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Hypereosinophilic Syndrome

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 пїЅ пїЅ 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 " пїЅ: 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

- Clinically relevant variants: - T-cell lymphocytic (L-HES): benign polyclonal hypergammaglobulinemia but may progress to T-cell lymphoma. CD3 " пїЅ/CD4+, interleukin (IL)-5 " пїЅproducing 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)

- 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 " пїЅ/CD4+ T lymphocytes.

- 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

- 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

- 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)

  • 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 damageHEA persistent blood eosinophilia >1.5 пїЅ пїЅ 109 cells/L on two examinations separated by at least 1 month and/or tissue HEExclusion of all other causes of organ damage and eosinophilia ( "MAAACP " пїЅ: 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/orExtensive tissue infiltration on histopathology and/orMarked 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 пїЅ пїЅ

  • Clinically relevant variants:T-cell lymphocytic (L-HES): benign polyclonal hypergammaglobulinemia but may progress to T-cell lymphoma. CD3 " пїЅ/CD4+, interleukin (IL)-5 " пїЅproducing 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 birthBenign HES: HE without end-organ damageComplex HES: multisystem organ involvementEpisodic HES: Periodic rise in IL-5 leads to angioedema and eosinophilia; resolves spontaneously; may progress to L-HESOverlap 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 speciesEDN 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 пїЅ пїЅ пїЅ translocation at 5q31-33 and FGFR1 пїЅ пїЅ пїЅ 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) пїЅ пїЅ

GENERAL PREVENTION

No known preventive measures пїЅ пїЅ

DIAGNOSIS

  • A persistently elevated eosinophil count >1.5 пїЅ пїЅ 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 " пїЅassociated systemic mastocytosis with eosinophilia, drug hypersensitivity reactions, and helminth infections
  • Chronic eosinophilic leukemia: clonality like F/P+HES but differs by having 2 " пїЅ20% blasts peripherally or 5 " пїЅ20% blasts in the marrow
  • Acute eosinophilic leukemia: a form of acute myelogenous leukemia (AML) with 50 " пїЅ80% immature eosinophils, >10% blast in marrow; may cause cardiac and neurologic complications

DIAGNOSTIC TESTS & INTERPRETATION

  • HE >1.5 пїЅ пїЅ 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/ пїЅ пїЅL (nuclear hypersegmentation, hypo- and hypergranularity): hypogranularity and vacuolization more common with cardiac diseaseOften 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)
  • GeneticsFluorescent 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, FGFR1Rule out c-KIT mutation (mastocytosis).RT-PCR or Southern blot: Assess IL-5-producing CD3 " пїЅ/CD4+ T lymphocytes.
  • ChemistriesIncreased IgEIncreased 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 tryptasePeripheral blood screening for FIP1L1-PDGFRAIf 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
  • HistopathologyOrgan 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+HESTyrosine kinase inhibitors (TKIs) in all patients with or without symptomsDanger 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 " пїЅHESCorticosteroids 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/day100 mg/day in PDGFRA400 mg/day in PDGFRB and FGFR1Generally, 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 pregnancyResistance: T674I point mutation, similar to CML
  • F/P " пїЅHES: 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 " пїЅHESImatinibTrial of 400 mg/day once stabilized on steroids or fail to respond/intolerant to steroidsInterferon-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 disturbancesHydroxyureaStart at 500 to 1,000 mg/day, increase to 2,000 mg/daySide effects: cytopenia, nausea, rash, alopecia, diffuse pulmonary infiltrates, elevated LFTs, teratogenMepolizumab (in clinical trials)Anti-IL5 antibody; administered 750 mg IV every 4 weeks; decreases steroid useFDA approved Orphan Drug DesignationSide effects: fatigue, headaches, arthralgia, pruritusAlemtuzumabAnti-CD52 antibody, IV administrationEffective for relapsed refractory idiopathic HES and chronic eosinophilic leukemia NOSSide 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. пїЅ пїЅ

ADDITIONAL THERAPIES

Investigational: пїЅ пїЅ

  • PDGFR fusion oncogenes proliferate autonomously and differentiate toward eosinophil lineage via nuclear factor (NF)- пїЅ пїЅB, suggesting treatment potential.
  • JAK 1/2 inhibitor, ruxolitinib, may have a role in treatment.

SURGERY/OTHER PROCEDURES

  • Allogeneic stem cell transplantPatients failing other treatment modalities and/or those with aggressive diseasePatients with L-HES progressing to T-cell lymphomaRole 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 пїЅ пїЅ

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 diseasePresentation with angioedemaCorticosteroid responsiveNo associated indicators of myeloproliferative disease (elevated B12 or tryptase, splenomegaly, abnormal lymphocytes, cytogenetic abnormalities)
  • Worse prognosis:Concurrent myeloproliferative disorderMale sexPeripheral blood blastsWBC count >100,000

REFERENCES

11 Pardanani пїЅ пїЅA, Brockman пїЅ пїЅSR, Paternoster пїЅ пїЅSF, et al. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood. 2004;104(10):3038 " пїЅ3045.22 Gotlib пїЅ пїЅJ. World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management. Am J Hematol. 2014;89(3):325 " пїЅ337.

ADDITIONAL READING

  • Chusid пїЅ пїЅMJ, Dale пїЅ пїЅDC, West пїЅ пїЅBC, et al. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). 1975;54(1):1 " пїЅ27.
  • Hsieh пїЅ пїЅFH. Hypereosinophilic syndrome. Ann Allergy Asthma Immunol. 2014;112(6):484 " пїЅ488.
  • Montano-Almendras пїЅ пїЅCP, Essaghir пїЅ пїЅA, Schoemans пїЅ пїЅH, et al. ETV6-PDGFRB and FIP1L1-PDGFRA stimulate human hematopoietic progenitor cell proliferation and differentiation into eosinophils: the role of nuclear factor- пїЅ пїЅB. Haematologica. 2012;97(7):1064 " пїЅ1072.
  • Ogbogu пїЅ пїЅPU, Bochner пїЅ пїЅBS, Butterfield пїЅ пїЅJH, et al. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol. 2009;124(6):1319.e3 " пїЅ1325.e3.
  • Simon пїЅ пїЅHU, Rothenberg пїЅ пїЅME, Bochner пїЅ пїЅBS, et al. Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol. 2010;126(1):45 " пїЅ49.
  • Tefferi пїЅ пїЅA, Gotlib пїЅ пїЅJ, Pardanani пїЅ пїЅA. Hypereosinophilic syndrome and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update. Mayo Clin Proc. 2010;85(2):158 " пїЅ164.
  • Valent пїЅ пїЅP, Klion пїЅ пїЅAD, Horny пїЅ пїЅHP, et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol. 2012;130(3):607 " пїЅ612.e9.
  • Verstovsek пїЅ пїЅS, Tefferi пїЅ пїЅA, Kantarjian пїЅ пїЅH, et al. Alemtuzumab therapy for hypereosinophilic syndrome and chronic eosinophilic leukemia. Clin Cancer Res. 2009;15(1):368 " пїЅ373.

CODES

ICD10

D72.1 Eosinophilia пїЅ пїЅ

ICD9

288.3 Eosinophilia пїЅ пїЅ

SNOMED

idiopathic hypereosinophilic syndrome (disorder) пїЅ пїЅ

CLINICAL PEARLS

  • HES encompasses a group of diseases with eosinophils >1,500/ пїЅ пїЅL 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.