eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Hypereosinophilic Syndrome

Bruce M Rothschild, MD, Professor of Medicine, The Northeastern Ohio Universities College of Medicine; Director, Arthritis Center of Northeast Ohio; Adjunct Professor, Department of Biomedical Engineering, University of Akron

Updated: Aug 15, 2008

Introduction

Background

Hypereosinophilic syndrome varies from an asymptomatic phenomenon to a life-threatening multisystem disease. It is characterized by an eosinophil count of more than 1500/μ L (usually many more) for more than 6 months and multiorgan involvement in the absence of other causes of eosinophilia and in the absence of eosinophil blast cells in the marrow or blood. Three subtypes are recognized: myeloproliferative, lymphocytic, and idiopathic.¹ Hypereosinophilic syndrome is very rare in children.

Pathophysiology

Extrinsic hypereosinophilia appears to be caused by eosinophilopoietin cytokines, including interleukin 5 (IL-5), interleukin 3 (IL-3), and granulocyte/monocyte cell–stimulating factor (GM-CSF); large numbers of circulating eosinophils result.

Toxicity is related to fibrosis, especially endomyocardial fibrosis, which is caused by eosinophil granules, including cationic granule proteins (eg, eosinophil-derived neurotoxin, eosinophil peroxidase, major basic protein, eosinophil cationic protein, transforming growth factor alpha and beta), tumor necrosis factor alpha , interleukin 1 beta (IL-1ß), macrophage inflammatory protein, interleukin 6 (IL-6), interleukin 8 (IL-8), IL-5, IL-3, and GM-CSF.

Urokinase-induced plasminogen activation and factor XII-dependent reactions predispose the patient to thrombotic reactions.

In platelet-derived growth factor receptor alpha (PDGFRA)-associated hypereosinophilic syndrome, eosinophilia is associated with formation of the FLIP1L1/PDFGRA gene, with resultant increased tyrosine kinase activity.

Frequency

Worldwide, hypereosinophilia is rare, especially in children.

Mortality/Morbidity

Death generally results from primary heart damage or secondary endocarditis. Survival is prolonged if the sequelae of organ damage, especially cardiac organ damage, can be controlled. Mean survival is 9 months; the 3-year survival rate is reported to be 12%.

Poor prognostic indicators include the following:

• Anemia
• Thrombocytopenia
• A WBC count higher than 100,000 cells/μ L
• Abnormal circulating basophilic cells
• Abnormal bone marrow
• An elevated vitamin B-12 level
• Abnormal leukocyte alkaline phosphatase levels

Race

The prevalence is low, with a racial distribution of cases as follows: 78% whites, 18% blacks, and 4% Asian Americans.

Sex

Hypereosinophilic syndrome has a 55.3% male predominance in the pediatric population.² The male-to-female ratio is 9:1 in adults.

Age

Persons aged 5-80 years can have hypereosinophilic syndrome. Persons aged 41-50 years are most commonly affected. The disease is rare in children.

One report documents a case of eosinophilia (WBC count, 80,000/μ L with 63% eosinophils) in an infant born to a mother with hypereosinophilic syndrome.³ The child's eosinophil count returned to normal in 8 months.

Clinical

History

Hypereosinophilia syndrome is a multisystem disease with symptoms related to eosinophil proteins and thrombotic phenomenon. Constitutional symptoms include fever, night sweats, anorexia, weight loss, fatigue, and nausea. Alcohol intolerance is occasionally noted.

• Abdominal/GI symptoms
  • Nausea
  • Abdominal pain
  • Diarrhea
  • Ascites
  • Hepatic thrombosis (Budd-Chiari syndrome)
• Pulmonary symptoms
  • Breathlessness
  • Nonproductive cough
• Dermatologic symptoms - Pruritic rash
• Vascular symptoms
  • Raynaud phenomenon
  • Thrombotic phenomenon, including retinal and hepatic (Budd-Chiari syndrome) symptoms
• Cardiac symptoms - Cardiac phenomenon (variant angina)
• Musculoskeletal symptoms
  • Arthralgias
  • Muscle pain
• Neurologic symptoms
  • Blurred vision
  • Confusion
  • Seizures
  • Psychosis
  • Dementia
• Gynecologic symptoms - Mastitis

Physical

Physical findings are those of a multisystem disease associated with thrombotic phenomenon and include the following:

