Excerpt from Hypereosinophilic Syndrome

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Background

Hypereosinophilic syndrome (HES) encompasses a wide range of clinical manifestations sharing 3 features defined by Chusid et al¹: (1) a peripheral eosinophil count of greater than 1.5 X 10⁹/L for longer than 6 months; (2) evidence of organ involvement, thus excluding benign eosinophilia; and (3) an absence of other causes of eosinophilia, such as parasite infestation (most common cause of eosinophilia worldwide), allergy (most common cause of eosinophilia in the United States), malignancy, and collagen-vascular disease.

The eMedicine Pediatric article Hypereosinophilic Syndrome and the Hematology article Hypereosinophilic Syndrome may be of interest. Additionally, see the Medscape Heart Failure Resource Center and the Cardiometabolic Risk Factor Management Resource Center.

Pathophysiology

HES etiology can involve (1) primitive involvement of myeloid cells, essentially due to the occurrence of an interstitial chromosomal deletion on band 4q12 leading to the creation of the FIP1L1-PDGFRA fusion gene (F/P⁺ variant), or (2) increased interleukin (IL)–5 production by a clonally expanded T-cell population (lymphocytic variant), most frequently characterized by a CD3^-CD4⁺ phenotype.²

Multiple cytokines stimulate eosinophil production, including IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5.³ In 3 patients with T-cell lymphomas, eosinophilia has been correlated with increased production of these cytokines by the lymphomas. IL-3 and GM-CSF act on other bone marrow–derived lineages, whereas the stimulatory activity of IL-5 appears to be limited to eosinophils and thus suggests it to be the dominant factor in eosinophil proliferation. At present, the source of IL-5 in HES has not been definitively determined, but evidence points to increased production by CD4⁺ T-lymphocyte clones.

However, IL-5 mRNA and protein have been found in eosinophils; therefore, the increase in this cytokine cannot be attributed merely to T cells. Also, because some patients with HES have concomitant neutrophilia, factors other than IL-5 are likely involved. GM-CSF and IL-3 have been shown to be produced by eosinophils, and GM-CSF production was demonstrated in the T-cell clones from patients with HES.

Eosinophils in HES infiltrate multiple organs where they inflict tissue damage through the release of granule proteins, including eosinophil peroxidase, major basic protein, eosinophil-derived neurotoxin, and eosinophil cationic protein. They also release proinflammatory cytokines (ie, interleukin 1 alpha, tumor necrosis factor–alpha, interleukin 6, interleukin 8, IL-3, IL-5, GM-CSF, macrophage inflammatory protein), which attract more eosinophils and other inflammatory cells to the area. Cardiac involvement is the most common cause of mortality in HES. In the heart, the infiltration by eosinophils results in endomyocardial fibrosis, with subsequent development of congestive heart failure (CHF) and death. This infiltration is necessary for tissue damage to occur because patients with peripheral eosinophilia due to other causes (eg, eosinophilic pneumonia) do not develop pathology similar to HES.

Fip1-like1-platelet-derived growth factor receptor alpha chain (FIP1L1-PDGFRA) mutation has been described in adult patients with HES. Specifically, a novel oncogenic mutation (FIP1L1-PDGFRA), which results in a constitutively activated platelet-derived growth factor receptor-alpha (PDGFRA), has been invariably associated with a primary eosinophilic disorder.

Pardanani et al⁴ examined both the prevalence and the associated clinicopathologic features of the mutation in FIP1L1-PDGFRA in 89 adults presenting with an absolute eosinophil count of higher than 1.5 X 10⁹/L. Pardanani and his team⁴ used a fluorescence in situ hybridization–based strategy to identify FIP1L1-PDGFRA in bone marrow cells. None of 8 patients with reactive eosinophilia demonstrated defects in FIP1L1-PDGFRA, whereas the rate of FIP1L1-PDGFRA in the remaining 81 patients with primary eosinophilia was 14% (11 patients). None (0%) of 57 patients with HES but 10 (56%) of 19 patients with systemic mast cell disease associated with eosinophilia (SMCD-eos) carried the mutated FIP1L1-PDGFRA. Thus, it seems FIP1L1-PDGFRA is not solely responsible for HES. However, a 40% partial response rate was observed in 10 HES cases after treatment with imatinib.

McPherson et al⁵ reported a 33-year-old man with recurrent papular skin lesions and marked peripheral eosinophilia whose skin histopathology showed a proliferation of CD30⁺ T cells consistent with lymphomatoid papulosis and in whom molecular analysis of peripheral blood mononuclear cells demonstrated the presence of the FIP1L1/PDGFRA fusion gene.

Frequency

United States

The exact incidence of HES is hard to determine because it is a diagnosis of exclusion. It is a rare condition, although numerous reports exist in the literature. At the National Institutes of Health (NIH) between 1971 and 1982, 50 cases of HES were diagnosed and followed up.⁶ The disease is rare in children.

International

HES is rare, and the exact incidence is uncertain.

Mortality/Morbidity

The course of HES varies from relatively indolent to fulminant and rapidly fatal.  The prognosis of HES has improved significantly since definition of HES and the development of imatinib. Ultimately, the mortality associated with HES id due to the occurrence of HES-related irreversible heart failure and the eventuality of malignant transformation of myeloid or lymphoid cells into a frank eosinophilic leukemia.²

Survival statistics vary. A review of 57 patients with advanced disease had a mean survival rate of 9 months and a 3-year survival rate of 12%; in another analysis of 40 patients, the 5-year survival rate was 80% and the 10-year survival rate was 42%. A study from the NIH in 1982⁶ noted a mean duration of disease of 4.8 years (range, 1-24 y). How newer treatments, such as cyclosporine, have affected mortality and morbidity is unclear.

Race

No racial predilection is recognized.

Sex

Male predominance (4-9:1 ratio) has been reported in historic series, but this is likely to reflect the quasi-exclusive male distribution of a sporadic hematopoietic stem cell mutation found in a recently characterized disease variant.²

Age

A study from the NIH⁶ of 50 patients reported that the mean age of onset was 33 years. In 70% of patients, the onset of disease occurs between 20-50 years. Although rare, this disease HES does occur in children. A review in 1987⁷ from Wales found 18 published reports of HES in children younger than 16 years. The incidence seems to decrease in elderly persons.

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