HypereosinophilicSyndromes.
Mónica De Gennaro, MD
The hypereosinophilic syndrome (HES) is characterized by the presence of marked unexplained blood and tissue eosinophilia associated with a variety of clinical manifestations.
Our understanding of these diseases has drastically changed over the past 15 years, along with new classifications that characterize patients with marked eosinophilia. The hypereosinophilic syndromes (HES) encompass a spectrum of diseases that have increased blood eosinophils and tissue damage in common. The clinical manifestations are protean and may involve any organ system, but especially the skin.The concept of hypereosinophilic syndromes (HES) was proposed by Hardy and Anderson (1968). Because of the absence of immature eosinophils, they speculated that the disease was driven by an underlying hypersensitivity mechanism.
HES was defined by Chusid et al (1975) who proposed three diagnostic criteria:
Peripheral blood eosinophilia with absolute eosinophil count greater than 1500 cells/mL, sustained for more than 6 months (or death before 6 months associated with signs and symptoms of hypereosinophilic disease).
Lack of evidence for parasitic, allergic or other known causes of eosinophilia.
presumptive signs of organ involvement, such as heart failure, gastrointestinal dysfunction, central nervous system abnormalities, fever, or weight loss
The 6-month time requirement helped exclude short-term episodes of eosinophilia, as exemplified by adverse reactions to medications; however, in the current decade, patients can be considered to have HES without waiting for the 6-month time requirement if the second and third criteria are clearly met and they appear to have a chronic and unremitting clinical course.Patients with marked eosinophilia and obvious tissue damage, for example cardiac involvement, should not be observed for 6 months before diagnosis and vigorous therapy is initiated.The accepted threshold for blood eosinophilia excludes patients with increased numbers of activated eosinophils in tissues unaccompanied by marked blood eosinophilia, although the pathophysiology in such patients is likely similar to those with peripheral eosinophilia >1500/mm3.For example, patients with a wide variety of disorders, including eosinophilic pneumonia, eosinophil- associated gastrointestinal disorders (EGID), Churg- Strauss syndrome (CSS), nasal polyposis with bronchial asthma, and eosinophilic dermatitis (Wells syndrome), may fulfill all HES criteria except for blood eosinophil levels, yet are not classified as HES.Conversely, some patients with blood eosinophilia >1500/mm3 do not exhibit signs of eosinophil-mediated organ damage such as in asthma or allergic rhinitis, for which the relationship to the eosinophilia is unclear.
Clinical presentation:
Men are affected more often than women and are the predominant gender in the myeloproliferative variant.
Age of diagnosis often falling between 20 and 50
Clinical features can vary from patient to patient.
HES presents with blood, heart, nervous system, lung and, especially, skin involvement
Endocardial clot formation often leads to valve dysfunction,
reduced cardiac output and embolization to brain, viscera and limbs.
Evidence of splinter haemorrhages can alert the clinician to
ongoing embolization. This situation should be considered a medical emergency and aggressively treated.
Hypereosinophilic syndromes may present with cutaneous abnormalities. The common patterns of cutaneous involvement are quite prevalent in L-HES variants.
Over 50% of patients have skin lesions of the trunk and/or extremities as the first manifestation of HES, including pruritic erythematous macules, papules, plaques, wheals and nodules. Urticaria and angioedema occur in all HES subtypes and are characteristic of lymphocytic HES. Mucosal ulcers may characterize myeloproliferative HES. A diagnosis of HES may be delayed or missed because an association between skin findings and HES is not appreciated.
Hematologic manifestations:Eosinophilia of greater than 1500/uL is present by definition.Peripheral eosinophils are generally mature, but eosinophilic myeloid precursors can occasionally be seen. In some cases of HES, morphologic abnormalities of the eosinophils can be seen at the gross and ultrastructural levels.Any cytogenetic or molecular evidence of eosinophil clonality indicates a diagnosis of chronic eosinophilic leukemia (CEL). Blasts may or may not be seen on the peripheral smear in CEL.Splenomegaly can be seen in HES, and hypersplenism may lead to anemia and thrombocytopenia . When the spleen is involved, it can be painful .Thrombocytosis and anemia have been reported .Bone marrow biopsy often shows increased eosinophils and eosinophil precursors.The cardiac involvement that can sometimes accompany HES is often themost concerning to both clinicians and patients because it has been, at leastin the past, the feature that is associated most often with clinical morbidityand mortality . M-HES variants are associated with a higher prevalence of cardiac findings.Nonspecific constitutional symptoms can be seen asa part of HES: The National Institutes of Health case series reported fatigue,fever cough breathlessness , muscle pains, angioedema , rash, and retinal lesions.
