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 can be myriad, depending on which organs are dysfunctional. Diagnosis involves excluding other causes of eosinophilia plus bone marrow and cytogenetic tests. Treatment may include glucocorticoids and sometimes imatinib (or other tyrosine kinase inhibitors) but depends on the specific subtype of hypereosinophilic syndrome.
Hypereosinophilic syndrome is traditionally defined as peripheral blood eosinophilia > 1500/mcL (> 1.5 × 109/L) persisting ≥ 6 months with evidence of organ dysfunction. (See also Eosinophil Production and Function.) An alternative definition is an eosinophil count > 1500/mcL (> 1.5 × 109/L) on 2 or more occasions at least 2 weeks apart.
Hypereosinophilic syndrome was once considered idiopathic, but molecular studies have shown that many cases are driven by specific clonal disorders (1). A major limitation of the traditional definition is that it excludes patients with known disease-related abnormalities (eg, chromosomal defects) who do not meet strict thresholds for the 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. Moreover, some patients may have very high eosinophil counts without tissue involvement, and conversely, some patients with tissue damage may have lesser eosinophil elevations, so evaluation for tissue damage is always important.
Clonal hypereosinophilic syndromes
There are 2 broad subtypes of clonal hypereosinophilic syndrome (see table ):
Myeloproliferative variant
Lymphoproliferative variant
The myeloproliferative variant is often associated with a small interstitial deletion in chromosome 4 at the CHIC2 site that causes the FIP1L1::PDGFRA fusion gene (which has tyrosine kinase activity that can transform hematopoietic cells). Patients often present with some of the following:
Anemia
Elevated serum tryptase levels
Elevated serum vitamin B12 levels
Hypogranular or vacuolated eosinophils
Myelofibrosis
Splenomegaly
Thrombocytopenia
Patients with the myeloproliferative subtype often develop endomyocardial fibrosis and may rarely develop acute myeloid leukemia or acute 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). -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 (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 (2). Other cytogenetic abnormalities include rearrangement of the gene for fibroblast growth factor receptor 1 (FGFR1) or Janus kinase 2 (PCM1-JAK2). ETV6-ABL1 and various FLT3 fusions also are gene rearrangements associated with hypereosinophilia.
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 glucocorticoids and occasionally develop T-cell lymphoma.
Hypereosinophilic syndrome variants include Gleich syndrome (episodic angioedema with eosinophilia), 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) (3).
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) (4). Other thrombotic manifestations (eg, cardiac mural thrombi) may also occur.
Idiopathic hypereosinophilic syndrome (also called hypereosinophilia of uncertain significance [HE-US]) is rare, has an unknown prevalence, and most often affects people age 20 through 50 years. 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.
Clonal Hypereosinophilic Syndromes
Feature | Myeloproliferative Variant | Lymphoproliferative Variant |
|---|---|---|
Genetics | Rearrangement of PDGFRA, PDGFRB, FGFR1, PCM1-JAK2, or ETV6-ABL1 | Clonal population of T cells with aberrant phenotype |
Clinical manifestations and laboratory findings | Anemia Elevated serum tryptase levels Elevated serum vitamin B12 levels Endomyocardial fibrosis Hypogranular or vacuolated eosinophils Myelofibrosis Splenomegaly Thrombocytopenia | Angioedema Circulating immune complexes (sometimes with serum sickness) Hypergammaglobulinemia (especially IgE) Skin abnormalities |
Increased risk of future disorder | T-cell lymphoma | |
Responsiveness to medications | Imatinib and other tyrosine kinase inhibitorsImatinib and other tyrosine kinase inhibitors | Glucocorticoids |
General references
1. Wang SA, Orazi A, Gotlib J, et al. The international consensus classification of eosinophilic disorders and systemic mastocytosis. Am J Hematol. 2023;98(8):1286-1306. doi:10.1002/ajh.26966
2. 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. 2002;347:481-487. doi:10.1056/NEJMoa020150
3. Shomali W, Gotlib J . World Health Organization-defined eosinophilic disorders: 2022 update on diagnosis, risk stratification, and management. Am J Hematol. 2022;97:129-148. doi:10.1002/ajh.26352
4. Taurisano G, Ruffi MC, Canalis S, Costanzo GAML. Hypereosinophilia: clinical and therapeutic approach in 2025. Curr Opin Allergy Clin Immunol. 2025;25(4):258-268, 2025. doi:10.1097/ACI.0000000000001078
Symptoms and Signs of Hypereosinophilic Syndrome
Symptoms are diverse and depend on which organs are dysfunctional (see table ).
