Hypereosinophilic syndrome is traditionally defined as peripheral blood eosinophilia > 1500/mcL (> 1.5 × 109/L) persisting ≥ 6 months. (See also Eosinophil Production and Function Eosinophil Production and Function Eosinophils are granulocytes (white blood cells that contain granules in their cytoplasm) derived from the same progenitor cells as monocytes-macrophages, neutrophils, and basophils. They are... read more .)
Hypereosinophilic syndrome was previously considered to be idiopathic, but molecular characterization has revealed that many cases have specific clonal disorders. 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 hypereosinophilic syndrome but who do not fulfill the traditional hypereosinophilic syndrome definition for degree or duration of eosinophilia. Another limitation is that some patients with eosinophilia and organ damage that characterize hypereosinophilic syndrome require treatment earlier than the 6 months necessary to confirm the traditional diagnostic criteria. Eosinophilia of any etiology can cause the same types of tissue damage.
Clonal hypereosinophilic syndromes
There are two broad subtypes of clonal hypereosinophilic syndrome (see table Clonal Hypereosinophilic Syndromes 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
Elevated serum vitamin B12 levels
Hypogranular or vacuolated eosinophils
Patients with the myeloproliferative subtype often develop endomyocardial fibrosis and may rarely develop acute myeloid leukemia Acute Myeloid Leukemia (AML) In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers... read more or acute lymphoblastic leukemia Acute Lymphoblastic Leukemia (ALL) Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer; it also strikes adults of all ages. Malignant transformation and uncontrolled proliferation of an abnormally differentiated... read more . 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 General references Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more ). Other cytogenetic abnormalities include rearrangement of the gene for fibroblast growth factor receptor 1 (FGFR1) or Janus kinase 2 (PCM1-JAK2).
Some patients have chronic eosinophilic leukemia, in which blast cells are increased on bone marrow examination but not more than 20%.
The lymphoproliferative variant is associated with a clonal population of T cells with aberrant phenotype. Polymerase chain reaction (PCR) shows a clonal T-cell receptor rearrangement. Patients more often have
Angioedema, skin abnormalities, or both
Circulating immune complexes (sometimes with serum sickness)
Hypergammaglobulinemia (especially high IgE)
Patients with the lymphoproliferative variant also more often respond favorably to corticosteroids and occasionally develop T-cell lymphoma.
Other hypereosinophilic syndrome variants include Gleich syndrome (cyclical eosinophilia and angioedema), familial hypereosinophilic syndrome mapped to 5q 31-33, and other organ-specific syndromes. In organ-specific eosinophilic syndromes, eosinophilic infiltration is confined to a single organ (eg, eosinophilic gastrointestinal disease, chronic eosinophilic pneumonia Chronic Eosinophilic Pneumonia Chronic eosinophilic pneumonia (CEP) is a disorder of unknown etiology characterized by an abnormal, chronic accumulation of eosinophils in the lung. (See also Overview of Eosinophilic Pulmonary... read more — 2 General references Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more ).
Hyperleukocytosis may occur in patients with eosinophilic leukemia and very high eosinophil counts (eg, > 100,000 cells/mcL [> 100 × 109/L]). 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).
Idiopathic hypereosinophilic syndrome
Idiopathic hypereosinophilic syndrome is rare, has an unknown prevalence, and most often affects people age 20 through 50. Only some patients with prolonged eosinophilia Eosinophilia Eosinophilia is defined as a peripheral blood eosinophil count > 500/mcL (> 0.5 × 109/L). Causes and associated disorders are myriad but often represent an allergic reaction or... read more 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.
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.
2. Shomali W, Gotlib J : World Health Organization-defined eosinophilic disorders: 2022 update on diagnosis, risk stratification, and management. Am J Hematol 97:129–148, 2022.
Symptoms and Signs of Hypereosinophilic Syndrome
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/mcL [> 100 × 109/L]) develop complications of hyperleukocytosis, such as manifestations of brain or lung hypoxia (eg, encephalopathy, dyspnea, respiratory failure). Other thrombotic manifestations (eg, cardiac mural thrombi) may also occur.
