Background
Hypereosinophilic syndrome (HES) encompasses a wide range of clinical manifestations sharing 3 features defined by Chusid et al [1] : (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.
Also see Pediatric Hypereosinophilic Syndrome and Hypereosinophilic Syndrome.
Pathophysiology
Hypereosinophilic syndrome 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, 3]
Multiple cytokines stimulate eosinophil production, including IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5. [4] 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 hypereosinophilic syndrome 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 hypereosinophilic syndrome 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 hypereosinophilic syndrome.
Eosinophils in hypereosinophilic syndrome 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 hypereosinophilic syndrome. 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 hypereosinophilic syndrome.
Fip1-like1-platelet-derived growth factor receptor alpha chain (FIP1L1-PDGFRA) mutation has been described in adult patients with hypereosinophilic syndrome. [5] 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 and results in clonal lines of pathologic cells. [6]
Pardanani et al [7] 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 team [7] 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 hypereosinophilic syndrome 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 hypereosinophilic syndrome. However, a 40% partial response rate was observed in 10 hypereosinophilic syndrome cases after treatment with imatinib.
McPherson et al [8] 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.
Etiology
Hypereosinophilic syndrome is a clonal proliferation of eosinophils. By definition, hypereosinophilic syndrome is an idiopathic condition.
Some have speculated that hypereosinophilic syndrome is not primarily a disease of eosinophils but rather a disease of T cells that secrete cytokines that result in such clonal proliferations. Such clonal eosinophils are activated and have more eosinophilic mediators than normal eosinophils.
Some cases of hypereosinophilic syndrome turn into leukemia, and, as such, chromosomal abnormalities are at the root of some cases of hypereosinophilic syndrome. A study from the NIH [9] found chromosomal abnormalities in 8 of 33 patients examined. Such abnormalities can include the Philadelphia chromosome.
Epidemiology
Frequency
United States
The exact incidence of hypereosinophilic syndrome 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 hypereosinophilic syndrome were diagnosed and followed up. [9] The disease is rare in children.
International
Hypereosinophilic syndrome is rare, and the exact incidence is uncertain.
Race
No racial predilection is recognized for hypereosinophilic syndrome.
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 characterized disease variant. [2]
Age
A study from the NIH [9] 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 hypereosinophilic syndrome does occur in children. [10] A review in 1987 [11] from Wales found 18 published reports of hypereosinophilic syndrome in children younger than 16 years. The incidence seems to decrease in elderly persons. Kim et al reported encephalitis in idiopathic hypereosinophilic syndrome in a 14-year-old girl. [12]
Prognosis
Good prognostic factors include the following:
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Good response to prednisone
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Urticaria/angioedema lesions as the type of skin involvement
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Absence of symptoms, particularly CHF
Poor prognostic factors include the following:
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Anemia
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Thrombocytopenia
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WBC count greater than 90 X 109/L
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Abnormal circulating cells
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Abnormal bone marrow
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Abnormal leukocyte alkaline phosphatase levels
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Chromosomal abnormalities (eg, Philadelphia chromosome) suggestive of a myeloproliferative disorder
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Early aggressive organ involvement (especially CHF)
Mortality/morbidity
The course of hypereosinophilic syndrome varies from relatively indolent to fulminant and rapidly fatal. The prognosis of hypereosinophilic syndrome has improved significantly since definition of hypereosinophilic syndrome and the development of imatinib. Ultimately, the mortality associated with hypereosinophilic syndrome id due to the occurrence of hypereosinophilic syndrome-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 1982 [9] 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.
A report published from the Mayo Clinic in 2013 noted a review of 247 cases of hypereosinophilic syndrome encompassing 19 years of data. Of these 247 patients, 23 died of a variety of hypereosinophilic syndrome–related diseases. [13]
Some hypereosinophilic syndrome cases resolve spontaneously, as was noted in a 2012 report of a 4-month-old infant. [14]
Patient Education
Instruct patients about the potential symptoms and the importance of rapid intervention.
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Urticarial and erythematous rash.
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Petechiae on an erythematous base.