• Cardiac signs
  • Endomyocardial fibrosis with myocarditis
  • Arrhythmia
  • Heart block
  • Congestive heart failure (CHF)
  • Valvular incompetence from fibrosis of chordae tendineae
  • Mitral and tricuspid regurgitation
  • Aortic valve disease (rare)
• Dermatologic signs
  • Vesiculobullous or petechial rash
  • Papulonodular
  • Livido reticularis
  • Angioedema
  • Blistering skin lesions
  • Cellulitis
  • Erythroderma
  • Erythema annulare
  • Ulcerating lesions of oral or nasal mucosa, genitalia, and anus
  • Subcutaneous nodules
  • Raynaud phenomenon
  • Subungual petechiae
  • Digital necrosis
• Musculoskeletal signs
  • Effusions of large joints
  • Multifocal bursitis, pauciarticular arthritis, subcutaneous nodules, pseudorheumatoid arthritis, and muscle weakness or tenderness (all rare)
• Vascular signs
  • Small-bowel necrosis
  • Subungual petechiae
  • Digital necrosis
• GI signs
  • Esophageal and gastric ulceration
  • Small-bowel necrosis
  • Sclerosing cholangitis
  • Chronic active hepatitis
  • Eosinophilic gastritis
  • Enterocolitis
  • Colitis
  • Ascites
  • Pancreatitis
  • Hepatosplenomegaly
• Pulmonary signs
  • Pulmonary infiltrates
  • Pleuritis
  • Pulmonary hypertension
• Neurologic signs
  • Coma
  • Encephalopathy
  • Peripheral neuropathy (This may occur as symmetric or asymmetric sensory neuropathy, painful paresthesias, mixed sensory and motor neuropathy, mononeuritis multiplex, or radiculopathy.)
  • Intracranial hemorrhage and/or stroke
• Ocular signs
  • Choroidal abnormalities (patchy and delayed filling, retinal vessel abnormality)
  • Pupillotonia
  • Keratoconjunctivitis sicca
  • Episcleritis
  • Retinal vein thrombosis

Causes

The cause is unknown, except in PDGFRA-associated hypereosinophilic syndrome, in which the formation of the fusion FLIP1L1/PDGFRA gene (secondary to a 4q12 microdeletion) is identified.

Differential Diagnoses

Other Problems to Be Considered

Allergic reaction
Combined immunodeficiency with eosinophilia
Churg-Strauss syndrome
Drug reaction
Eosinophilic fasciitis
Eosinophilic gastroenteritis
Eosinophilic leukemia
Eosinophilic panniculitis
Eosinophilic pneumonia
Eosinophilic urethritis
Eczema
Hereditary eosinophilia
Malignant disease
Parasitic infection
Pulmonary infiltrate with eosinophilia
Radiation-induced eosinophilia
Sweet syndrome

Workup

Laboratory Studies

• Hypereosinophilic syndrome is characterized by an eosinophil count of 1500/μ L (usually many more).
• Evaluate for a 4q12 microdeletion (800 kb) that produces recombination fusion, forming the FIP1L1/PDGFRA gene.^4,5 The formation of the FIP1L1/PDGFRA fusion gene results in increased tyrosine kinase activity, rendering poor response to steroids but sensitivity to imatinib.⁶
• The erythrocyte sedimentation rate (ESR) is usually elevated but can be normal.
• Leukocyte alkaline phosphatase levels may be high or low.
• Hypergammaglobulinemia in the form of extremely high immunoglobulin E (IgE) levels is noted in one third of patients.
• Immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) levels are only rarely elevated.
• Rheumatoid factor is only rarely present.
• Coombs test results may be positive.
• Results of rapid plasma reagent (RPR) tests are rarely positive.
• Hematuria, proteinuria, and azotemia may be present.
• Synovial fluid eosinophilia is prominent.
• Chromosomal analysis rarely reveals abnormalities. When abnormal chromosomes are present, a workup for eosinophilic leukemia is recommended. Eosinophilic leukemia is an unrelated disorder. The presence of chromosome abnormalities or eosinophil blast cells in the circulating blood or marrow may allow the leukemia to be recognized.
• A laboratory workup is also indicated to rule out disorders that can mimic the hypereosinophilic syndrome (see Differentials).

Imaging Studies

• Chest radiography may reveal nonspecific focal or diffuse, interstitial, or alveolar infiltrates.
• CT scanning may reveal pulmonary nodules with a halo of ground-glass attenuation, as well as nonspecific focal or diffuse, interstitial, or alveolar infiltrates.
• Ultrasonography findings of the affected liver may be normal.
• Technetium-99m sulfur colloid scanning may reveal nonhomogenous uptake in the presence of liver disease.

Other Tests

• Electrocardiography may reveal atrial fibrillation, ST-segment depression, T-wave changes, conduction abnormalities, left atrial atrophy, or left ventricular hypertrophy.
• Electrocardiography reveals involvement in 90% of patients with hypereosinophilic syndrome.

Procedures

• Bone marrow biopsy may reveal myelofibrosis.
• The presence of eosinophil blast cells suggests the alternative diagnosis of eosinophilic leukemia, an unrelated disorder.

