●FGFR1 – The gene for fibroblast growth factor receptor 1 is located on chromosome 8p11 and is often involved in a translocation with the ZMYM2 gene (zinc finger, MYM2) on chromosome 13q12 [23,24].
●PCM1-JAK2 – Myeloid neoplasm with t(8;9)(p22;q24.1), which results in the fusion of PCM1 (pericentriolar material 1) and JAK2 (Janus kinase 2) [25-30]. PCM1-JAK2 is included as a provisional entity in the WHO classification system [21].
The most common chromosomal aberration is an interstitial deletion of chromosome 4q12, which creates the FIP1L1-PDGFRA fusion from Fip1-like1 (FIP1L1) and platelet-derived growth factor receptor alpha (PDGFRA). The resultant protein, FIP1L1-PDGFRA, displays constitutive tyrosine kinase activity [19,31-35]. The prevalence of the FIP1L1-PDGFRA among patients fulfilling HES criteria is estimated to be between 10 and 14 percent, although this is not certain [9,13,36]. (See "Hypereosinophilic syndromes: Treatment", section on 'Other tyrosine kinase inhibitors'.)
M-HES may also be caused by other chromosomal rearrangements, including fusion of PDGFRA with other partner genes, rearrangements involving PDGFRB, or point mutations in PDGFRA [10,22,37-40]. There have also been case reports of HES with JAK2 V617F and t(8;9)(p22;p24) creating PCM1-JAK2 [25-30,41,42]. Clonal eosinophilia has also been noted in patients with KIT-positive systemic mastocytosis (KIT D816V) [43]. Neither JAK2 V617F nor KIT D816V is typically imatinib-sensitive, but patients with KIT D816V may respond to midostaurin. (See "Advanced systemic mastocytosis: Management and prognosis", section on 'Midostaurin'.)
Rare patients with IHES in whom bone marrow blasts are increased or clonality is documented (eg, by an abnormal karyotype or targeted next generation sequencing) have aggressive disease that is similar to that of chronic eosinophilic leukemia, not otherwise specified (CEL-NOS), [44].
T cell lymphocytic variants — Lymphocytic variant HES (L-HES) is characterized by a predominance of skin and soft tissue involvement, although other clinical manifestations of HES, including cardiovascular, pulmonary, and rheumatological/articular involvement, are also present. In this variant, which is classified as a subvariant of secondary/reactive HES, IL-5-producing T cell subsets have been identified in the peripheral blood [45]. The most frequently reported abnormal T cell phenotype in L-HES is CD3-CD4+ [46]. In the largest cohort of patients with CD3-CD4+ associated L-HES reported, the majority of patients had elevated serum immunoglobulin E (IgE), skin involvement, and lymphadenopathy. Total lymphocyte counts were elevated in just one-third of patients [46]. The prevalence of this variant among all patients with HES is not well-defined. In one series of 60 patients with idiopathic eosinophilia, 16 were found to have abnormal IL-5-producing T cells [14]. This disorder may evolve to lymphoma [45]. (See 'Skin disease' below and 'Laboratory features' below.)
Molecular disease mechanisms remain largely unknown. However, one study identified a gain-of-function mutation in STAT3 in isolated CD3-CD4+ T cells from one patient; two other patients had evidence for upregulation of STAT3-dependent pathways, but this mutation was not found [47]. A gain-of-function somatic mutation in STAT5B has also been described in two children presenting with L-HES [48].
In addition to IL-5, the abnormal T cells produce other T helper type 2 (Th2) cytokines such as IL-4 and IL-13, as well as GM-CSF. The effects of these Th2 cytokines on other cells (eg, B cells) account for associated biologic features of L-HES. Indeed, B cell stimulation leads to increased IgE synthesis and polyclonal hypergammaglobulinemia [49].
Familial HES — Autosomal dominant transmission of marked eosinophilia has been reported. In one family, eosinophilia began at birth and most family members remained asymptomatic, but progression with fatal endomyocardial fibrosis occurred in a few individuals; the gene was mapped to chromosome 5q31-33 [50]. In another family, IL-5 production by PBMC was increased, in the absence of IL-4 or IL-13 [51]. Familial forms also exist in several of the single-organ HES variants, including eosinophilic esophagitis and eosinophilic fasciitis and do not appear to differ in clinical presentation from the sporadic forms [52-54].
Idiopathic HES — Despite careful evaluation of HE, the etiology in as many as 75 percent of cases of presumed HES remains undefined. The terms "idiopathic HES" [55] and "HES of unknown etiology" are used to distinguish these patients from those in earlier series, which included patients with now defined subtypes. Among patients with multisystem organ involvement, some demonstrate features of myeloproliferative disease similar to those encountered in FIP1L1-PDGFRA-positive individuals, whereas others appear to have more of an "immuno-allergic" disorder suggesting possible involvement of T cells.
Organ-restricted hypereosinophilic conditions — Organ-restricted hypereosinophilic conditions are defined as single organ involvement together with eosinophilia >1.5 x 109/L or lower levels of blood eosinophilia with clear-cut organ involvement.
Overlap disorders include a wide variety of single organ-restricted eosinophilic disorders, such as eosinophilic gastrointestinal disorders, chronic eosinophilic pneumonia, and Well's syndrome. A number of these eosinophilic disorders can be difficult or impossible to distinguish from IHES when accompanied by blood eosinophilia >1.5 x 109/L. Whether to pursue an extensive evaluation for other end-organ involvement remains a matter of clinical judgment and should be dictated by the clinical signs and symptoms, degree of eosinophilia, and response to therapy. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)" and "Eosinophilic gastrointestinal diseases" and "Overview of pulmonary eosinophilia" and "Eosinophil biology and causes of eosinophilia", section on 'Disorders with eosinophilic involvement of specific organs'.)