Abnormalities in Patients With Hypereosinophilic Syndrome
System | Prevalence | Manifestations |
|---|---|---|
Constitutional | ≈ 50% | Anorexia Fatigue Fever Myalgias Weakness Weight loss |
Cardiopulmonary | > 70% | Mural thrombi with emboli Restrictive or infiltrative cardiomyopathy or mitral or tricuspid regurgitation with cough, dyspnea, heart failure, arrhythmias, endomyocardial disease, Pulmonary infiltrates, pleural effusions; fibrosis with dyspnea, cough, and bronchospasm |
Dermatologic | > 50% | Angioedema Dermatographism Pruritus Rashes (including eczema and urticaria) |
Hematologic | > 50% | Anemia Lymphadenopathy Splenomegaly Thromboembolic phenomena Thrombocytopenia |
Neurologic | > 50% | Cerebral emboli with focal deficits Diffuse encephalopathy with altered behavior and cognitive function and spasticity Peripheral neuropathy |
Gastrointestinal (GI) | > 40% | Abdominal cramps Diarrhea Nausea |
Immunologic | ≈ 40% | Circulating immune complexes with serum sickness Elevated levels of immunoglobulins (especially IgE) |
Diagnosis of Hypereosinophilic Syndrome
Exclusion of secondary eosinophilia
Tests to identify organ damage
Bone marrow examination with cytogenetic examination 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.
Evaluation for organ damage should include blood chemistry tests (including liver enzymes, creatine kinase, renal function, and troponin); ECG; echocardiography; pulmonary function tests; and high-resolution 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 immune deficiency states or syndromic causes of eosinophilia (1).
Diagnosis reference
1. Taurisano G, Ruffi MC, Canalis S, Costanzo GAML. Hypereosinophilia: clinical and therapeutic approach in 2025. Curr Opin Allergy Clin Immunol. 2025;25(4):258-268, 2025. doi:10.1097/ACI.0000000000001078
Treatment of Hypereosinophilic Syndrome
Glucocorticoids 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 medications to control eosinophil counts (eg, hydroxyurea, interferon alfa, etoposide, cladribine)
Supportive care
Treatments include immediate therapy, definitive therapies (treatments directed at the disorder itself), and supportive therapies (1). 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).
Immediate therapy
For patients with very severe eosinophilia, complications of hyperleukocytosis such as dyspnea or mental status changes may occur (usually in patients with eosinophilic leukemia). In these cases, high-dose glucocorticoids (eg, ranging from prednisone 1 mg/kg or equivalent to 1 gram of methylprednisolone) should be initiated as soon as possible. If the eosinophil count is lower (eg, by For patients with very severe eosinophilia, complications of hyperleukocytosis such as dyspnea or mental status changes may occur (usually in patients with eosinophilic leukemia). In these cases, high-dose glucocorticoids (eg, ranging from prednisone 1 mg/kg or equivalent to 1 gram of methylprednisolone) should be initiated as soon as possible. If the eosinophil count is lower (eg, by≥ 50%) after 24 hours, the glucocorticoid 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 medications may be started. 50%) after 24 hours, the glucocorticoid 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 medications may be started.
Although leukopheresis can be used in the immediate treatment of hyperleukocytosis in hypereosinophilic syndrome, urgent intervention should prioritize pharmacologic cytoreduction rather than leukapheresis due to lack of evidence for improved outcomes (including prevention of end-organ damage) and potential procedural risks (2).
It is important to consider possible Strongyloides infection prior to administration of high-dose glucocorticoids, because glucocorticoids can precipitate potentially fatal disseminated infection (hyperinfection syndrome).
