BASICS
DESCRIPTION
- Hypereosinophilic syndrome (HES): a group of disorders characterized by an overproduction of eosinophils that subsequently infiltrate and damage multiple organs
- Hypereosinophilia (HE): with eosinophilia-mediated organ damage
- HE
- A persistent blood eosinophilia >1.5 � � 109 cells/L on two examinations separated by at least 1 month and/or tissue HE
- Exclusion of all other causes of organ damage and eosinophilia ( "MAAACP " �: malignancy, asthma, allergy, Addison disease [AD], connective tissue disease, parasitic infection).
- Tissue HE defined by the following:
- Eosinophils >20% of all nucleated cells on bone marrow section and/or
- Extensive tissue infiltration on histopathology and/or
- Marked deposition of eosinophil granular proteins in tissue
- System(s) affected: hematologic, cardiac, cutaneous, pulmonary, neurologic, gastrointestinal (GI); rheumatologic, ocular
EPIDEMIOLOGY
A rare condition, prevalence 0.36 to 6.3/100,000, typically seen between 20 and 50 years � �
- Clinically relevant variants:
- T-cell lymphocytic (L-HES): benign polyclonal hypergammaglobulinemia but may progress to T-cell lymphoma. CD3 " �/CD4+, interleukin (IL)-5 " �producing T cells. Prominent skin findings include erythroderma, plaques, and/or urticaria.
- Myeloproliferative (F/P+HES): almost exclusively in males with FIP1L1-PDGFRa fusion (Fip1-like-1 fused with platelet derived growth factor receptor alpha [F/P]2 and increased serum B12, bicytopenia, organomegaly, increased serum tryptase, and positive mast cell abnormalities)
- Familial HES: AD asymptomatic eosinophilia present at birth
- Benign HES: HE without end-organ damage
- Complex HES: multisystem organ involvement
- Episodic HES: Periodic rise in IL-5 leads to angioedema and eosinophilia; resolves spontaneously; may progress to L-HES
- Overlap HES: restricted eosinophilia to a single organ (GI, pulmonary, cardiac, vascular)
- Other clinical situations with HE:
- Churg-Strauss syndrome (eosinophilic vasculitis that can affect skin, sinuses, heart, lungs, peripheral nerves), Gleich syndrome (episodic HES with pruritus, urticaria, fever, weight gain, increase serum IgM, and leukocytosis)
- Immunodysregulation (collagen vascular disease, sarcoid, ulcerative colitis, autoimmune lymphoproliferative syndrome, HIV)
- HE of undetermined significance (no complications related to tissue eosinophilia)
Incidence
- Peak incidence in 4th decade of life
- Uncommon in children
- Incidence decreases in elderly
- Predominant sex: male > female (9:1)
ETIOLOGY AND PATHOPHYSIOLOGY
- Primary molecular defect resulting in clonal eosinophilic proliferation and/or overproduction or functional abnormalities of eosinophilopoietic cytokines and/or defects in normal suppressive regulation of eosinophilopoiesis
- Three hematopoietic cytokines: IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulate bone marrow myeloid progenitors to overproduce eosinophils; IL-5 is most specific for eosinophil differentiation.
- Pathogenesis:
- HES: Eosinophils infiltrate organs and release toxic granules containing major basic protein, eosinophil peroxidase, eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), Charcot-Leyden crystals, VIP, and substance P; neurotoxic, cytotoxic, and prothrombotic; creates oxidative burst, reactive oxygen species
- EDN and ECP activate fibroblasts: fibrosis and organ dysfunction
Genetics
- F/P+HES: Microdeletion at 4q12 causing gene fusion creates constitutively active tyrosine kinase.
