(Idiopathic Hypereosinophilic Syndrome)
(See also Eosinophil Production and Function.)
Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the absence of parasitic, allergic, or other secondary causes of eosinophilia. Symptoms are myriad, depending on which organs are dysfunctional. Diagnosis involves excluding other causes of eosinophilia plus bone marrow and cytogenetic tests. Treatment usually begins with prednisone and, in one common subtype, includes imatinib.
Hypereosinophilic syndrome (HES) is traditionally defined as peripheral blood eosinophilia > 1500/μL persisting ≥ 6 mo.
HES was previously considered to be idiopathic but is now known to result from various disorders, some of which have known causes. One limitation of the traditional definition is that it does not include those patients with some of the same abnormalities (eg, chromosomal defects) that are known causes of HES but who do not fulfill the traditional HES definition for degree or duration of eosinophilia. Another limitation is that some patients with eosinophilia and organ damage that characterize HES require treatment earlier than the 6 mo necessary to confirm the traditional diagnostic criteria.
HES is rare, has an unknown prevalence, and most often affects people age 20 through 50. Only some patients with prolonged eosinophilia develop organ dysfunction that characterizes hypereosinophilic syndrome. Although any organ may be involved, the heart, lungs, spleen, skin, and nervous system are typically affected. Cardiac involvement can cause significant morbidity and mortality.
There are two broad subtypes of hypereosinophilic syndrome (see Table: Subtypes of Hypereosinophilic Syndrome):
The myeloproliferative variant is often associated with a small interstitial deletion in chromosome 4 at the CHIC2 site that causes the FIP1L1/PDGFRA-associated fusion gene (which has tyrosine kinase activity that can transform hematopoietic cells). Patients often have
Patients with this subtype often develop endomyocardial fibrosis and may rarely develop acute myeloid or lymphoblastic leukemia. Patients with the FIP1L1/PDGFRA-associated fusion gene are more often males and may be responsive to low-dose imatinib (a tyrosine kinase inhibitor).
A small proportion of patients with the myeloproliferative variant of hypereosinophilic syndrome have cytogenetic changes involving platelet derived growth factor receptor beta (PDGFRB) and may also be responsive to tyrosine kinase inhibitors such as imatinib (1).
The lymphoproliferative variant is associated with a clonal population of T cells with aberrant phenotype. PCR shows a clonal T cell receptor rearrangement. Patients more often have
They also more often respond favorably to corticosteroids and occasionally develop T-cell lymphoma.
Other HES variants include chronic eosinophilic leukemia, Gleich syndrome (cyclical eosinophilia and angioedema), familial hypereosinophilic syndrome mapped to 5q 31-33, and other organ-specific syndromes. Hyperleukocytosis may occur in patients with eosinophilic leukemia and very high eosinophil counts (eg, > 100,000 cells/μL). Eosinophils can form aggregates that occlude small blood vessels, causing tissue ischemia and microinfarctions. Common manifestations include brain or lung hypoxia (eg, encephalopathy, dyspnea or respiratory failure).
Subtypes of Hypereosinophilic Syndrome
1. Apperley JF, Gardembas M, Melo JV, et al: Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 347:481–487, 2002.
Symptoms are diverse and depend on which organs are dysfunctional (see Table: Abnormalities in Patients With Hypereosinophilic Syndrome).
Abnormalities in Patients With Hypereosinophilic Syndrome
Occasionally, patients with very severe eosinophilia (eg, eosinophil counts of > 100,000/μL) develop complications of hyperleukocytosis, such as manifestations of brain or lung hypoxia (eg, encephalopathy, dyspnea or respiratory failure).
Evaluation for hypereosinophilic syndrome should be considered in patients who have peripheral blood eosinophilia >1500/μL present on more than one occasion that is unexplained, particularly when there are manifestations of organ damage. Testing to exclude disorders causing eosinophilia should be done.