Specific/defined syndromes associated with HE — Eosinophilia >1.5 x 109/L can be seen at times in a variety of conditions associated with immunodysregulation. Examples include inflammatory bowel disease, autoimmune lymphoproliferative syndrome, HIV infection, IgG4-related disease, hyperimmunoglobulin E syndromes (eg, DOCK8 deficiency), CARD9 deficiency, collagen vascular diseases, and sarcoidosis [56-64]. The etiology of the eosinophilia in such cases is unknown, and its impact on disease complications and clinical manifestations remains inconclusive, but it appears to correlate with the severity of the underlying condition and, in some cases, with prognosis. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis" and "Autosomal dominant hyperimmunoglobulin E syndrome", section on 'Dedicator of cytokinesis 8 and tyrosine kinase 2 deficiencies' and "Primary disorders of phagocyte number and/or function: An overview".)
Episodic angioedema with eosinophilia (Gleich syndrome) — Episodic angioedema with eosinophilia is a rare disorder characterized by recurrent episodes of angioedema, urticaria, pruritus, fever, weight gain, oliguria, elevated serum immunoglobulin M (IgM), and leukocytosis with marked blood eosinophilia. Symptoms generally appear at intervals of three to four weeks and resolve spontaneously within several days. A diuresis may occur with resolution. Based on the approximately 50 cases that have been reported, patients are typically between 10 and 34 years of age when symptoms initially develop. The contribution of eosinophils to clinical manifestations remains uncertain, although increased deposition of eosinophil granule protein in angioedematous skin has been noted. In a subset of patients with Gleich syndrome, a clonally expanded CD3-CD4+ T cell population is present. Detection of Th2 cytokines within activated CD4 T cells by flow cytometry [65] and elevated serum IL-5 levels prior to their peak hypereosinophilia [65-67] suggests that their hypereosinophilia is T cell-driven. Such patients can be classified as L-HES on a pathogenic basis. In others, the clinical presentation can be similar to L-HES, as L-HES can involve intermittent urticaria or angioedema, but T cell investigations are normal. Although development of other end-organ manifestations appears to be uncommon, this has been described [68]. Clinical flares may conserve their episodic nature over time or may progress to nonepisodic HES.
In a study of four unrelated patients, cyclic changes were found in several other cell types in addition to eosinophils, revealing that it is a multilineage disorder [65]. Neutrophils increased just before or with eosinophils, and lymphocytes rose concomitant with eosinophils. Clinical flares were also preceded by a rise in serum levels of type II cytokines (IL-5, IL-13, IL-9, and IL-10). CD3-CD4+ T lymphocytes were found in all four patients and were shown to cycle with total lymphocytes as well [65]. In another patient, periodic increases in GM-CSF, but not IL-5, were observed [69]. (See "Eosinophil biology and causes of eosinophilia", section on 'Disorders with eosinophilic involvement of specific organs'.)
Eosinophilic granulomatosis with polyangiitis — Eosinophilic granulomatosis with polyangiitis (EGPA, formerly called Churg-Strauss) is difficult to categorize, particularly in the absence of documented eosinophilic vasculitis on tissue biopsy. The authors prefer to view EGPA as an organ-restricted eosinophilic disorder, since it is a disease of one organ (blood vessels), although clinical manifestations can involve the sinuses, lungs, skin, heart, peripheral nerves, and other structures. However, other experts believe it is more appropriately classified as a defined syndrome associated with HE (table 1). This issue remains an area of debate.
In some patients presenting with HE and pulmonary disease, determining if eosinophilia and organ involvement represents chronic eosinophilic pneumonia (organ-restricted), IHES, or EGPA can be difficult clinically [70]. Many patients meet diagnostic criteria for these disorders. This is particularly challenging in the early stages of EGPA before the development of vasculitis and in patients who are antineutrophil cytoplasmic antibody (ANCA)-negative. Moreover, both disorders usually respond initially to glucocorticoids, and while glucocorticoid therapy is beneficial, it may further impede the clinician's ability to distinguish between these two conditions. Therefore, histologic assessment for vasculitis is recommended when symptoms suggest small- and medium-sized blood vessel damage, as therapeutic strategies to treat end-organ injury differ, especially for the choice of second-line agents [71]. Early in disease, pathology usually reveals eosinophil tissue infiltration without the distinguishing granulomas and frank vasculitis of late-stage EGPA [72]. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)" and "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)
Hypereosinophilia of undetermined significance — Patients with persistent HE of unknown etiology and no apparent organ damage or dysfunction are classified as "hypereosinophilia of undetermined significance" (HEUS). Although some patients with asymptomatic HE are likely normal variants, they cannot be differentiated at the present time from patients who will ultimately progress to symptomatic HES [73,74]. (See 'Diagnosis of hypereosinophilia of undetermined significance' below.)
CLINICAL FEATURES — Patients may present with various combinations of symptoms and signs of end-organ damage mediated by eosinophils. In many patients, the onset of symptoms is insidious, and eosinophilia is detected incidentally. However, in others, the initial manifestations are severe and life-threatening due to the rapid evolution of cardiovascular or neurologic complications.