- Other PDGFRA fusion partners besides FIP1L1; PDGFRb � � � translocation at 5q31-33 and FGFR1 � � � translocation at 8p11-13
- PDGFRA mutations account for 14% of HES cases (1)
- L-HES: clonal T-cell expansion; mutations such as 16q breakage, partial 6q or 10p deletions, trisomy 7
- Familial eosinophilia: autosomal dominant, at 5q31 to q33; eosinophilia at birth, often asymptomatic
- Cardiac disease more in males, carriers of HLA-Bw44
RISK FACTORS
Male gender (F/P+HES) � �
GENERAL PREVENTION
No known preventive measures � �
DIAGNOSIS
- A persistently elevated eosinophil count >1.5 � � 109 cells/L on two examinations at least 1 month apart and/or tissue HE (2)[C]
- Eosinophil-mediated organ damage in which other potential causes for the damage have been excluded
HISTORY AND PHYSICAL EXAM
- Dermatologic manifestations (37%) may cause pruritic lichenified eczematous rash with papules and nodules, plus dermatographism, and/or recurrent urticaria and angioedema; may also cause erythroderma. Mucosal ulcerations are more common in patients with FIP1L1-PDGFRa fusion
- Pulmonary manifestations (25%) may cause dyspnea, wheezing, and nonproductive cough.
- GI manifestations (14%): gastritis/enteritis; diarrhea, vomiting, abdominal pain (embolic bowel infarction); hepatic manifestations of hepatitis, Budd-Chiari syndrome
- Cardiac manifestations (5%) may cause endocarditis, myocarditis, shortness of breath, chest pain, ventricular failure, cardiomegaly, and/or restrictive cardiomyopathy; eosinophilic myocarditis more common in patients with FIP1L1-PDGFRα fusion
- Asymptomatic HE (6%)
- Neurologic manifestations may result from thromboembolic disease, behavioral changes, memory loss, confusion, and neuropathy.
- Ocular manifestations: blurry vision/blindness from microemboli
- Other: myalgias, arthralgias
DIFFERENTIAL DIAGNOSIS
- Leukemias, lymphomas, paraneoplastic syndromes, KIT mutation " �associated systemic mastocytosis with eosinophilia, drug hypersensitivity reactions, and helminth infections
- Chronic eosinophilic leukemia: clonality like F/P+HES but differs by having 2 " �20% blasts peripherally or 5 " �20% blasts in the marrow
- Acute eosinophilic leukemia: a form of acute myelogenous leukemia (AML) with 50 " �80% immature eosinophils, >10% blast in marrow; may cause cardiac and neurologic complications
DIAGNOSTIC TESTS & INTERPRETATION
- HE >1.5 � � 109 cells/L on two occasions; may be discovered incidentally on routine lab testing
- CBC with differential and peripheral smear:
- Leukocytosis of 10,000 to 30,000 (>90,000 carries poor prognosis)
- Mature eosinophils ≥1,500 cells/ � �L (nuclear hypersegmentation, hypo- and hypergranularity): hypogranularity and vacuolization more common with cardiac disease
- Often normal platelets but may have thrombocytosis or thrombocytopenia in cases with features of myeloproliferative disorder (plus tear drop cells)
- Normocytic anemia (anemia of chronic disease)
- Genetics
- Fluorescent in situ hybridization (FISH) analysis or reverse transcription-polymerase chain reaction (RT-PCR) assess FIP1L1/PDGFRA translocation/other TK mutations such as PDGFRA variants, PDGFRB, FGFR1
- Rule out c-KIT mutation (mastocytosis).
- RT-PCR or Southern blot: Assess IL-5-producing CD3 " �/CD4+ T lymphocytes.
- Chemistries
- Increased IgE
- Increased serum tryptase and B12 levels (F/P+myeloproliferative HES)
- L-HES: increased IL-5, IgG, IgM, thymus and activation-regulated chemokine (TARC) levels
- ECG: T-wave inversion, restrictive cardiomyopathy
Initial Tests (lab, imaging)
- Elevated serum tryptase
- Peripheral blood screening for FIP1L1-PDGFRA
- If negative, then bone marrow biopsy and cytogenetics for FIP1L1/PDGFRA, BCR/ABL, c-KIT translocations; T-lymphocyte phenotyping with flow cytometry and T-cell receptor (TCR) analysis (2)[B]
- If all negative, consider idiopathic HES.