Diagnosis of Hypereosinophilic Syndrome
Exclusion of secondary eosinophilia
Tests to identify organ damage
Bone marrow examination with cytogenetic testing if secondary causes of eosinophilia are not identified
Evaluation for hypereosinophilic syndrome should be considered in patients who have peripheral blood eosinophilia > 1500/mcL (> 1.5 × 109/L) present on more than one occasion that is unexplained, particularly when there are manifestations of organ damage. Testing to exclude disorders causing eosinophilia Testing Eosinophilia is defined as a peripheral blood eosinophil count > 500/mcL (> 0.5 × 109/L). Causes and associated disorders are myriad but often represent an allergic reaction or... read more should be done.
Evaluation for organ damage should include blood chemistry tests (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-polymerase chain reaction (rtPCR) or fluorescence in situ hybridization (FISH) are done to identify the FIP1L1/PDGFRA-associated fusion gene or other common fusion transcripts and to evaluate for clonality of the T cell–receptor to exclude the lymphocytic variant of hypereosinophilic syndrome and other possible causes of eosinophilia.
Prognosis for Hypereosinophilic Syndrome
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 and other responsive gene fusions.
Treatment of Hypereosinophilic Syndrome
Corticosteroids for hypereosinophilia and often for ongoing treatment of organ damage
Imatinib for patients with the FIP1L1/PDGFRA-associated fusion gene or other similar gene fusions
Sometimes drugs to control eosinophil counts (eg, hydroxyurea, interferon alfa, etoposide, cladribine)
Treatments include immediate therapy, definitive therapies (treatments directed at the disorder itself), and supportive therapies (1 Treatment references Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more ). There is no set level of eosinophilia at which organ damage occurs or at which treatment must be started, but most experts recommend starting therapy at an absolute eosinophil count of 1500 to 2000 eosinophils/mcL (1.5 to 2 × 109/L).
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 hours, the 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 (or similar fusion genes involving PDGFA/B) are usually treated with imatinib (2 Treatment references Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more ) and, particularly if heart damage is suspected, corticosteroids as well. Imatinib started at diagnosis may forestall organ damage. If imatinib is ineffective or poorly tolerated, another tyrosine kinase inhibitor (eg, dasatinib, nilotinib, sorafenib) can be used, or allogeneic hematopoietic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more 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) orally 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 once a day for 2 weeks, then tapered. Patients without symptoms and organ damage are monitored for at least 6 months for these complications. If corticosteroids cannot be easily tapered, a corticosteroid-sparing drug (eg, hydroxyurea, interferon alfa) can be used.
Mepolizumab, a fully humanized monoclonal IgG antibody that inhibits binding of IL-5 to its receptor, may be used for the treatment of idiopathic hypereosinophilia (3, 4 Treatment references Hypereosinophilic syndrome is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the... read more ).
Supportive drug therapy and surgery may be required for cardiac manifestations (eg, infiltrative cardiomyopathy Overview of Cardiomyopathies A cardiomyopathy is a primary disorder of the heart muscle. It is distinct from structural cardiac disorders such as coronary artery disease, valvular disorders, and congenital heart disorders... read more , valvular lesions Overview of Cardiac Valvular Disorders Any heart valve can become stenotic or insufficient (also termed regurgitant or incompetent), causing hemodynamic changes long before symptoms. Most often, valvular stenosis or insufficiency... read more , heart failure Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more ). 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.
Reslizumab, an anti-IL5 monoclonal antibody that is used in severe asthma, is being examined in hypereosinophilia, as is benralizumab, another anti-IL5 receptor antibody. Novel inhibitors of FGFR1 are being evaluated in this rare population of patients with hypereosinophilia. JAK2 inhibitors are being examined in those with JAK2 rearrangements.
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.
3. Roufosse F, Kahn JE, Rothenberg FE, et al: Efficacy and safety of mepolizumab in hypereosinophilic syndrome: a phase III, randomized, placebo-controlled trial. J Allergy Clin Immunol 146: 1397–1405, 2020. doi: 10.1016/j.jaci.2020.08.037
4. Rothenberg ME, Klion AD, Roufosse FE, et al: Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med 358:1215–28, 2008.
Hypereosinophilic syndrome is peripheral blood eosinophilia (> 1500/mcL [> 1.5 × 109/L]) not caused by parasitic, allergic, or other secondary causes of eosinophilia, that has persisted ≥ 6 months and caused organ damage or dysfunction.
Hypereosinophilic syndrome 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.