Signs and symptoms at presentation — A retrospective multicenter series of 188 patients reported the frequency of specific symptoms at presentation [9]. The following types of signs and symptoms were noted:
●Dermatologic (eg, rash) – 37 percent
●Pulmonary (cough and breathlessness) – 25 percent
●Gastrointestinal – 14 percent
●Cardiac – 5 percent
●Neurologic – 4 percent
Six percent of patients presented with incidentally detected and clinically asymptomatic hypereosinophilia (HE).
Cardiac disease — Eosinophilic myocarditis is a major cause of morbidity and mortality among patients with hypereosinophilic syndrome (HES) [5,75-77]. Platelet-derived growth factor receptor alpha (PDGFRA)-associated HES has an increased incidence of incapacitating and potentially lethal cardiac involvement in the absence of therapy [35]. The signs and symptoms of myocarditis are described in detail separately (table 2). (See "Clinical manifestations and diagnosis of myocarditis in adults".)
Eosinophil-mediated cardiac damage involves increased numbers of eosinophils in conjunction with other ill-defined stimuli that recruit and/or activate eosinophils within the heart tissues. Extracellular deposition of eosinophil granule proteins and evidence of eosinophil activation are present at sites of myocardial injury [77]. The clinicopathologic changes in cardiac tissue associated with HES appear similar in patients with idiopathic HES (IHES) and in those with a known underlying etiology of persistent HE, including eosinophilic leukemia, granulocyte macrophage colony-stimulating factor (GM-CSF) administration, drug reactions, and parasitic infections [5,78]. (See "Approach to the patient with unexplained eosinophilia".)
The development of cardiac disease in HES is unpredictable. Some patients with sustained eosinophilia never develop cardiac involvement, and the severity of cardiac injury does not clearly correlate with the degree of peripheral eosinophilia. Cardiac involvement does, however, appear to be more common in patients with the Fip1-like1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) fusion [35,79].
Eosinophil-mediated heart damage evolves through three stages, although these stages may be overlapping and not clearly sequential [5]:
●An acute necrotic stage
●An intermediate phase characterized by thrombus formation along the damaged endocardium
●A fibrotic stage characterized by altered cardiac function/heart failure due to either restrictive cardiomyopathy and/or compromise/entrapment of the chordae tendineae leading to mitral and tricuspid regurgitation
Patients with HES often develop cardiopulmonary symptoms and signs during the thrombotic and fibrotic stages.
The acute necrotic stage is characterized pathologically by endocardial damage, myocardial infiltration with eosinophils and lymphocytes, eosinophil degranulation, myocardial necrosis, and the formation of sterile microabscesses. The disease is usually clinically silent at this phase. Physical examination generally is normal, although conjunctival and/or subungual splinter hemorrhages (which probably represent small emboli from the endocardial surface) are sometimes noted. Elevations in serum troponin levels can be sensitive indicators of early and ongoing eosinophil-associated myocardial damage in forms of HES and eosinophilic granulomatosis with polyangiitis (EGPA) [80-82].
Echocardiography can be normal during the acute necrotic stage. Several reports have shown that contrast-enhanced cardiac magnetic resonance imaging (MRI) reliably detects all stages and aspects of eosinophil-mediated heart damage, including the early stage of myocardial eosinophilic inflammation (image 1) [83,84]. Endomyocardial biopsy may provide definitive evidence of eosinophil-associated cardiac involvement, but is typically reserved for patients in whom there is uncertainty whether infiltrating eosinophils are causing cardiac disease. Staining of biopsy specimens with antibodies for eosinophil granule proteins, including major basic protein 1 (MBP1), can demonstrate eosinophil-related tissue damage even in the absence of significant eosinophil accumulation [85].
The second stage of heart disease involves thrombus formation along areas of damaged endocardium. The thrombogenic sequelae of eosinophilic tissue infiltration may arise from the actions of eosinophil peroxidase in forming hypothiocyanous acid, a compound which diffuses into endothelial cells and strongly induces tissue factor expression by these cells [86]. Tissue factor, believed to be crucial in thrombus formation, is also expressed by eosinophils directly [87]. The major complication of intracardiac thrombus formation is the detachment and distant embolization of thrombotic material, leading to embolic strokes, ischemia of extremities, and other embolic events. (See 'Thrombotic complications' below and "Echocardiography in detection of cardiac and aortic sources of systemic embolism".)
In the third fibrotic stage, fibro-inflammatory remodeling of valvular structures can lead to entrapment, rupture of chordae tendineae, or fusion of valves to the endocardial surface. Symptoms and signs present at this stage include dyspnea, chest pain, and signs of left and/or right ventricular failure. Evaluation may demonstrate mitral or tricuspid regurgitation, cardiomegaly, restrictive cardiomyopathy, or T wave inversions on the electrocardiogram. Echocardiography and cardiac MRI can show intracardiac thrombi or evidence of fibrosis, such as thickening of the posterior mitral valve leaflet or the posterior wall, late gadolinium enhancement on cardiac MRI, and increases in endomyocardial echodensity in areas of fibrosis (image 1) [88]. (See "Endomyocardial fibrosis" and "Definition and classification of the cardiomyopathies".)
Cardiac involvement in eosinophil-related diseases may also develop by other mechanisms, including myocardial and pericardial damage from small vessel vasculitis [89-91]. Echocardiography can evaluate myocardial function and MRI can demonstrate myocardial damage [92].