Definitive therapy
Patients with the FIP1L1::PDGFRA-associated fusion gene (or similar fusion genes involving PDGFA or PDGFB) are usually treated with imatinib () are usually treated with imatinib (3) and, particularly if heart damage is suspected, glucocorticoids as well. Imatinib started at diagnosis may forestall organ damage. The recommended dose for chronic phase disease is 100 mg once per day orally for patients with the FIP1L1::PDGFRA rearrangement and 100 to 400 mg once per day orally (typically 400 mg) for those with the PDGFRB rearrangement. If imatinib is ineffective or poorly tolerated, another tyrosine kinase inhibitor (eg, dasatinib, nilotinib, sorafenib) can be used, or allogeneic is ineffective or poorly tolerated, another tyrosine kinase inhibitor (eg, dasatinib, nilotinib, sorafenib) can be used, or allogeneichematopoietic stem cell transplantation can be used. Case reports suggest ruxolitinib, a JAK2 inhibitor may be useful in the rare cases that are associated with the JAK2 mutation (can be used. Case reports suggest ruxolitinib, a JAK2 inhibitor may be useful in the rare cases that are associated with the JAK2 mutation (4).
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 glucocorticoid responsiveness (ie, a decrease in the eosinophil count). In patients with symptoms or organ damage, -associated fusion gene, even if asymptomatic, are often given one dose of prednisone 60 mg (or 1 mg/kg) orally to determine glucocorticoid 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 glucocorticoids cannot be easily tapered, a glucocorticoid-sparing medication (eg, hydroxyurea, interferon alfa) can be used. 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 glucocorticoids cannot be easily tapered, a glucocorticoid-sparing medication (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 of six months or greater duration without a secondary non-hematologic cause in patients age 12 and older (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 of six months or greater duration without a secondary non-hematologic cause in patients age 12 and older (5, 6). Reslizumab (anti-IL-5), benralizumab (anti-IL-5 receptor), and dupilumab (anti-Il-4 receptor) are other biologics that are being evaluated in clinical trials for treatment of hypereosinophilic syndrome. Some are already in use for other eosinophilic disorders such as severe eosinophilic asthma (). Reslizumab (anti-IL-5), benralizumab (anti-IL-5 receptor), and dupilumab (anti-Il-4 receptor) are other biologics that are being evaluated in clinical trials for treatment of hypereosinophilic syndrome. Some are already in use for other eosinophilic disorders such as severe eosinophilic asthma (7).
Novel inhibitors of FGFR1 are being evaluated in this rare population of patients with hypereosinophilia (8).
Supportive care
Supportive medication therapy and surgery may be required for cardiac manifestations (eg, infiltrative cardiomyopathy, valvular lesions, heart failure). Thrombotic complications may require the use of antiplatelet medications (eg, aspirin, clopidogrel, ticlopidine); anticoagulation is indicated if a left ventricular mural thrombus is present or if transient ischemic attacks persist despite use of ). Thrombotic complications may require the use of antiplatelet medications (eg, aspirin, clopidogrel, ticlopidine); anticoagulation is indicated if a left ventricular mural thrombus is present or if transient ischemic attacks persist despite use ofaspirin.
Treatment references
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. 2009;124:1319-1325. doi:10.1016/j.jaci.2009.09.022
2. Gwinner W, Menne J, Lonnemann G, Bahlmann F, Koch KM, Haller H. Life-threatening complications of extracorporeal treatment in patients with severe eosinophilia. Int J Artif Organs. 2005;28(12):1224-1227. doi:10.1177/039139880502801205
3. Cortes J, Ault P, Koller C, et al. Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic syndrome. Blood. 2003;101:4714-4716. doi:10.1182/blood-2003-01-0081
4. Klion AD. Approach to the patient with suspected hypereosinophilic syndrome. Hematology Am Soc Hematol Educ Program. 2022; 2022(1):47-54. doi: 10.1182/hematology.2022000367
5. 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. 2020;146:1397-1405. doi: 10.1016/j.jaci.2020.08.037
6. Rothenberg ME, Klion AD, Roufosse FE, et al. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008;358:1215-1228. doi:10.1056/NEJMoa070812
7. Papaioannou O, Sampsonas F, Tsiri P, et al. Biologic Agents in Idiopathic Hypereosinophilic Syndrome. Pharmaceuticals (Basel). 2025;18(4):543. doi:10.3390/ph18040543
8. Shomali W, Gotlib J. World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management. Am J Hematol. 2024;99(5):946-968. doi:10.1002/ajh.27287
Prognosis for Hypereosinophilic Syndrome
Death usually results from organ, particularly cardiac, 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 Death usually results from organ, particularly cardiac, 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 theFIP1L1::PDGFRA-associated fusion gene and other responsive gene fusions.
Key Points
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 myeloid/lymphoid neoplastic cause.
Give glucocorticoids 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. Give glucocorticoids 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.