Lung involvement:It can be variable. The most common feature is a chronic, nonproductive cough with a normal chest radiograph.Asthma-like wheezing is not common in true HES, and its presence raisesthe suspicion of Churg-Strauss syndrome as the diagnosis. Overall, pulmonary symptoms can range from mild to severe, and can include development of restrictive or obstructive lung disease and even adult respiratory distress syndrome. Gastrointestinal involvement including hepatic manifestations: Eosinophilic esophagitis, gastritis, enteritis, or colitis can occur in anycombination as part of HES, or can be considered separate entities from HES if they occur in isolation without meeting the criteria for HES . Specific hepatic involvement can occur, including a chronic, active, hepatitis-like picture, and hepatic vein obstruction leading to Budd-Chiari syndrome.Ocular symptoms such as blurry vision can occur in HES, and arethought to be caused by microembolic phenomena or local microthrombosis .
Rheumatologic/connective tissue involvement
Although not among the more common HES findings, arthralgias, arthritis, effusions of the large joints, and Raynaud’s phenomenon have been reported with HES . Raynaud’s phenomenon can be so severe that digital necrosis can occur. Although myalgias can occur quite commonly in HES along with other constitutional/systemic symptoms , focal myositis or diffuse myositis (polymyositis) is rare.
Classification: The Hypereosinophilic Diseases Working Group of the International Eosinophil Society proposed this classification
It is difficult to classify patients on the basis of etiology.
Organ-restricted hypereosinophilic disorders when accompanied by blood eosinophilia >1500/mm3 as well as CSS and isolated blood eosinophilia >1500/mm3 were included in the new classification scheme of HESs. It was concluded that all patients with blood eosinophilia >1500/mm3 without a secondary cause (eg, allergic diseases, drug hypersensitivity, parasitic helminth infections, HIV infection, nonhematologic malignancies)should be considered to have HES or a disorder that overlaps in definition with HES, regardless of the number and nature of affected organs or potential pathogenic mechanisms.
In the lymphocytic forms of HES, lymphocytes generate increased amounts of at least 1 eosinophil hematopoietin (IL-3 and/or IL-5)
Many patients classified as having undefined, overlapping, or associated HES forms likely have a lymphocytic form. This is exemplified by the case of episodic angioedema and eosinophilia, currently classified under undefined HES in which cyclic elevations in IL-5 levels precede the episodic eosinophilia and clinical symptoms and appearance of a detectable IL-5–secreting clone
Similarly, lymphocytic overexpression of IL-5 has been demonstrated in a number of organ-restricted eosinophilic disorders, including eosinophilic pneumonia, eosinophilic intrinsic asthma, CSS, eosinophilic sinus disease, eosinophilic dermatitis, and. eosinophil-associated gastrointestinal disorder (EGID), suggesting that they may also represent T cell–driven HES
Clearly, there is a considerable overlap between myeloproliferative forms of HES and chronic eosinophilic leukemia (CEL), and many patients, including those with detectable FIP1L1/ PDGFRA fusion genes, fulfill the current WHO criteria for CEL
Patients are classified as having one of the myeloproliferative forms of HES if they have clinical (hepatomegaly, splenomegaly), laboratory (circulating myeloid precursors, increased serum vitamin B12 or tryptase, anemia, thrombocytopenia), hematologic (myeloid fibrosis, left shift in maturation of myeloid precursors), and/or cytogenetic abnormalities suggestive of myeloproliferative disease.
The identification of the FIP1L1/PDGFRA mutation in a subset of patients meeting diagnostic criteria for the myeloproliferative form of HES provides a diagnostic marker that predicts poor prognosis with a high prevalence of tissue fibrosis and a therapeutic response to tyrosine kinase inhibitors with activity against PDGFRA.
The classification scheme proposed in 2006 was based predominantly on clinical phenotype and included the following categories: myeloproliferative, lymphocytic, familial,idiopathic, overlap (blood eosinophilia >1500/mm3 in the setting of single organ involvement), and associated (blood eosinophilia
>1500/mm3 in association with a second diagnosis, such as inflammatory bowel disease or autoimmune lymphoproliferativedisorder, in which eosinophilia has been reported with increasedfrequency but rarely leads to end organ manifestations).Although this scheme has been helpful in the managementand predicting prognosis for some patients, the majority of casesfall under the ‘‘idiopathic’’ heading, meaning that pathogenesis
and disease course, remain unknown.