Neurologic disease — HES may be complicated by cerebral thromboemboli, encephalopathy, peripheral neuropathy, or longitudinal and/or transverse sinus thrombosis [93]. Neurologic complaints, particularly those associated with cerebral thromboemboli, are occasionally the presenting symptoms of HES.
●Cerebral thromboemboli can arise from intracardiac thrombi and manifest as embolic strokes or transient ischemic episodes. MRI imaging can reveal multiple infarcts in watershed border zone distributions [94]. (See 'Cardiac disease' above.)
●Encephalopathy can present with behavioral changes, confusion, ataxia, and memory loss. Affected patients may also have signs of upper motor neuron injury, such as increased muscle tone, heightened deep tendon reflexes, and a positive Babinski response. How these changes occur is not known. Encephalopathic changes are more likely with markedly elevated blood leukocyte and eosinophil numbers and may derive from microvascular occlusion.
●Peripheral neuropathy accounts for approximately one-half of the neurologic manifestations of HES. The neuropathy may be symmetric or asymmetric, involve sensory with or without motor nerves, and may produce mononeuritis multiplex or radiculopathy with denervation muscle atrophy. (See "Differential diagnosis of peripheral nerve and muscle disease".)
The pathophysiology of the peripheral neuropathy in patients with HES remains largely unexplained. Biopsies of affected nerves generally show an axonal neuropathy with varying degrees of axonal loss, but no evidence of vasculitis or eosinophilic infiltration.
Thrombotic complications — A number of case reports suggest that venous and arterial blood vessels may be damaged in HES, although the mechanisms remain largely unknown. Patients have been reported to develop femoral artery occlusion [95], intracranial sinus thrombosis [96,97], or digital gangrene in the setting of progressive Raynaud phenomenon.
Microvascular thrombosis and occlusion due to eosinophil-related damage to endothelium combined with activation of the coagulation system has been reported in association with acute renal failure and cold-induced Raynaud phenomenon causing digital necrosis [5,98,99]. While eosinophils may impact coagulation pathways at different levels, the precise mechanisms leading to hypercoagulability remain elusive [77]. (See "Pathogenesis and pathophysiology of Raynaud phenomenon".)
Ocular manifestations — Ocular symptoms, particularly blurred vision, may be related to microemboli or local thrombosis [5,100,101], although uveitis has also been described.
Skin disease — Common skin manifestations of HES include eczema (involving hands, flexural areas, or dispersed plaques), erythroderma, generalized thickening of the skin (lichenification), dermographism, recurrent urticaria, and angioedema [5,102]. Biopsies of papular or nodular lesions show perivascular infiltration with eosinophils and mild-to-moderate perivascular neutrophilic and mononuclear infiltrates without vasculitis.
Less commonly, mucosal ulcers, which are often difficult to treat, develop in the mouth, nose, pharynx, esophagus, and stomach, or on the penis or anus. Biopsy of these ulcers demonstrates a nonspecific mixed cellular infiltrate without eosinophilia, vasculitis, or microthrombi [5]. Eosinophil granule deposition may be seen on immunofluorescence staining. Several cases of HES with concomitant lymphomatoid papulosis, a T cell-mediated chronic dermatosis, have also been described [103]. (See "Lymphomatoid papulosis".)
The presence and type of dermatologic lesions may provide valuable prognostic information.
●Lymphocytic variants of HES (L-HES) can present with prominent cutaneous symptoms. In the series mentioned previously, 14 of 16 L-HES patients had cutaneous lesions, including erythroderma, urticaria, and plaques [14]. Patients with cutaneous symptoms should be investigated for the presence of abnormal T cells to exclude cutaneous T cell lymphoma. Patients with L-HES should be monitored for development of T cell lymphoma. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)
●Patients who experienced angioedema and urticaria, with or without other symptoms, were likely to have a benign course without cardiac or neurologic complications, as noted in the previously mentioned series of referred HES subjects [100,104]. Some of these patients might have had the syndrome of episodic angioedema and eosinophilia (Gleich syndrome), which had not yet been recognized. (See 'Episodic angioedema with eosinophilia (Gleich syndrome)' above.)
●Patients with mucosal ulcerations are more likely to have FIP1L1-PDGFRA-positive HES.
●The existence of lymphomatoid papulosis should prompt a search for the FIP1L1-PDGFRA mutation, as this association has been reported in a small number of cases [103]. (See "Lymphomatoid papulosis".)
Pulmonary disease — Pulmonary involvement is common in HES and may result from eosinophilic infiltration of the lung with subsequent fibrosis, heart failure, or pulmonary emboli [100]. In a 2011 retrospective series of 49 patients seen at the Mayo Clinic, respiratory symptoms were reported in 63 percent of patients [105]. The most common presenting symptoms were dyspnea (45 percent), cough (39 percent), and wheezing (24 percent). Abnormal chest radiography or computed tomography (CT) findings were seen in 43 percent of patients and included parenchymal infiltrates (37 percent), pleural effusion (14 percent), intrathoracic lymphadenopathy (12 percent), and pulmonary emboli (4 percent). Infiltrates were most commonly patchy ground glass infiltrates. Of note, two of the patients with bilateral parenchymal infiltrates had no respiratory symptoms. Lung biopsy, when performed, revealed eosinophilic infiltrates. Differentiation from other diseases that cause pulmonary infiltrates with eosinophilia is reviewed separately. (See "Overview of pulmonary eosinophilia".)