Evaluation for organ damage should include blood chemistries (including liver enzymes, creatine kinase, renal function, and troponin); ECG; echocardiography; pulmonary function tests; and CT of the chest, abdomen, and pelvis. Bone marrow aspirate and biopsy with flow cytometry, cytogenetic testing, and reverse transcriptase-PCR or fluorescence in situ hybridization (FISH) is done to identify the FIP1L1/PDGFRA-associated fusion gene and other possible causes of eosinophilia (eg, BCR-ABL abnormalities characteristic of chronic myelogenous leukemia).
Death usually results from organ, particularly heart, dysfunction. Cardiac involvement is not predicted by the degree or duration of eosinophilia. Prognosis varies depending on response to therapy. Response to imatinib improves the prognosis among patients with the FIP1L1/PDGFRA-associated fusion gene. Current therapy has improved prognosis.
Treatments include immediate therapy, definitive therapies (treatments directed at the disorder itself), and supportive therapies (1).
For patients with very severe eosinophilia, complications of hyperleukocytosis, or both (usually patients with eosinophilic leukemia), high-dose IV corticosteroids (eg, prednisone 1 mg/kg or equivalent) should be initiated as soon as possible. If the eosinophil count is much lower (eg, by ≥ 50%) after 24 h, corticosteroid dose can be repeated daily; if not, an alternative treatment (eg, hydroxyurea) is begun. Once the eosinophil count begins to decline and is under better control, additional drugs may be started.
Patients with the FIP1L1/PDGFRA-associated fusion gene are usually treated with imatinib (2) and, particularly if heart damage is suspected, corticosteroids. If imatinib is ineffective or poorly tolerated, another tyrosine kinase inhibitor (eg, dasatinib, nilotinib, sorafenib) can be used, or allogeneic hematopoietic stem cell transplantation can be used.
Patients without the FIP1L1/PDGFRA-associated fusion gene, even if asymptomatic, are often given one dose of prednisone 60 mg (or 1 mg/kg) po to determine corticosteroid responsiveness (ie, a decrease in the eosinophil count). In patients with symptoms or organ damage, prednisone is continued at the same dose for 2 wk, then tapered. Patients without symptoms and organ damage are monitored for at least 6 mo for these complications. If corticosteroids cannot be easily tapered, a corticosteroid-sparing drug (eg, hydroxyurea, interferon alfa) can be used. Mepolizumab, a fully human monoclonal antibody against interleukin-5 (a regulator of eosinophil production), is undergoing clinical trials.
Supportive drug therapy and surgery may be required for cardiac manifestations (eg, infiltrative cardiomyopathy, valvular lesions, heart failure). Thrombotic complications may require the use of antiplatelet drugs (eg, aspirin, clopidogrel, ticlopidine); anticoagulation is indicated if a left ventricular mural thrombus is present or if transient ischemic attacks persist despite use of aspirin.
1. Ogbogu PU, Bochener BS, Butterfield HJ, et al: Hypereosinophilic syndromes: A multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol 124:1319–1325, 2009.
2. Cortes J, Ault P, Koller C, et al: Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic syndrome. Blood 101:4714–4716, 2003.
Hypereosinophilic syndrome (HES) is peripheral blood eosinophilia (> 1500/μL) not caused by parasitic, allergic, or other secondary causes of eosinophilia, that has persisted ≥ 6 mo and caused organ damage or dysfunction.
HES appears to be a manifestation of a number of hematopoietic disorders, some of which have a genetic cause.
Any organ may be involved but the heart, lungs, spleen, skin, and nervous system are typically affected; cardiac involvement can cause significant morbidity and mortality.
Do tests for organ involvement, including liver enzymes; creatine kinase, creatinine, and troponin levels; ECG and echocardiography; pulmonary function tests; and CT of the chest, abdomen, and pelvis.
Do bone marrow examination with cytogenetic testing to identify a cause.
Give corticosteroids for severe eosinophilia and/or organ damage. Tyrosine kinase inhibitors such as low-dose imatinib may be of benefit in subtypes associated with distinct chromosomal abnormalities.