Histologic Findings

• Activated eosinophil levels are noted in the blood and involved structures; this finding is associated with fibrosis.

Treatment

Medical Care

• No therapy is indicated in absence of organ damage.
• Angioedema and urticaria suggest a benign course.
• Mucosal ulcers do not respond to corticosteroids.
• Rapid intervention for cardiac disease is essential.
• Reducing the eosinophil load is the major goal of treatment. Although seemingly important, aggressive control of eosinophilia is hypothetical because all reports about treatment approaches are essentially anecdotal for this rare disorder. In the absence of organ disease, however, any indication for treatment is unclear, except with respect to thrombosis risk.
• Therapy to prevent the risk of thrombosis may be reasonable for all patients.

Surgical Care

• Cardiac surgery is indicated for annuloplasty, valve replacement, thrombectomy, and aortic prostheses.
• Because patients with mechanical valve replacements are especially prone to thrombosis, bioprostheses are recommended.
• Splenectomy may ameliorate platelet sequestration and is indicated for splenic infarction and pain due to splenic distention.

Consultations

• Obtaining subspecialty input from a rheumatologist and hematologist is essential.

Medication

No therapy is indicated in the absence of organ damage. Treatment is directed at organ system involvement and at reducing the eosinophil load and perhaps the eosinophil effect.

Corticosteroids

These agents interfere with eosinophilopoiesis by antagonizing IL-5, IL-3, and granulocyte/monocyte cell–stimulating factor. They also suppress eosinophilia; however, discontinue corticosteroids if eosinophilia is not suppressed. Response to steroids is considered a good prognostic indicator.

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Dosing

Adult

60 mg/d PO; eventually taper or change to alternate-day regimen

Pediatric

1 mg/kg PO qd; eventually taper or change to alternate-day regimen

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase glucocorticoid metabolism (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; active infection; ocular herpes simplex; chickenpox, measles, or live virus exposure

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May mask infections; abrupt discontinuation of glucocorticoids when used >2 wk may cause adrenal crisis; may cause hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections

Immunosuppressant and immunomodulator agents

These drugs are used to inhibit DNA synthesis, but only case reports of their effectiveness are available.

Hydroxyurea (Hydrea)

Interferes with DNA synthesis. Used to reduce total leukocyte count to <10,000/µL. Requires 7-14 d for effectiveness.

Dosing

Adult

1-3 g/d PO, continued as long as no significant reduction in platelet count occurs

Pediatric

20-30 mg/kg/d PO

Interactions

Potentiates pancreatitis with antiretroviral medications; coadministration with fluorouracil can increase neurotoxicity

Contraindications

Documented hypersensitivity; bone marrow depression, leukopenia <2500/µL, or thrombocytopenia <100,000/µL; pancreatitis

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Closely monitor blood counts at least weekly; severe anemia requires resolution before initiating therapy; renal failure requires dose adjustment; erythema occurs if individual has received radiation therapy in past; produces anemia, which often requires blood transfusion, and thrombocytopenia, which occasionally requires platelet transfusion

Vincristine (Oncovin)

Used to reduce total leukocyte count to <10,000/µL. Effective in 1-3 d and spares bone marrow toxicity but may cause paresthesias.

Dosing

Adult

1.5-2 mg IV as a single dose at 2-wk intervals

Pediatric

<10 kg: 0.05 mg/kg IV
>10 kg: 1.5-2 mg/m² IV
Not to exceed 2 mg/dose

Interactions

Acute pulmonary reaction may occur when taken concurrently with mitomycin-C; asparaginase, CYP3A4 inhibitors (eg, itraconazole, quinupristin/dalfopristin, sertraline, ritonavir), GM-CSF (eg, sargramostim, filgrastim), or nifedipine increase toxicity; CYP3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin) may decrease effects

Contraindications

Documented hypersensitivity; IT administration (may be fatal); bone marrow depression; cytopenia; demyelinating form of Charcot-Marie-Tooth syndrome

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Ensure vascular access intact because extravasation produces severe tissue damage; if severe tissue damage occurs, injection of hyaluronidase and application of heat helps disperse drug and reduce damage; do not inject directly but only through IV access line established as nonleaking; obtain CBC count before each dose; does not cross blood-brain barrier, but do not administer intrathecally; avoid eye contamination; hydrate patient to avoid uric acid nephropathy; if uric acid elevations are severe, consider allopurinol prophylaxis; if bilirubin >3 mg/dL, reduce dose by 50%; may cause paresthesias

Cyclophosphamide (Cytoxan)

Used to reduce total leukocyte count to <10,000/µL.