Some early studies of HES patients found that T-cell clones from the patients’peripheral blood displayed eosinophilopoietic activity. Thisfinding led to the idea that an abnormal T-cell population could be the drivingfactor in some patients who have HES, with recruitment of eosinophilsbeing a secondary process. The finding of elevated immunoglobulin (Ig)E. in some patients who had HES separately suggested that some HES casesmay be driven by a Th-2 process. In 1994, a patient who had HES wasdescribed who was found to have a clonal T-cell population that secretedelevated IL-5 levels. Since then, about 40 such patients who had identifiableclonal T-cell populations that can secrete IL-5 have been described inthe literature. Such patients, in whom a clonal lymphocyte populationcan be identified (by flow cytometry or reverse transcriptase polymerase
chain reaction [RT-PCR] for T-cell receptor (TCR) usage), are defined ashaving L-HES subtypes.
Lymphocytic variant HES (L-HES): It is characterized by polyclonal eosinophil expansion in response to marked overproduction of IL-5 by deregulated T cells in vivo. These T cells can be detected on the basis of abnormal surface phenotypes, including CD32CD41 and CD31CD42CD82, and are sometimes monoclonal.Published case reports indicate that these T-cell clonesmight be prone to malignant transformation (T-cell lymphoma).Clinically, patients often present with predominant cutaneous manifestations, although other organs can be targeted as well; increased serum IgE levels; and hypergammaglobulinemia.
Characteristic clinical features of the myeloproliferative
variant
Affects males predominantly, Often FIP1L1-PDGFRa fusion gene mutation positive. Dysplastic eosinophils on peripheral smear. Elevated serum B12- Elevated serum tryptase.Anemia or thrombocytopenia. Myelofibrosis
Hepatosplenomegaly.Increased bone marrow cellularity.
Atypical/spindle-shaped mast cells in bone marrow
Frequently responds to imatinib
Endomyocardial damage/necrosis
Cardiac intramural thrombi and endomyocardial fibrosis
A familial form of HES appears to be a very rare entity. A five-generation kindred with eosinophilia that follows an autosomal dominant pattern has been described. The affected members have chronic high peripheral blood eosinophil counts, yet most remain fairly asymptomatic. It has been suggested that familial eosinophilia can be differentiated from HES by a more benign clinical course that may be related to a relative lack of eosinophil activation.The overlap category is intended to capture cases that do not accurately fit the criteria for HES, but rather, have an apparent restriction of tissuespecific eosinophilia to specific organs. This category includes the EGIDs (including eosinophilic esophagitis and gastroenteritis), eosinophilic pneumonia, and eosinophilia-myalgia syndrome .The associated category is intended to capture cases of peripheral eosinophilia that can occur in association with other defined diagnoses, such asChurg-Strauss syndrome, systemic mastocytosis, inflammatory bowel disease, sarcoidosis, and human immunodeficiency virus (HIV).The last category is the undefined category . Cases of unexplained eosinophiliathat do not meet the three key criteria of HES, but also do notmeet the other miscellaneous categories described can be classified undereither benign or episodic. Benign cases include patients who have chronicperipheral eosinophilia greater than 1500/uL, but no specific organ involvement.Such patients may have long-lasting chronic peripheral blood eosinophilia(in some cases very high counts) and may never develop any organinvolvement or problematic symptom. However, in some cases, organ involvementmay develop later in a patient who initially appeared to haveonly benign peripheral blood eosinophilia. For this reason, such patientsare still included as undefined, despite not meeting Chusid’s criteria. Patients who have the episodicangioedema with eosinophilia syndrome (Gleich’s syndrome) would fitunder the episodic classification.Gleich’s syndrome is characterized by intermittent episodes of peripheral blood eosinophilia, accompanied by angioedema. In between episodes,the patients are usually asymptomatic, with normal or mildly elevated eosinophil counts.The clinical features of these with complex HEShave not been specifically compiled, but the disease manifestations can be diverse. Also, the frequency of cases that meet the definition of complex HES in comparison to M-HES and L-HES has not been specifically reported but, these undefined complex HES patients likely represent most patients who have HES.Further study of this patient group is clearly needed.
Long-term prognosis and life expectancy:the clinical course and long-term prognosis in these patients is also highly variable, ranging from minimal symptoms, requiring little-to-no treatment,to severe disabling disease, leading to either directly related mortality, or, perhaps, transformation to leukemia or lymphoma, with subsequent morbidity or mortality. The bad outcomes reported in older case series were often related to issues secondary to severe organ damage (particularly cardiac) or transformation to myelogenous or lymphoid malignancy. M-HES patients can transform to acute myeloid leukemia, including those with the FIP1L1-PDGFRa mutation.LHES patients are not necessarily free of worry because these cases may eventually progress to T-cell lymphoma. HES mortality and survival rates seem to be improving. Chusid and colleagues originally reported a 12% 3-year survival rate in 1975, whereasFauci and colleagues [9] reported a 70% 10-year survival rate in 1982, and Lefebvre reported an 80%5-year survival and 42% 15-year survival in 1989 .More recent survival statistics are not available, but are likely to be betterwith the new medication options and faster diagnosis of cases.