Gastrointestinal disorders — Eosinophilic gastritis, enteritis, and/or colitis may occur secondary to HES and cause weight loss, abdominal pain, vomiting, and/or severe diarrhea [5]. Hepatic involvement may take the form of chronic active hepatitis, focal hepatic lesions, eosinophilic cholangitis, or the Budd-Chiari syndrome. (See "Eosinophilic gastrointestinal diseases" and "Etiology of the Budd-Chiari syndrome".)
LABORATORY FEATURES — By definition, patients must have peripheral blood hypereosinophilia (HE) (>1.5 x 109/L) (picture 1) or tissue HE (as defined by the criteria discussed previously) [75]. (See 'Definitions' above.)
In peripheral blood HE, circulating eosinophils are usually mature, although eosinophilic and/or myeloid precursors may also be present. Total leukocyte counts in excess of 90 x 109/L are associated with a poor prognosis [5].
Anemia may be present, especially in patients with the myeloproliferative variants, and either thrombocytopenia or thrombocytosis may be noted [106].
Complications of eosinophilic tissue/organ infiltration may result in elevated liver enzymes, serum troponin, and rarely, increased blood urea nitrogen and creatinine levels.
Certain abnormalities observed on routine blood tests may suggest a specific hypereosinophilic syndrome (HES) variant, including elevated serum vitamin B12 (myeloproliferative variants) or immunoglobulin E (IgE) (lymphocytic variant HES [L-HES]), although neither is entirely sensitive or specific.
EVALUATION AND DIAGNOSIS — Hypereosinophilic syndrome (HES) should be suspected in patients with persistent eosinophilia >1.5 x 109/L in the peripheral blood on at least two occasions. An evaluation should be pursued even if the patient is asymptomatic.
The initial evaluation of a patient with eosinophilia (ie, elevated but not >1.5 x 109/L) is presented separately. The specific testing required to rule out common etiologies of hypereosinophilia (HE) differs depending upon findings from a thorough history and physical examination. (See "Approach to the patient with unexplained eosinophilia".)
Initial studies — The following initial tests are recommended to assess for end-organ involvement:
●Blood chemistries, including liver enzymes, creatine kinase, renal function, and troponin
●Electrocardiogram
●Echocardiogram
●Pulmonary function tests
●Chest radiograph and computed tomography (CT)
●Abdominal CT
●Tissue biopsies and additional studies as clinically indicated
In addition, several biomarkers are under study for their predictive value regarding HES subtypes and should be measured (see 'Diagnosis of HES subtypes' below):
●Serum tryptase (most consistently elevated in myeloproliferative variants [M-HES], variable in other subtypes)
●Serum vitamin B12 (elevated in M-HES)
●Serum immunoglobulins (particularly immunoglobulin E [IgE]) (often elevated in lymphocytic variants of HES [L-HES], variable in M-HES and other subtypes)
Referral — HES is a heterogenous disorder, and patients may present to generalists or specialists. The evaluation should involve other specialists (hematology, infectious disease, allergy/immunology, pulmonary, cardiology, neurology) as dictated by the patient's specific signs and symptoms.
Hematologic evaluation — Patients with persistent unexplained HE should undergo further evaluation to identify possible HES subtypes or underlying causes not previously identified.
●Molecular testing for the FIP1L1-PDGFRA mutation should be performed on peripheral blood by performing fluorescence in situ hybridization (FISH) for the CHIC2 locus, which is located between the two fusion partners and therefore absent in the presence of the FIP1L1-PDGFRA fusion, or RT-PCR for the fusion transcript (commercially available in the US) [31,107].
●T lymphocyte phenotyping on peripheral blood by multiparameter flow cytometry [108], including concomitant staining and analyses for (at a minimum) CD3, CD4, and CD8 (to detect CD3-CD4+ subsets), should be performed in all cases. T cell receptor rearrangement studies on peripheral blood and/or bone marrow (available at specialty academic centers) should be done concomitantly to diagnose L-HES. (See 'T cell lymphocytic variants' above.)
●Bone marrow aspiration and biopsy should be examined for cellularity, dysplasia, CD34 expression, reticulin fibrosis, mast cells, and karyotype. If these studies do not establish a diagnosis, molecular studies should be performed, including FGFR1 and PDGFRB fusion genes, BCR-ABL1, JAK2 V617F, KIT D816V, and clonal T cell receptor rearrangements.
The bone marrow in patients with HES demonstrates increased eosinophils and eosinophil precursors. Patients with increased serum tryptase or atypical mast cells on bone marrow biopsy should also be screened for KIT D816V associated with systemic mastocytosis. (See 'Myeloproliferative HES variants' above and "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)
Cytogenetics are normal in most patients, but karyotyping plays an important role in the diagnosis of some M-HES variants. It is the only diagnostic technique for identifying cases with translocations involving PDGFRB and FGFR1. In contrast, karyotyping will not identify certain chromosomal rearrangements (eg, FIP1L1-PDGFRA fusion, because the interstitial deletion is small, only 800 kb) or point mutations (eg, PDGFRA point mutations).
Depending upon the clinical presentation and the urgency to initiate therapy, investigations may be performed sequentially, starting with those that appear more likely to be informative. For example, if a patient presents with splenomegaly, mucosal ulcers of the oral cavity, and signs of heart failure, studies aimed at evaluating etiologies of M-HES (eg, assays related to the presence of the FIP1L1-PDGFRA fusion) are indicated. Ideally, diagnostic testing for myeloproliferative or lymphocytic etiologies for HES should be performed expeditiously prior to initiating clinically indicated HES therapies that might suppress cell populations necessary to ascertain etiologies of HES variants.