Dosing

Adult

50-125 mg/d PO

Pediatric

10-15 mg/kg IV q7-10d; alternatively, 3-5 mg/kg IV twice weekly or 1-5 mg/kg/d PO

Interactions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones
Chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Contraindications

Bone marrow depression, cytopenia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor blood counts and perform urinalyses weekly; complicates general anesthesia; toxicity increased in adrenalectomized (possibly also steroid-treated) patients; may compromise wound healing; treatment >90 d increases likelihood of sterility induction

Busulfan (Myleran)

Used to reduce total leukocyte count to <10,000/µL.

Dosing

Adult

4-8 mg/d PO

Pediatric

60 mcg/kg/d PO or 1.8 mg/m²/d PO

Interactions

Thioguanine increases toxicity; acetaminophen, phenytoin, or itraconazole may decrease clearance; high doses of cyclophosphamide and busulfan may cause cardiac tamponade

Contraindications

Bone marrow depression, cytopenia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Requires extreme vigilance in monitoring; requires weekly blood counts because WBC count may actually increase in first 10-15 d of treatment, do not alter dose for apparent inadequate response; patient must promptly report fever, sore throat, local infection, bleeding, any anemia-indicative symptom, breathing difficulties, or weakness

Methotrexate (Rheumatrex)

Used to reduce total leukocyte count to <10,000/µL.

Dosing

Adult

30 mg PO 2-3 times/wk

Pediatric

Not established; perhaps, 30 mg/m² PO qwk

Interactions

Intestinal absorption reduced by tetracycline, chlorambucil, nonabsorbable broad-spectrum antibiotics; hepatotoxicity increased by etretinate or other retinoids; may decrease theophylline clearance; charcoal lowers levels; coadministration with etretinate may increase hepatotoxicity; response may be decreased by folic acid or its derivatives contained in some vitamins
Probenecid, NSAIDs, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, can increase plasma levels; may decrease phenytoin plasma levels; may increase plasma levels of thiopurines; fatal reactions reported when administered concurrently with NSAIDs

Contraindications

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor blood counts closely; elimination reduced in impaired renal function, ascites, or pleural effusion; liver disease may preclude use; decisions about folic acid replacement must be individualized

Chlorambucil (Leukeran)

Used to reduce total leukocyte count to <10,000/µL.

Dosing

Adult

4-10 mg/m²/d PO for 4 consecutive days every other mo

Pediatric

0.1-0.2 mg/kg/d PO; use for minimal time because of risk of secondary malignancies

Interactions

None reported

Contraindications

Blood dyscrasias, thrombocytopenia, leukopenia, severe anemia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Requires weekly blood counts; may cause chromosome damage and sterility; do not administer within 4 wk of radiation therapy; induces secondary malignancies; caution in history of seizure disorders or current bone marrow suppression; total doses >6.5 mg/kg increases risk of irreversible bone marrow damage

Etoposide (VP16-213, VePesid)

Podophyllotoxin derivative that acts as topoisomerase II inhibitor to cause DNA damage.

Dosing

Adult

50-100 mg/m²/d PO on days 1, 3, and 5

Pediatric

Administer as in adults

Interactions

May prolong the effects of warfarin and increase methotrexate clearance; cyclosporine and etoposide have additive effects in the cytotoxicity of tumor cells

Contraindications

Documented hypersensitivity; IT administration may cause death; blood dyscrasias, thrombocytopenia, leukopenia, severe anemia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Closely monitor blood counts before each cycle; withhold therapy platelet count <50,000/µL or absolute neutrophil count <500/µL; administer as slow infusions over 30-60 min; anaphylactic reactions can occur; reduce dose in presence of renal insufficiency; do not use acrylic or acrylonitrile/butadiene/styrene (ABS) plastics in the infusions

Interferon alfa 2a or 2b (Roferon-A, Intron-A)

Empirically applied to many diseases as immunomodulator. Acts at biologically active sites in eosinophil action.

Dosing

Adult

8 million U/d IM/SC initially, then 2 million U/d or 5-7 million U 3 times per wk

Pediatric

Not established; consider 2.5-5 million U/m²/d IM/SC; deaths reported with doses of 30 million U/m²/d

Interactions

Reduces theophylline clearance

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Assess CBC counts before therapy; check preservative and biologic source to ensure patient is not allergic; brands not interchangeable; avoid tasks requiring mental alertness after high dose therapy; warn patient that depression and suicidal ideation are adverse effects; can cause flulike symptoms; caution in severe hepatic or renal insufficiencies, seizure disorders, multiple sclerosis, or compromised CNS

Cyclosporine (Sandimmune, Neoral)

Inhibits T-cell clonal release of eosinophilopoietin cytokines.

