eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Hypereosinophilic Syndrome

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
Contributor Information and Disclosures

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
  • 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.

More on Hypereosinophilic Syndrome

Overview: Hypereosinophilic Syndrome
Differential Diagnoses & Workup: Hypereosinophilic Syndrome
Treatment & Medication: Hypereosinophilic Syndrome
Follow-up: Hypereosinophilic Syndrome
References
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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. 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].

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  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].

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  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].

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  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].

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Further Reading

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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

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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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