- Echocardiogram
- Abdominal/chest CT: Assess end-organ involvement.
Diagnostic Procedures/Other
- Tissue biopsy (organ-restricted disease); bone marrow aspirate and biopsy
- Histopathology
- Organ infiltration with eosinophils and lymphocytes, tissue necrosis, eosinophil degranulation, and microabscesses
TREATMENT
- Consider FIP1L1/PDGFRA (F/P) transcript status.
- Initial treatment involves a trial of glucocorticoids alone in all patients EXCEPT those with F/P+ (2)[B].
MEDICATION
- F/P+HES
- Tyrosine kinase inhibitors (TKIs) in all patients with or without symptoms
- Danger of heart failure (rapid release of killed eosinophil contents) at start of therapy: Obtain troponin, monitor carefully, treat with corticosteroids 1 to 2 mg/kg/day concurrently or prior to initiation of therapy if complications arise, cardiac enzymes elevated, abnormal echocardiogram.
- TKIs induce complete molecular response (no F/P transcript); not yet known to be curative
- F/P " �HES
- Corticosteroids are the mainstay of treatment.
- A corticosteroid-sparing agent (interferon-alfa, anti-CD52 agents in L-HES, IL-5 inhibitors, chemotherapeutic agents) may be used if steroids are not tolerated or fail to manage disease.
- May respond to TKI, suggesting non-F/P tyrosine kinase activity
First Line
- F/P+, PDGFRA/B, FGFR1 HES: imatinib mesylate (Gleevec) at 100 to 400 mg/day
- 100 mg/day in PDGFRA
- 400 mg/day in PDGFRB and FGFR1
- Generally, lower doses needed to induce/maintain remission than with chronic myelogenous (or myeloid) leukemia (CML). Therapy is continued indefinitely.
- Side effects: thrombocytopenia, anemia, nausea, diarrhea, increased liver function tests (LFTs); avoid pregnancy
- Resistance: T674I point mutation, similar to CML
- F/P " �HES: prednisone: initial challenge of 60 mg once to determine responsiveness, followed by 1 mg/kg/day for 1 to 2 weeks. A taper should be initiated based on disease severity, persistent eosinophilia:
- Intolerance should prompt decreasing dose and adding second agent.
- Once stable, may add corticosteroid-sparing agent
Second Line
- F/P+HES: Patients rarely have shown resistance to imatinib; initiate trial of other TKI such as nilotinib, sorafenib, or dasatinib.
- F/P " �HES
- Imatinib
- Trial of 400 mg/day once stabilized on steroids or fail to respond/intolerant to steroids
- Interferon-alfa:
- Effective dose 1 to 8 million U 3 to 7 times a week; start low; increase as tolerated.
- Side effects: flulike symptoms, cytopenia, depression, elevated LFTs, GI disturbances
- Hydroxyurea
- Start at 500 to 1,000 mg/day, increase to 2,000 mg/day
- Side effects: cytopenia, nausea, rash, alopecia, diffuse pulmonary infiltrates, elevated LFTs, teratogen
- Mepolizumab (in clinical trials)
- Anti-IL5 antibody; administered 750 mg IV every 4 weeks; decreases steroid use
- FDA approved Orphan Drug Designation
- Side effects: fatigue, headaches, arthralgia, pruritus
- Alemtuzumab
- Anti-CD52 antibody, IV administration
- Effective for relapsed refractory idiopathic HES and chronic eosinophilic leukemia NOS
- Side effects: infusion reactions and hematologic toxicity with immunosuppression, leading to increased risk of opportunistic infections, especially CMV reactivation
ISSUES FOR REFERRAL
Refer to a hematologist and appropriate specialist depending on target organ involvement. � �
ADDITIONAL THERAPIES
Investigational: � �
- PDGFR fusion oncogenes proliferate autonomously and differentiate toward eosinophil lineage via nuclear factor (NF)- � �B, suggesting treatment potential.
- JAK 1/2 inhibitor, ruxolitinib, may have a role in treatment.