Dosing

Adult

2.5 mg/kg/d PO; not to exceed 10 mg/kg/d; toxicity problematic at high dose

Pediatric

Not established; possibly 2.5 mg/kg/d PO; not to exceed 10 mg/kg/d; toxicity problematic at high dose

Interactions

NSAIDs or grapefruit juice increase levels; octreotide may decrease levels by interfering with bioavailability; increases digoxin, methotrexate, and diclofenac levels; coadministration with other nephrotoxic drugs (eg, amphotericin B, ketoconazole, tacrolimus, cimetidine, ranitidine, gentamicin, tobramycin, vancomycin, trimethoprim, sulfamethoxazole, NSAIDs) may potentiate renal dysfunction; CYP3A4 inhibitors (eg, diltiazem, nicardipine, verapamil, fluconazole, itraconazole, ketoconazole, clarithromycin, erythromycin, methylprednisolone, allopurinol, bromocriptine, danazol, metoclopramide, indinavir, nelfinavir, ritonavir, saquinavir) may increase levels; CYP3A4 inducers (eg, rifampin, carbamazepine, phenobarbital, phenytoin, ticlopidine) may decrease levels
Live attenuated virus vaccines may not result in protective immunization when administered with cyclosporine or within 3-12 mo following discontinuation of cyclosporine

Contraindications

Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis because may increase risk of cancer

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor BUN, creatinine, and serum bilirubin levels, BP, and LFT results q2wk for first 3 mo and monthly thereafter; reduce dose by 25% if hypertension occurs; may increase risk of infection and lymphoma; reserve IV use for only patients who cannot take drug PO

Sorafenib (Nexavar)

Multikinase inhibitor that targets serine/threonine and tyrosine receptor kinases in both the tumor cell and the tumor vasculature. Targets kinases involved in tumor cell proliferation and angiogenesis, thereby decreasing tumor cell proliferation. These kinases include RAF kinase, VEGFR-2, VEGFR-3, PDGFR-beta, KIT, and FLT-3.

Dosing

Adult

400 mg PO bid 1 h ac or 2 h pc

Pediatric

Not established

Interactions

CYP450 2B6 and 2C8 inhibitor; predominantly eliminated by UGT1A1 pathway (caution when coadministered with other drugs eliminated by UGT1A1 [eg, irinotecan]); coadministration with warfarin may increase INR or bleeding

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Common adverse reactions include hand or foot skin reaction and rash (modify dose); may increase risk of hemorrhage, cardiac ischemia and/or infarction, alopecia, pruritus, or diarrhea; caution with severe hepatic impairment (ie, Child-Pugh C)

Imatinib mesylate (Gleevec)

Specifically designed to inhibit tyrosine kinase activity of the bcr-abl kinase in Ph+ leukemic chronic myeloid leukemia (CML) cell lines. Well absorbed after PO administration, with maximum concentrations achieved within 2-4 hours. Elimination is primarily in feces in form of metabolites. FDA-approved for chronic hypereosinophilic syndrome in adults. Also indicated to treat pediatric patients with Ph+ chronic phase CML whose disease has recurred after stem cell transplant, or have demonstrated interferon alpha resistance.

Dosing

Adult

100-400 mg PO qd with food

Pediatric

Up to 260 mg/m²/d PO with food

Interactions

CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, clarithromycin) increase imatinib distribution; CYP3A4 substrates (eg, simvastatin) increases imatinib maximum concentration by a factor of 2-3.5-fold; CYP3A4 inducers (eg, phenytoin, dexamethasone, carbamazepine, rifampin, phenobarbital, St. John's Wort) decrease imatinib AUC by approximately one-fifth of typical AUC; likely to increase blood levels of drugs that are substrates of CYP2C9, CYP2D6, and CYP3A4/5 (eg, benzodiazepines, dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, warfarin)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Dose must be reduced or interrupted if edema or anemia occur, transaminases or bilirubin become elevated, or grade 3-4 neutropenia or thrombocytopenia develop; Stevens Johnson syndrome has been reported; pediatric patient commonly experience musculoskeletal pain; may cause/exacerbate CHF or left ventricular dysfunction, monitor patients with preexisting cardiac disease); complete blood counts and liver function testing are advised weekly for 1 month, biweekly for a month and then every 2-3 months; do not breast feed

Anti-inflammatory agents

Dapsone is a sulfone antimicrobial. Its anti-inflammatory action, which enables its use for dermatologic conditions, is not fully understood but does not appear to be associated with its antibacterial action.

Dapsone (Avlosulfon)

Sulfone specifically useful for skin involvement.

