Hypereosinophilic Syndrome

Updated: Jan 25, 2017
  • Author: Venkata Anuradha Samavedi, MBBS, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Background

Hypereosinophilic syndrome (HES) is a myeloproliferative disorder (MPD) characterized by persistent eosinophilia that is associated with damage to multiple organs. [1, 2, 3, 4, 5, 6, 7] Peripheral eosinophilia with tissue damage has been noted for approximately 80 years, but Hardy and Anderson first described the specific syndrome in 1968. [8] In 1975, Chusid et al defined the three features required for a diagnosis of hypereosinophilic syndrome [4] :

  • A sustained absolute eosinophil count (AEC) greater than >1500/µl, which persists for longer than 6 months
  • No identifiable etiology for eosinophilia
  • Signs and symptoms of organ involvement

However, due to advances in the diagnostic techniques, secondary causes of eosinophilia can be identified in a proportion of cases that would have otherwise been classified as idiopathic hypereosinophilic syndrome.

The differential diagnosis (see DDx) of hypereosinophilic syndrome includes other causes of eosinophilia, [1, 9, 10, 11] which may be classified as familial or acquired. Familial eosinophilia is an autosomal dominant disorder with a stable eosinophil count and a benign clinical course. Acquired eosinophilia is further divided into secondary, clonal, and idiopathic eosinophilia. [12]

Secondary eosinophilia

Secondary eosinophilia is a cytokine-derived (interleukin-5 [IL-5]) reactive phenomenon. Worldwide, parasitic diseases are the most common cause, whereas in developed countries, allergic diseases are the most common cause. [1] Other causes include the following:

Clonal eosinophilia

Clonal eosinophilia is diagnosed by bone marrow histology, cytogenetics, and molecular genetics. Causes include the following:

  • Acute leukemia – Pre-B acute lymphoblastic leukemia (ALL), acute myeloid leukemia M4 with bone marrow eosinophilia (AML-M4Eo)
  • Chronic myeloid disorders

Molecularly defined disorders include the following:

  • BCR-ABL chronic myeloid leukemia
  • PDGFRA (platelet-derived growth factor receptor, alpha polypeptide)–rearranged eosinophilia – Systemic mastocytosis–chronic eosinophilic leukemia (SM-CEL)
  • PDGFRβ-rearranged eosinophilia
  • KIT-mutated systemic mastocytosis

Clinicopathologically assigned disorders include the following:

  • Myelodysplastic syndrome (MDS)
  • Myeloproliferative disorders (MPDs) – Classic MPD ( polycythemia) and atypical MPD (chronic eosinophilic leukemia, systemic mastocytosis, chronic myelomonocytic leukemia)

Idiopathic eosinophilia

Idiopathic eosinophilia is a diagnosis of exclusion when secondary and clonal causes of eosinophilia are excluded. Hypereosinophilic syndrome is a subset of idiopathic eosinophilia characterized by persistent eosinophilia (AEC >1500/µL) of longer than 6 months' duration associated with organ damage. However, long-term follow-up and X-linked clonality studies indicate that at least some patients with hypereosinophilic syndrome have an underlying clonal myeloid malignancy or a clonal or phenotypically abnormal T-cell population, suggesting a true secondary process.

The literature now favors the view that cases of idiopathic hypereosinophilic syndrome with FIP1L1 indeed represent chronic eosinophilic leukemia, because these patients have a molecular genetic abnormality, specifically an FIP1L1–PDGFRA fusion gene. [15] In addition, there are documented cases of acute transformation to either AML or granulocytic sarcoma in some cases of hypereosinophilic syndrome after an interval as long as 24 years. In such cases, a diagnosis of chronic eosinophilic leukemia is made in retrospect when acute transformation provides indirect evidence that the condition was likely to have been a clonal, neoplastic, MPD from the beginning.

In addition, some patients with hypereosinophilic syndrome present with features typical of MPDs, such as hepatosplenomegaly, the presence of leukocyte precursors in the peripheral blood, increased alkaline phosphatase level, chromosomal abnormalities, and reticulin fibrosis. Cytogenetic studies in such cases may be normal, but molecular genetic studies may show aberrations.

The best-described aberration is the interstitial deletion on chromosome 4q12, resulting in fusion of the 5’ portion of the FIP1L1 gene to the 3’ portion of the PDGFRA gene. This fusion gene encodes for the FIP1L1–PDGFR alpha protein, the constitutively activated tyrosine kinase activity that induces eosinophilia. The prevalence of such a mutation is 0.4% in unselected cases of eosinophilia, but it can be as high as 12–88% in cohorts that meet the World Health Organization (WHO) criteria for idiopathic hypereosinophilic syndrome, particularly those with features of MPD (increased levels of tryptase and mast cells in the bone marrow).

