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
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.)
Hypereosinophilic syndrome was previously considered to be idiopathic, but molecular characterization has revealed that many cases have specific clonal disorders (1). 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 2 broad subtypes of clonal hypereosinophilic syndrome (see table Clonal Hypereosinophilic Syndromes):
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-associated fusion gene (which has tyrosine kinase activity that can transform hematopoietic cells). Patients often have
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
2). Other cytogenetic abnormalities include rearrangement of the gene for fibroblast growth factor receptor 1 (FGFR1) or Janus kinase 2 (PCM1-JAK2). Recently, ETV6-ABL1 and various FLT3 fusions have been added to the 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 corticosteroids and occasionally develop T-cell lymphoma.
Other 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).
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 | Corticosteroids |
Idiopathic hypereosinophilic syndrome
Idiopathic hypereosinophilic syndrome 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.
General references
1. Wang SA, Orazi A, Gotlib J, et al: The international consensus classification of eosinophilic disorders and systemic mastocytosis. Am J Hematol 98(8):1286–1306, 2023. 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 347:481–487, 2002.
3. 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
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, and pleural effusions |
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) |
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.
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 (1).
Diagnosis reference
1. 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
Treatment of Hypereosinophilic Syndrome
Corticosteroids for hypereosinophilia and often for ongoing treatment of organ damage
FIP1L1/PDGFRA-associated fusion gene or other similar gene fusions
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
≥
It is important to consider possible Strongyloides infection prior to administration of high-dose corticosteroids, since corticosteroids can precipitate potentially fatal disseminated infection (hyperinfection syndrome).
Definitive therapy
Patients with the FIP1L1/PDGFRA-associated fusion gene (or similar fusion genes involving PDGFA/B2) and, particularly if heart damage is suspected, corticosteroids as well. Imatinib started at diagnosis may forestall organ damage. If imatinibhematopoietic stem cell transplantation3).
Patients without the FIP1L1/PDGFRAprednisone
Supportive care
Supportive medication therapy and surgery may be required for cardiac manifestations (eg, infiltrative cardiomyopathy, valvular lesions, heart failureaspirin.
Investigational therapy
Novel inhibitors of FGFR1 are being evaluated in this rare population of patients with hypereosinophilia.
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 124:1319–1325, 2009. doi:10.1016/j.jaci.2009.09.022
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. doi:10.1182/blood-2003-01-0081
3. 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
4. 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
5. 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. doi:10.1056/NEJMoa070812
Prognosis for Hypereosinophilic Syndrome
FIP1L1/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 cause.