Diagnosis of HES subtypes
Diagnosis of myeloproliferative variants — Chronic eosinophilic leukemia (CEL)/M-HES are characterized by increased serum vitamin B12 levels, chromosomal abnormalities, anemia and/or thrombocytopenia, elevated serum tryptase, hepatomegaly, splenomegaly, and circulating leukocyte precursors (table 1). The above described hematologic evaluation may detect cytogenetic abnormalities in a subset of patients.
●In a large, retrospective, multicenter study, very high levels of vitamin B12 (>2000 picograms/mL) were a marker for the presence of the FIP1L1-PDGFRA fusion [9]. Elevations of serum tryptase were more frequent in FIP1L1-PDGFRA-positive M-HES, compared with patients without the mutation (82 versus 20 percent), and mean values were higher (31 versus 19 pg/mL).
●In another retrospective analysis of 44 patients with FIP1L1-PDGFRA-positive HES, the median age at diagnosis was 41 years, and all but one patient was an adult male [35]. Common laboratory findings included elevated vitamin B12 (82 percent), increased tryptase (78 percent), anemia (37 percent), thrombocytopenia (37 percent), and glucocorticoid resistance.
CEL is the result of an autonomous clonal proliferation of eosinophil precursors. Patients with CEL by definition do not demonstrate the Philadelphia chromosome or BCR-ABL fusion gene. As in other subtypes of HES, the peripheral blood demonstrates mature eosinophils with only a small number of eosinophilic myelocytes or promyelocytes. There may be a variety of morphologic abnormalities, including sparse granulation, cytoplasmic vacuolization, or hyper/hyposegmentation, but none of these changes are sensitive or specific for CEL. The bone marrow contains less than 20 percent blasts. The key criteria for making the diagnosis of CEL are the presence of a clonal cytogenetic or molecular genetic abnormality or blast cells that account for more than 2 or 5 percent of the peripheral blood or bone marrow, respectively [21,109].
The World Health Organization (WHO) classification system of hematopoietic and lymphoid tissues includes a special category for myeloid and lymphoid disorders with eosinophilia and abnormalities of PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 [110]. Such a diagnosis is made by the identification of genetic abnormalities in any of the following:
●Platelet-derived growth factor receptor alpha (eg, the FIP1L1-PDGFRA fusion)
●Platelet-derived growth factor receptor beta (PDGFRB) such as t(5;12)(q31-35;p13) [19]
●Fibroblast growth factor receptor 1 (FGFR1)
●Janus kinase 2 (JAK2), such as a PCM1-JAK2 fusion formed by t(8;9)(p22;p24)
Testing for FIP1L1-PDGFRA and JAK2 mutations can be performed on peripheral blood and are available commercially in the United States. Tests for the less common chromosomal fusion events including PDGFRB and FGFR1 are not commercially available, but karyotypes are usually abnormal in such cases.
The presence of an elevated serum tryptase concentration in the setting of myeloproliferative features may help to identify HES patients with the FIP1L1-PDGFRA fusion gene [79]. HES patients with elevated tryptase levels have increased numbers of mast cells on bone marrow biopsy, similar to patients with systemic mastocytosis (picture 2). In both conditions, these mast cells may be morphologically abnormal (ie, spindle-shaped), although peritrabecular clustering of mast cells is uncommon in PDGFRA-positive disease.
It is important to distinguish FIP1L1-PDGFRA-positive HES patients from those with systemic mastocytosis and eosinophilia due to a mutation in c-kit, because D816V, the most common c-kit mutation, is resistant to imatinib, the standard therapy for FIP1L1-PDGFRA-positive disease [13,111]. Cases with other c-kit mutations may respond to imatinib therapy. Both c-kit mutations and FIP1L1-PDGFRA may coexist in a subset of patients [112]. (See 'Differential diagnosis' below.)
Rare patients with clonal eosinophilia do exist who lack myeloproliferative features. Human androgen receptor analysis (HUMARA) can be used to demonstrate clonal populations of mature eosinophils in these patients. These X-linked analyses can only be performed on females [113,114].
Diagnosis of L-HES — T lymphocytic variants of HES (L-HES) often involve cutaneous signs and symptoms, although they can also present with cardiac, pulmonary, or neurologic events [108]. They are characterized by the following laboratory findings:
●Abnormal T cell surface markers – The most frequently encountered subset is CD3-CD4+, although CD3+CD4-CD8-, CD4+CD7-, and other populations of T cells have also been reported [14,15,49,115-117]. . In a subset of patients with CD3-CD4+ T cell associated disease, the proportion of aberrant cells in peripheral blood is very low (<2percent), making detection by routine flow cytometry challenging. When possible, further analysis of membrane-expressed markers including CD2, CD5, and CD45RO allows a more sensitive and accurate diagnosis of this variant (higher intensity staining for CD2 and CD5 compared to normal CD4 T cells, and positivity for CD45RO). A literature review of published cases of L-HES and 2 large cohort studies confirmed that the frequency of cutaneous manifestations was especially high among patients with a CD3-CD4+ T cell [45,46,118]. Routine analyses, even multiparameter flow cytometry of CD3, CD4, and CD8 expression on lymphocytes, have not been sufficient to detect all phenotypes. In some patients with no phenotypic abnormalities on flow cytometry, clonal populations of T cells can be identified by polymerase chain reaction (PCR). However, the significance of a clonal population of T cells found by PCR alone, in the absence of abnormalities on flow cytometry, is unknown, and the diagnosis of L-HES should not be made in this situation, without some of the additional findings described below. (See 'Skin disease' above.)