Patients with hypereosinophilic syndrome with the PDGFRA mutation have a very high incidence of cardiac involvement and carry a poor prognosis without therapy. Fortunately, the results of imatinib therapy in such cases of hypereosinophilic syndrome are very encouraging.

The other subset of idiopathic eosinophilia, hypereosinophilic syndrome with clonal or immunophenotypically aberrant T-cells, is associated with increased secretion of IL-5 and cutaneous manifestations. Simon et al reported immunophenotypic abnormality in 16 of 60 patients with hypereosinophilic syndrome. [16] Moreover, nine patients had CD3+CD4+CD8- T cells, three had CD3+CD4-CD8+ cells, three had CD3+CD4-CD8- cells, and two had CD3-CD4+ cells (one patient had two distinct populations). Progression to T-cell lymphoma was observed in this subset of patients with hypereosinophilic syndrome, particularly those with the CD3-CD4+ phenotypes. [16, 17]

Chronic eosinophilic leukemia

Chronic eosinophilic leukemia is caused by autonomous proliferation of clonal eosinophilic precursors. Simplified criteria for the diagnosis of chronic eosinophilic leukemia include the following:

  • Eosinophil count of at least 1500/µL
  • Peripheral blood blast count of >2% and a bone marrow blast cell count that is >5% but <19% of all nucleated cells
  • Criteria for atypical chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia, and chronic granulocytic leukemia ( BCR-ABL–positive CML) are not met
  • Myeloid cells are demonstrated to be clonal (eg, by detection of clonal cytogenetic abnormality or by demonstration of a very skewed expression of X chromosome genes)

Some of the cytogenetic abnormalities that have been described in chronic eosinophilic leukemia include t(5:12) and t(8:13), and molecular genetic abnormalities include the FIP1L1-PDGFRA fusion gene and ETV6-PDGFRβ.

Other resources

Other sources of information are as follows:

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Pathophysiology

Eosinophil production is governed by several cytokines, including IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). IL-5 appears to be the most important cytokine that is responsible for differentiation of the eosinophil line. [2, 9]

Unlike neutrophils, eosinophils can survive in the tissues for weeks. Their survival in tissues depends on the sustained presence of cytokines. Only eosinophils and basophils and their precursors have receptors for IL-3, IL-5, and GM-CSF. In vitro, eosinophils survive less than 48 hours in the absence of cytokines.

Eosinophil granules contain toxic cationic proteins, which are the primary mediators of tissue damage. These toxins include major basic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, and eosinophil cationic protein. The latter two are ribonucleases. Free radicals produced by the eosinophilic peroxidase and the respiratory burst oxidative pathway of the infiltrating eosinophils further enhance the damage.

Eosinophils amplify the inflammatory cascade by secreting chemoattractants that recruit more eosinophils. Such chemoattractants include the following:

  • Eotaxin
  • Platelet-activating factor
  • The cytokine RANTES (regulated upon activation, normal T cell expressed, and secreted).

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.

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Epidemiology

Frequency

Various sources indicate that true hypereosinophilic syndrome is rare. The most common cause of eosinophilia in the United States is an allergic reaction or allergic disease. Worldwide, the most common cause of eosinophilia is parasitosis. [18]

Mortality/Morbidity

Hypereosinophilic syndrome is a chronic and progressive disorder that is potentially fatal. Blast transformation could occur after many years. True idiopathic hypereosinophilic syndrome is generally indolent, but patients with characteristics suggestive of a myeloproliferative/neoplastic disorder and those who develop chronic heart failure have a worse prognosis.

An older review of 57 patients with advanced hypereosinophilic syndrome reported a mean survival of 9 months and a 3-year survival rate of 12%. [4] A later analysis from France noted an 80% survival at 5 years and a 42% survival at 15 years among 40 patients with hypereosinophilic syndrome. [19]

Race-, Sex- and Age-related Demographics

No racial predilection is reported for hypereosinophilic syndrome. There is a male predominance in hypereosinophilic syndrome, with a male-to-female ratio of 9:1.

Hypereosinophilic syndrome is most commonly diagnosed in patients aged 20-50 years, with a peak incidence in the fourth decade. Hypereosinophilic syndrome is rare in children. The incidence of hypereosinophilic syndrome seems to decrease in the elderly population.

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