SURGERY/OTHER PROCEDURES
- Allogeneic stem cell transplant
- Patients failing other treatment modalities and/or those with aggressive disease
- Patients with L-HES progressing to T-cell lymphoma
- Role has not been well established.
- Cardiac surgery for complications of HES is helpful. If valve replacement is necessary, use porcine valve because of underlying hypercoagulable state.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- Emergency treatment for eosinophilia >100,000 includes high-dose corticosteroids (prednisone 1 mg/kg).
- If levels fail to decrease in 24 hours: vincristine 1 to 2 mg/m2, imatinib 400 mg, or plasmapheresis
- Heart failure, splenic rupture, organ failure; very high eosinophilia
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Depends on etiology of disease, response to treatment, and severity of end-organ damage � �
Patient Monitoring
- Weekly CBC on treatment; longer when stable
- L-HES: increased risk of T-cell lymphoma; CBC every 3 months; flow cytometry biannually to monitor abnormal lymphocytosis
- Patients on imatinib: LFTs and CBC monthly; RT-PCR for the F/P transcript; echocardiogram every 3 months
- Screen for organ involvement every 6 months: cardiac enzymes, pulmonary function tests, LFTs, renal function tests, ECG, echocardiogram
- Anticoagulation is unnecessary unless thrombi is present.
PROGNOSIS
- Better prognosis:
- Absence heart disease
- Presentation with angioedema
- Corticosteroid responsive
- No associated indicators of myeloproliferative disease (elevated B12 or tryptase, splenomegaly, abnormal lymphocytes, cytogenetic abnormalities)
- Worse prognosis:
- Concurrent myeloproliferative disorder
- Male sex
- Peripheral blood blasts
- WBC count >100,000
REFERENCES
11 Pardanani � �A, Brockman � �SR, Paternoster � �SF, et al. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood. 2004;104(10):3038 " �3045.22 Gotlib � �J. World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management. Am J Hematol. 2014;89(3):325 " �337.
ADDITIONAL READING
- Chusid � �MJ, Dale � �DC, West � �BC, et al. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). 1975;54(1):1 " �27.
- Hsieh � �FH. Hypereosinophilic syndrome. Ann Allergy Asthma Immunol. 2014;112(6):484 " �488.
- Montano-Almendras � �CP, Essaghir � �A, Schoemans � �H, et al. ETV6-PDGFRB and FIP1L1-PDGFRA stimulate human hematopoietic progenitor cell proliferation and differentiation into eosinophils: the role of nuclear factor- � �B. Haematologica. 2012;97(7):1064 " �1072.
- Ogbogu � �PU, Bochner � �BS, Butterfield � �JH, et al. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol. 2009;124(6):1319.e3 " �1325.e3.
- Simon � �HU, Rothenberg � �ME, Bochner � �BS, et al. Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol. 2010;126(1):45 " �49.
- Tefferi � �A, Gotlib � �J, Pardanani � �A. Hypereosinophilic syndrome and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update. Mayo Clin Proc. 2010;85(2):158 " �164.
- Valent � �P, Klion � �AD, Horny � �HP, et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol. 2012;130(3):607 " �612.e9.
- Verstovsek � �S, Tefferi � �A, Kantarjian � �H, et al. Alemtuzumab therapy for hypereosinophilic syndrome and chronic eosinophilic leukemia. Clin Cancer Res. 2009;15(1):368 " �373.
CODES
ICD10
D72.1 Eosinophilia � �
ICD9
288.3 Eosinophilia � �
SNOMED
idiopathic hypereosinophilic syndrome (disorder) � �
CLINICAL PEARLS
- HES encompasses a group of diseases with eosinophils >1,500/ � �L and end-organ damage without an identifiable secondary cause.
- F/P+ transcript status should be determined to help guide the course of treatment.
- Prognosis and treatment depend on subtype.
- Cardiac disease is a dangerous complication of HES and may not be reversible.
- Many ongoing clinical trials are looking at the use of anti-IL-5 and anti-CD52 drugs.