●T cell clonality – Clonality of phenotypically aberrant T cells has been demonstrated in many cases through analysis of T cell receptor gene rearrangement patterns. T cell receptor studies should be performed, although demonstration of T cell clonality is not sufficient to define L-HES.
●Cytogenetic studies – Conventional chromosomal karyotypes are generally normal, although rare cases with 16q breakage, partial 6q or 10p deletions, and trisomy 7 have been reported [117,119].
●Increased serum IgE and polyclonal hypergammaglobulinemia – The abnormal T cells in this variant produce T helper type 2 (Th2) cytokines, leading to increased immunoglobulin E (IgE) synthesis and polyclonal hypergammaglobulinemia [49]. Serum IgE and gammaglobulin levels should be determined, although increases are neither necessary nor specific for diagnosis of L-HES [108].
●EBV infection – The development of L-HES may also be driven by chronic active Epstein-Barr virus (EBV) infection, in which eosinophilopoietic cytokines are produced by an infected T cell clone [120]. The authors routinely measure EBV DNA levels with quantitative PCR assays on blood or plasma in patients presenting with eosinophilia and a T cell clone.
●Investigational tests – Elevations in serum thymus and activation-regulated chemokine (TARC) and abnormally high production of interleukin-5 (IL-5) by T cells in vitro are other abnormalities that have been reported in some patients with L-HES [9,121,122]. However, these tests are not routinely available through commercial laboratories, are costly, and can be difficult to interpret because normal values are not well-established.
Diagnosis of familial HES — All patients should be queried about a family history of eosinophilia and/or endomyocardial fibrosis. However, routine testing of family members is of low yield and should only be performed if there is a suggestive family history or patient concern.
Diagnosis of organ-restricted HES — Organ-restricted hypereosinophilic conditions are defined as single organ involvement together with eosinophilia >1.5 x 109/L or lower levels of blood eosinophilia with clear-cut organ involvement. (See 'Organ-restricted hypereosinophilic conditions' above.)
Diagnosis of specific defined syndromes associated with HE — Overlap syndromes and associated forms of HES are described above. (See 'Specific/defined syndromes associated with HE' above.)
Diagnosis of hypereosinophilia of undetermined significance — The diagnosis of hypereosinophilia of undetermined significance (HEUS) is a diagnosis of exclusion and thus involves the same studies described for HES. HE is usually detected on routine complete blood count or as part of an evaluation for transient symptoms that do not prove to be related to eosinophilia, and patients must have no apparent organ damage or dysfunction. Available data regarding these patients suggests that there are no laboratory features that clearly distinguish this disorder from HES or that predict progression to HES [74,121].
In a retrospective series of 40 patients with HEUS, from a single center, mean age at diagnosis was 61 (range 17 to 85) and median follow-up was 55 months (range 6 months to 19 years) [74]. Median absolute eosinophil count (AEC) was 4.2 x 109/L (range 1.5 to 55.4 x 109/L). One-half of patients had a leukocytosis at the time of diagnosis (mean 11.2 x 109/L) and 65 percent had increased serum IgE levels (mean 528 int. units/mL, range 12 to 4089 int. units/mL). One patient had elevated serum B12 levels. One patient developed cardiac complications that responded to glucocorticoid therapy after 11 years of monitoring.
Another series described eight patients with HEUS followed for at least five years on no therapy and compared them with patients with symptomatic HES and with normal controls [121]. Geometric mean peak AEC was 3.9 x 109/L and 5.1 x 109/L in patients with HEUS and HES, respectively, and not statistically different. The AEC decreased over time in six patients and normalized in one after eight years. Markers of eosinophil activation were not different between patients with HEUS and HES. The only statistically significant difference observed between patients with HEUS and HES was the serum IgE level (98 versus 625 U/mL), indicating that increased IgE may be a predictive marker for development of eosinophil-mediated complications. However, this requires validation in a prospective study.
DIFFERENTIAL DIAGNOSIS — A variety of conditions can be associated with secondary blood or tissue eosinophilia and clinical manifestations of hypereosinophilic syndromes (HES), including leukemias and lymphomas, paraneoplastic syndromes, KIT mutation-associated systemic mastocytosis with eosinophilia, drug hypersensitivity reactions, and helminth infections. These are important to diagnose, as treatment should be directed at the underlying cause rather than the eosinophilia itself. (See "Approach to the patient with unexplained eosinophilia".)
The relationships among HES, acute leukemias, chronic eosinophilic leukemias (CEL), and myelodysplastic syndromes continue to be refined [19,31,111,123,124]. Patients with HES can develop T cell lymphomas or acute lymphoblastic leukemia [45,111], and patients with acute lymphocytic leukemia (ALL), especially those with pre-B cell ALL, can present clinically with HES, although molecular evidence of a clonal B lymphocyte population can usually be detected at presentation [111,125].