Dosing

Adult

50-300 mg/d PO

Pediatric

Not established; consider 0.8-4 mg/kg/d PO; not to exceed 100 mg/d

Interactions

May inhibit anti-inflammatory effects of clofazimine; hematologic reactions may increase with folic acid antagonists (eg, pyrimethamine); monitor for agranulocytosis during the second and third months of therapy; probenecid increases toxicity; coadministration with trimethoprim may increase toxicity of both drugs; because of increased in renal clearance, levels may significantly decrease when administered concurrently with rifampin

Contraindications

Documented hypersensitivity; G-6-PD or methemoglobin reductase deficiencies; hemoglobin M or hemolysis-inducing conditions

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Perform weekly CBC counts for first month; then perform WBC counts monthly for 6 mo; then semiannually; discontinue if significant reduction in platelets, leukocytes, or hematopoiesis observed
Caution in methemoglobin reductase deficiency, G-6-PD deficiency (patients receiving >200 mg/d), or hemoglobin M because of high risk for hemolysis and Heinz body formation; caution in patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; peripheral neuropathy can occur (rare); phototoxicity may occur when exposed to UV light

Anticoagulant and antiplatelet agents

These agents are used in an effort to reduce frequency of thrombotic events. Warfarin and aspirin have well-established roles in preventing thrombosis. Warfarin acts as an anticoagulant by antagonizing vitamin K in its role as a cofactor in the carboxylation process of coagulation factors II, VII, IX, and X. Aspirin possess antiplatelet ability by permanently inactivating cyclooxygenase (COX) activity of prostaglandin synthase-1 and prostaglandin synthase-2 (ie, COX-1 and COX-2).

Thromboxane A₂ (TXA₂) induces platelet aggregation and vasoconstriction. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit TXA₂ by reversible inhibition of COX-1. The level of reversible inhibition provided by NSAIDS may be inadequate to effectively block platelet aggregation in vivo. However, the NSAID indobufen, which is not available in the United States, is a potent inhibitor and has biochemical activity comparable to aspirin. Further investigation of effective antiplatelet drugs is essential to overcome obstacles associated with aspirin (eg, toxicity, resistance).

Warfarin (Coumadin)

Used to achieve sufficient anticoagulation to prevent thrombotic events. Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Adjust dose to maintain INR of 2-3 in absence of associated anticardiolipin syndrome.

Dosing

Adult

5-15 mg/d PO qd for 2-5 d initially adjusted according to desired INR (ie, 2-3); maintenance dose must be monitored periodically by INR; if recurrent emboli occur, maintain INR of 3-3.5

Pediatric

0.1-0.2 mg/kg/d PO, adjust doses over initial 5 d according to target INR; then monitor maintenance dose with periodic INR and adjust accordingly

Interactions

Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, PO contraceptives, and sucralfate
Medications that may increase anticoagulant effects include PO antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac

Contraindications

Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers; recent or contemplated CNS, eye, or major trauma surgery; GI, genitourinary or respiratory bleeding; dissecting aorta; infectious endocarditis or pericarditis

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

PT must be monitored weekly until stable at desired INR and then monthly or with changes in concomitant medication or diet; do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes mellitus; patients with protein C or S deficiency are at risk of developing skin necrosis

Aspirin (Anacin, Ascriptin, Bayer)

Inhibits prostaglandin synthesis, preventing formation of platelet-aggregating TXA₂. May be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis.

Dosing

Adult

81 mg/d PO or 1 mg/kg/d PO; some patients need as much as 12 times typical dose

Pediatric

Administer as in adults

Interactions

Increases toxicity of lithium, methotrexate, and possibly cyclosporine (especially renal with methotrexate, cyclosporine); may impair diuretic effectiveness
Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose lowering effect of sulfonylurea drugs

Contraindications

Documented hypersensitivity; liver damage, hypoprothrombinemia, vitamin K deficiency, bleeding disorders, asthma, porphyria; do not use in children (<16 y) with flu because of association with Reye syndrome

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Assess ADP-induced and collagen-induced platelet aggregation to titer the aspirin; may cause transient decrease in renal function and aggravate chronic kidney disease; avoid in severe anemia, history of blood coagulation defects, or current anticoagulant use

Interleukin inhibitor

Results from a Phase III study demonstrate significantly more patients who received mepolizumab for treatment of hypereosinophilic syndrome were able to maintain disease control with reduced corticosteroid use (84% vs 43%, p<0.001).⁷

Mepolizumab (Bosatria)

Humanized anti-interleukin-5 monoclonal immunoglobulin G1 antibody. Orphan drug status in the United States and the European Union.

Dosing

Adult

750 mg IV q4wk

Pediatric

Unknown. Could find no reports on pediatric usage for this disorder.

Interactions

Limited data available; none reported

Contraindications

Documented hypersensitivity; bacterial infection, parasitic infestations, collagen vascular disease, vasculitis, graft-versus host disease, malignancy

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Limited data available

Follow-up

Further Inpatient Care

• Monitoring for eosinophil count, cardiac disease, adverse effects of treatment, and complications is essential.

