Pediatric Hypereosinophilic Syndrome 

Updated: Aug 02, 2018
Author: Bruce M Rothschild, MD; Chief Editor: Harumi Jyonouchi, MD 

Overview

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.[1] Three subtypes are recognized: myeloproliferative, lymphocytic, and idiopathic.[2] 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), resulting in large numbers of circulating eosinophils.

Toxicity of hypereosinophilia is related to fibrosis, especially endomyocardial fibrosis. Fibrosis is caused by mediators contained in eosinophil granules,[3] 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 complications.

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

FIP1L1/PDGFR point mutations often camouflage assays of TK activity, but do not necessarily affect imatinib effectiveness.[4]

Eosinophilic esophagitis is associated with genetically based loss of esophageal tissue differentiation, with both up and down regulation of proteases and their inhibitors.[5]

Epidemiology

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.[6] 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.[7] The child's eosinophil count returned to normal in 8 months.

 

Presentation

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 include the following:

  • Nausea

  • Abdominal pain

  • Diarrhea

  • Ascites

  • Hepatic thrombosis (Budd-Chiari syndrome)

Pulmonary symptoms include the following:

  • Breathlessness

  • Nonproductive cough

Dermatologic symptoms include a pruritic rash.

Vascular symptoms include the following:

  • Raynaud phenomenon

  • Thrombotic phenomenon, including retinal and hepatic (Budd-Chiari syndrome) symptoms

Cardiac symptoms include cardiac phenomenon (variant angina).

Musculoskeletal symptoms include the following:

  • Arthralgias

  • Muscle pain

Neurologic symptoms include the following:

  • Blurred vision

  • Confusion

  • Seizures

  • Psychosis

  • Dementia

Gynecologic symptoms include mastitis.

Physical

Physical findings are those of a multisystem disease associated with thrombotic phenomenon.

Cardiac signs include the following:

  • 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 include the following:

  • 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 include the following:

  • Effusions of large joints

  • Multifocal bursitis, pauciarticular arthritis, subcutaneous nodules, pseudorheumatoid arthritis, and muscle weakness or tenderness (all rare)

Vascular signs include the following:

  • Small-bowel necrosis

  • Subungual petechiae

  • Digital necrosis

GI signs include the following:

  • Esophageal and gastric ulceration

  • Small-bowel necrosis

  • Sclerosing cholangitis

  • Chronic active hepatitis

  • Eosinophilic gastritis

  • Enterocolitis

  • Colitis

  • Ascites

  • Pancreatitis

  • Hepatosplenomegaly

Pulmonary signs include the following:

  • Pulmonary infiltrates

  • Pleuritis

  • Pulmonary hypertension

Neurologic signs include the following:

  • 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 include the following:

  • Choroidal abnormalities (patchy and delayed filling, retinal vessel abnormality)

  • Pupillotonia

  • Keratoconjunctivitis sicca

  • Episcleritis

  • Retinal vein thrombosis

Causes

The cause is unknown, except in platelet-derived growth factor receptor alpha (PDGFRA)-associated hypereosinophilic syndrome. In this condition, the formation of theFLIP1L1/PDGFRA fusion gene (secondary to a 4q12 microdeletion) results in increased activity of tyrosine kinase of PDFGRA, resulting in eosinophilia or PDGFRA-associated chronic eosinophilic leukemia. Formation of the FLIP1L1/PDGFRA fusion gene is known to be found in 10-15% of patients with hypereosinophilic syndrome.

 

DDx

 

Workup

Laboratory Studies

Hypereosinophilic syndrome is characterized by an eosinophil count of more than 1500/μL (usually many more).

It is necessary to evaluate for a 4q12 microdeletion (800 kb) that produces recombination fusion, forming the FIP1L1/PDGFRA fusion gene.[8, 9] The formation of the FIP1L1/PDGFRA fusion gene results in increased tyrosine kinase activity of PDGFRA, rendering poor response to steroids but sensitivity to imatinib.[10]

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 may be positive. Results of rapid plasma reagin (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 cardiac 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 hypereosinophilic syndrome with absence of organ damage. Presence of angioedema and urticaria suggest a benign course (see the image below). However, therapy to prevent the risk of thrombosis may be reasonable for all patients suffering from hypereosinophilic syndrome.[11]

Urticarial and erythematous rash. Urticarial and erythematous rash.

Corticosteroids have been used as first-line treatment. However, mucosal ulcers do not respond to corticosteroids. Other immunosuppresants and immunomodulating agents have been used as detailed in the medication section. These include hydroxyurea, vincristine, cyclophosphamide, busulfan, methotrexate, chlambucil, etoposide, cyclosproin, and alemtuzumab.

Rapid intervention for cardiac disease is essential.

Reducing the eosinophil load is the major goal of treatment.[12] Although seemingly important, therapeutic benefits of aggressive control of eosinophilia are hypothetical, because all reports about treatment approaches are essentially anecdotal for this rare disorder. In the absence of organ disease, any indication for treatment is unclear, except for preventive measures for thrombosis.

A small experimental study found that alemtuzumab (humanized anti-CD52 murine monoclonal antibody) was helpful in patients with advanced hypereosinophilic syndrome refractory to other standard therapies. Escalating doses of 5 mg, 10 mg, and 30 mg IV on days 1-3, and then at tolerated dose 3 times per week for 3 weeks, were suggested. If a full response is seen, weekly administration is indicated by authors. The authors also suggest clinical evaluation of alemtuzumab in a larger clinical trial is warranted.[13]

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

Medication Summary

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.

A small experimental study found that alemtuzumab was helpful in advanced hypereosinophilic syndrome refractory to other standard therapies. Escalating doses of 5 mg, 10 mg, and 30 mg IV on days 1-3, and then at tolerated dose 3 times per week for 3 weeks, were suggested. If a full response is seen, consider weekly administration. The authors suggest clinical evaluation of alemtuzumab in a larger clinical trial is warranted.[13]

Corticosteroids

Class Summary

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.

Immunosuppressant and immunomodulator agents

Class Summary

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.

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.

Cyclophosphamide (Cytoxan)

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

Busulfan (Myleran)

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

Methotrexate (Rheumatrex)

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

Chlorambucil (Leukeran)

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

Etoposide (VP16-213, VePesid)

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

Interferon alfa 2b (Intron A)

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

Cyclosporine (Sandimmune, Neoral)

Inhibits T-cell clonal release of eosinophilopoietin cytokines.

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.

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.  In patients with confirmed formation of FIP1L1-PDGFRA fusion gene, imatinib is expected to be effective by blocking tyrosine kinase activity of PDGFRA; this fusion gene induced hyperactivity of tyrosine kinase of PDGFRA.

Anti-inflammatory agents

Class Summary

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.

Anticoagulant and antiplatelet agents

Class Summary

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.

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.

Interleukin inhibitor

Class Summary

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).[14]

Mepolizumab

Humanized anti-interleukin-5 monoclonal immunoglobulin G1 antibody. Pending FDA approval for severe eosinophilic asthma. 

 

Follow-up

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.

Further Inpatient Care

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

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 platelet-derived growth factor receptor alpha (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.