Acute eosinophilic leukemia — Acute eosinophilic leukemia may be distinguished from other forms of HES by the marked increase in the number of immature eosinophils in the blood and/or marrow, the finding of greater than 10 percent blast forms in the marrow, infiltration of tissues (including the central nervous system and bones) with immature eosinophil forms, and a clinical course similar to other acute leukemias, with pronounced anemia, thrombocytopenia, and susceptibility to infection. Cardiac and neurologic complications can develop in acute eosinophilic leukemia. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)
Chronic myeloid or myelomonocytic leukemia — Patients with chronic myeloid leukemia (CML) or chronic myelomonocytic leukemia (CMML) may demonstrate an absolute eosinophilia, although clinical complications due to the eosinophilia are relatively uncommon. CML can be identified by the detection of BCR::ABL fusion mRNA, the BCR::ABL1 protein, or the Philadelphia chromosome. CMML has a peripheral blood monocytosis and characteristic findings on bone marrow examination. Other myeloproliferative/myelodysplastic neoplasms involve a translocation between chromosomes 5 and 12, leading to autonomous tyrosine kinase activity of platelet-derived growth factor receptor beta (PDGFRB). (See "Clinical manifestations and diagnosis of chronic myeloid leukemia" and "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis", section on 'Diagnosis' and "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'Diagnosis and classification'.)
Systemic mastocytosis with eosinophilia — Systemic mastocytosis with eosinophilia can be confused with Fip1-like1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA)-associated disease [79]. However, systemic mastocytosis is usually associated with D816V mutations in the KIT gene. Systemic mastocytosis is characterized clinically by approximately equal sex distribution, a characteristic skin rash (urticaria pigmentosa) in more indolent forms, and prominent gastrointestinal symptoms. In contrast, HES (with the FIP1L1-PDGFRA mutation) demonstrates a male predominance and is associated with heart failure and restrictive pulmonary disease [126].
Aside from mutational analysis, the two disorders are most reliably distinguished by the ratio of absolute eosinophil count (AEC) to serum total tryptase (AEC/tryptase), which is >100 in HES with FIP1L1-PDGFRA mutation, and <100 in systemic mastocytosis with eosinophilia [126]. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)
SUMMARY AND RECOMMENDATIONS
●Definitions – The hypereosinophilic syndromes (HES) are disorders marked by the sustained overproduction of eosinophils, associated with damage to one or more organs due to eosinophilic infiltration and mediator release.
•Hypereosinophilia (HE) in peripheral blood is defined as an absolute eosinophil count (AEC) >1.5 x 109/L (or >1500 cells/microL) on two examinations (at least one month apart) and/or tissue HE defined by any of the following (see 'Hypereosinophilia' above):
-The percentage of eosinophils in a bone marrow section exceeds 20 percent of all nucleated cells, and/or
-A pathologist is of the opinion that tissue infiltration by eosinophils is extensive, and/or
-Marked deposition of eosinophil granule proteins is found (in the absence or presence of major tissue infiltration by eosinophils).
•HES are defined as the association of HE (as defined above), with eosinophil-mediated organ damage and/or dysfunction, in which other potential causes for the damage have been excluded. (See 'Hypereosinophilic syndrome' above.)
●Epidemiology – The HES are most common in patients 20 to 50 years of age, with the exception of common underlying causes of HE that can occur at any age (parasitic infection, drug allergy, neoplastic disease). The Fip1-like1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA)-associated variant affects mostly males, whereas other variants appear to affect males and females in roughly equal proportions. (See 'Epidemiology' above.)
●Pathophysiology – HES are characterized by overproduction of eosinophils, which results either from clonal proliferation or from overproduction of eosinophilopoietic cytokines, such as interleukin 5 (IL-5). (See 'Pathophysiology' above.)
●HES variants
•Important clinically-relevant subtypes, in which underlying molecular or immunologic defects can be identified, include myeloproliferative variants, T cell lymphocytic variants, and familial eosinophilia (table 1). Together, these represent 20 to 30 percent of cases. These subtypes are associated with a more clearly defined clinical presentation and prognosis, and, in the case of the FIP1L1-PDGFRA-associated myeloproliferative variant, response to specific therapies. (See 'HES variants' above.)
•The majority of patients do not have an identifiable etiology and are therefore classified as "idiopathic hypereosinophilic syndrome" (IHES). In these patients, HES may be difficult to distinguish from other eosinophil-associated disorders, including eosinophilic granulomatosis with polyangiitis (EGPA). (See 'Idiopathic HES' above.)
●Hypereosinophilia of undetermined significance – HEUS describes patients with persistent unexplained HE, but without apparent complications related to tissue eosinophilia. This terminology highlights both the lack of an explanation for HE and the inability to predict whether the patient will eventually develop clinical manifestations related to eosinophilic organ infiltration, and thus progress to HES. (See 'Hypereosinophilia of undetermined significance' above.)
●Clinical features – The signs and symptoms of HES result from the overproduction of eosinophils that infiltrate and damage various tissues. The organ systems most commonly affected in HES are the skin, lungs, gastrointestinal tract, heart, and nervous system. In many patients, the onset of symptoms is insidious and eosinophilia may even be detected incidentally. In a minority, the initial manifestations are severe and life-threatening due to the rapid evolution of cardiovascular or neurologic complications. (See 'Clinical features' above.)
●Evaluation and diagnosis – The diagnosis of HES should be considered in patients with sustained blood eosinophilia of >1.5 x 109/L, documented on at least two occasions, or evidence of tissue HE. Once secondary causes of eosinophilia that require therapy directed at the underlying cause are excluded (eg, helminth infection, drug hypersensitivity, and neoplastic disease), patients with persistent eosinophilia should be evaluated accordingly, regardless of the presence or absence of symptoms. This evaluation involves an assessment of end-organ involvement as well as specialized studies to identify patients with myeloproliferative or clonal lymphocytic variants. (See 'Evaluation and diagnosis' above.)