Further Outpatient Care

• Monitoring for eosinophil count, cardiac disease, adverse effects of treatment, and complications is also an essential part of outpatient care.
• The frequency of monitoring depends on the apparent stability of disease. Initially, weekly monitoring is indicated; motoring is performed monthly if the patient enters a chronic phase.

Inpatient & Outpatient Medications

• In the presence of organ involvement, a steroid trial is indicated. If steroidal trial fails, vincristine is used when immediate reduction of eosinophil levels is imperative. Dapsone is considered for skin involvement.
• Because most treatment reports are anecdotal, therapy with alkylating agents is the next consideration. Treatment choices should be individualized for each patient.
• Because of the risk of thrombotic phenomenon, antiplatelet therapy with aspirin or a NSAID, but not a COX-2–specific agent, is indicated. In the presence of actual thrombotic activity, warfarin (Coumadin) is indicated. Coumadin may also be considered in significant cardiac involvement.
• In PDGFRA-associated hypereosinophilic syndrome, imatinib, which inhibits the activity of fusion kinase FIP1L1/PDGFRA, is a first-line treatment.

Complications

• Patients with thrombotic phenomenon require constant monitoring.

Prognosis

• The prognosis is poor, and treatment reports are anecdotal.
  • The mean survival is 9 months. The 3-year survival rate is reported to be 12%.
  • Survival is prolonged if sequelae of organ damage, especially cardiac, can be controlled.
• Poor prognostic indicators include the following:
  • Anemia
  • Thrombocytopenia
  • A WBC count higher than 100,000/µL
  • Circulating basophilic abnormal cells
  • Abnormal bone marrow
  • An elevated vitamin B-12 level
  • Abnormal leukocyte alkaline phosphatase levels

Patient Education

• Patients and their families must be alerted to look for signs of thrombotic disease; any change in pulmonary, cardiac, or neurologic status; bruising; or a sore throat. These are indications for urgent reassessment.

Miscellaneous

Medicolegal Pitfalls

• Be sure to eliminate other diagnostic possibilities.
• Be alert for thrombotic events.

Special Concerns

• Attention to cardiac involvement and thrombotic phenomenon is essential.

References

1. Martinelli G, Rondoni M, Ottaviani E, Paolini S, Baccarani M. Hypereosinophilic syndrome and molecularly targeted therapy. Semin Hematol. 2007;44(Suppl 2):S4-S16.

2. James J. Pediatric hypereosinophilic syndrome (HES) differs from adult HES. Pediatrics. 2006;118:S49-S50. [Full Text].

3. Carey JP, Burke AC. Transient hypereosinophilia in the infant of a mother with hypereosinophilic syndrome. Arch Intern Med. Sep 1982;142(9):1754-5. [Medline].

4. Roche-Lestienne C, Lepers S, Soenen-Cornu V, et al. Molecular characterization of the idiopathic hypereosinophilic syndrome (HES) in 35 French patients with normal conventional cytogenetics. Leukemia. May 2005;19(5):792-8. [Medline].

5. Schoch C, Reiter A, Bursch S, et al. Chromosome binding analysis, FISH and RT-PCR performed in parallel in hyperesosinophilic syndrome establishes the diagnosis of chronic eosinophilic leukemia in 22% of cases: A study of 40 patients. Blood. 2004;104:2444.

6. Miyazawa K, Kakazu N, Ohyashiki K. Clinical features of hypereosinophilic syndrome: FIP1L1-PDGFRA fusion gene-positive disease is a distinct clinical entity with myeloproliferative features and a poor response to corticosteroid. Int J Hematol. Jan 2007;85(1):5-10. [Medline].

7. [Best Evidence] Rothenberg ME, Klion AD, Roufosse FE, et al. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med. Mar 20 2008;358(12):1215-28. [Medline].

8. Adame J, Cohen PR. Eosinophilic panniculitis: diagnostic considerations and evaluation. J Am Acad Dermatol. Feb 1996;34(2 Pt 1):229-34. [Medline].

9. Adams HW, Mainz DL. Eosinophilic ascites. A case report and review of the literature. Am J Dig Dis. Jan 1977;22(1):40-2. [Medline].

10. Alfaham MA, Ferguson SD, Sihra B, Davies J. The idiopathic hypereosinophilic syndrome. Arch Dis Child. Jun 1987;62(6):601-13. [Medline].

11. Anders HJ, Schattenkirchner M. Destructive joint lesions and bursitis in idiopathic hypereosinophilic syndrome. Rheumatology (Oxford). Feb 1999;38(2):185-6. [Medline].

12. Bain BJ. Eosinophilic leukaemias and the idiopathic hypereosinophilic syndrome. Br J Haematol. Oct 1996;95(1):2-9. [Medline].

13. Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). Jan 1975;54(1):1-27. [Medline].

14. Cryer PE, Kissane J. Hypereosinophilic syndrome with pulmonary hypertension. 1976;60:239-247.

15. Davies J, Spry CJ, Sapsford R, et al. Cardiovascular features of 11 patients with eosinophilic endomyocardial disease. Q J Med. Winter 1983;52(205):23-39. [Medline].

16. Flaum MA, Schooley RT, Fauci AS, Gralnick HR. A clinicopathologic correlation of the idiopathic hypereosinophilic syndrome. I. Hematologic manifestations. Blood. Nov 1981;58(5):1012-20. [Medline].

17. Kang EY, Shim JJ, Kim JS, Kim KI. Pulmonary involvement of idiopathic hypereosinophilic syndrome: CT findings in five patients. J Comput Assist Tomogr. Jul-Aug 1997;21(4):612-5. [Medline].

18. Katz HT, Haque SJ, Hsieh FH. Pediatric hypereosinophilic syndrome (HES) differs from adult HES. J Pediatr. Jan 2005;146(1):134-6. [Medline].

19. Layzer RB, Shearn MA, Satya-Murti S. Eosinophilic polymyositis. Ann Neurol. Jan 1977;1(1):65-71. [Medline].

20. Lierman E, Folens C, Stover EH, et al. Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant. Blood. Aug 15 2006;108(4):1374-6. [Medline].

21. Parrillo JE, Borer JS, Henry WL, et al. The cardiovascular manifestations of the hypereosinophilic syndrome. Prospective study of 26 patients, with review of the literature. Am J Med. Oct 1979;67(4):572-82. [Medline].

22. Postovsky S, Daitzchman M, Dale A, Elhasid R, Ben Arush MW. Unusual presentation of mastoid eosinophilic granuloma in a young patient. Pediatr Hematol Oncol. Jun 2001;18(4):283-9. [Medline].

23. Spark RP, Gleason DM, DeBenedetti CD, Gigax JH. Is eosinophilic ureteritis an entity? 2 case reports and review. J Urol. Jun 1991;145(6):1256-60. [Medline].

24. Tefferi A. Blood eosinophilia: a new paradigm in disease classification, diagnosis, and treatment. Mayo Clin Proc. Jan 2005;80(1):75-83. [Medline].

25. van den Hoogenband HM. Skin lesions as the first manifestation of the hypereosinophilic syndrome. Clin Exp Dermatol. May 1982;7(3):267-71. [Medline].

26. Wardlaw AJ, Moqbel R, Kay AB. Eosinophils: biology and role in disease. Adv Immunol. 1995;60:151-266. [Medline].

27. Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood. May 15 1994;83(10):2759-79. [Medline].

28. White WL, Wahner HW, Brown ML, James EM. Sequential liver imaging in the hypereosinophilic syndrome: discordant images with scintigraphy, ultrasound, and computed tomography. Clin Nucl Med. Feb 1981;6(2):75-7. [Medline].

Keywords

disseminated eosinophilic collagen disease, endomyocardial disease, eosinophilia, eosinophilic leukocytosis, myeloproliferative, lymphocytic, idiopathic, hypereosinophilic syndrome, endomyocardial fibrosis, platelet-derived growth factor receptor alpha, PDGFRA, secondary endocarditis, anemia, thrombocytopenia, ascites, hepatic thrombosis, Budd-Chiari syndrome, Raynaud phenomenon, thrombotic phenomenon, mastitis, dementia, endomyocardial fibrosis, myocarditis, arrhythmia, congestive heart failure, valvular incompetence, mitral regurgitation

tricuspid regurgitation, aortic valve disease, vesiculobullous rash, papulonodular rash, livido reticularis, angioedema, cellulitis, erythroderma, erythema annulare, subungual petechiae, digital necrosis, multifocal bursitis, pauciarticular arthritis, small-bowel necrosis, sclerosing cholangitis, chronic active hepatitis, enterocolitis, pancreatitis, hepatosplenomegaly, pleuritis, pulmonary hypertension, encephalopathy, pupillotonia, keratoconjunctivitis sicca, episcleritis, retinal vein thrombosis

Contributor Information and Disclosures

Author

Bruce M Rothschild, MD, Professor of Medicine, The Northeastern Ohio Universities College of Medicine; Director, Arthritis Center of Northeast Ohio; Adjunct Professor, Department of Biomedical Engineering, University of Akron
Bruce M Rothschild, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Rheumatology, American Federation for Clinical Research, American Heart Association, American Society for Clinical Pharmacology and Therapeutics, International Skeletal Society, New York Academy of Sciences, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

James M Oleske, MD, MPH, François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School
James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: "no financial interest" None None

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

David J Valacer, MD, Consulting Staff, Hoffman La Roche Pharmaceuticals
David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

CME Editor

David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville
David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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