eMedicine Specialties > Hematology > Immune System and Disorders

Hypereosinophilic Syndrome

Author: Venkata Samavedi, MBBS, MD, Internist in Houston, TX
Coauthor(s): Ronald A Sacher, MB, BCh, MD, FRCPC, Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center; Vincent E Herrin, MD, Associate Professor of Medicine, Divisions of Hematology and Oncology, University of Mississippi School of Medicine; Joe C Files, MD, Director, Division of Hematology, Associate Chairman, Professor, Department of Internal Medicine, University of Mississippi Medical Center; Youwen Zhou, MD, PhD, FRCP(C), Associate Professor, Department of Dermatology and Skin Science, University of British Columbia; Director, Hyperhidrosis Specialty Clinic, Co-Director, Psoriasis and Phototherapy Centre, Consulting Physician, Department of Dermatology, Vancouver General Hospital, Co-Director, Vitiligo and Pigmentation Clinic, Oncologist Consultant, Skin Tumor Program, BC Cancer Agency; Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA
Contributor Information and Disclosures

Updated: Oct 4, 2009

Introduction

Background

Hypereosinophilic syndrome (HES) is a myeloproliferative disorder (MPD) characterized by persistent eosinophilia that is associated with damage to multiple organs.^1,2,3,4 Peripheral eosinophilia with tissue damage has been noted for approximately 80 years, but Hardy and Anderson first described the specific syndrome in 1968.⁵ In 1975, Chusid et al defined the 3 features required for a diagnosis of hypereosinophilic syndrome⁴ :

1. A sustained absolute eosinophil count (AEC) greater than >1500/µl is present, which persists for longer than 6 months. 
2. No identifiable etiology for eosinophilia is present.
3. Patients must have signs and symptoms of organ involvement.

However, due to advances in the diagnostic techniques, secondary causes of eosinophilia can be identified in a proportion of cases which would have otherwise been classified as idiopathic hypereosinophilic syndrome.

The differential diagnosis (see Differentials and Other Problems to Be Considered) of hypereosinophilic syndrome includes other causes of eosinophilia^1,6,7,8 , which may be classified as familial and acquired. Familial eosinophilia is an autosomal dominant disorder with a stable eosinophilic count and benign clinical course. Acquired eosinophilia is further divided into secondary, clonal and idiopathic eosinophilia.⁹

Secondary eosinophilia

Secondary eosinophilia is a cytokine-derived (interleukin-5 [IL-5]) reactive phenomenon. Worldwide, parasitic diseases are the most common cause, whereas in developed countries, allergic diseases are the most common cause.¹ Other causes include malignancies (metastatic cancer, T-cell lymphoma,¹⁰ colon cancer), pulmonary eosinophilia Loffler syndrome,¹¹ Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis), connective tissue disorders (scleroderma, polyarteritis nodosa), skin diseases (dermatitis herpitiformis), inflammatory bowel disease, sarcoidosis, and Addison disease.

Clonal eosinophilia

Clonal eosinophilia is diagnosed by bone marrow histology, cytogenetics, and molecular genetics and include the following:

1. Acute Leukemia (Pre-B acute lymphoblastic leukemia [ALL], acute myeloid leukemia [AML]-M4EO)
2. Chronic myeloid disorders

Molecularly defined disorders include the following:

• BCR-ABL chronic myeloid leukemia
• PDGFRA –rearranged eosinophilia (platelet-derived growth factor receptor, alpha polypeptide) (systemic mastocytosis –chronic eosinophilia [SE-CEL])
• PDGFRβ – rearranged eosinophilia
• KIT –mutated systemic mastocytosis

Clinicopathologically assigned disorders include the following:

• Myeloproliferative syndrome (MDS)
• MPDs
  • Classic MPD (polycythemia)
  • Atypical MPD
    • Chronic eosinophilic leukemia
    • Systemic mastocytosis
    • Chronic myelomonocytic leukemia

1. Eosinophil count of at least 1500/µL
2. Peripheral blood blast count of >2% and a bone marrow blast cell count that is >5% but <19% of all nucleated cells
3. Criteria for atypical CML, chronic myelomonocytic leukemia, and chronic granulocytic leukemia (BCR-ABL –positive CML) are not met
4. Myeloid cells are demonstrated to be clonal (eg, by detection of clonal cytogenetic abnormality or by demonstration of a very skewed expression of X chromosome genes)

Pathophysiology

Eosinophil production is governed by several cytokines, including IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). IL-5 appears to be the most important cytokine that is responsible for differentiation of the eosinophil line.^2,6  

Unlike neutrophils, eosinophils can survive in the tissues for weeks. Their survival in tissues depends on the sustained presence of cytokines. Only eosinophils and basophils and their precursors have receptors for IL-3, IL-5, and GM-CSF. In vitro, eosinophils survive less than 48 hours in the absence of cytokines.

Eosinophil granules contain toxic cationic proteins, which are the primary mediators of tissue damage. These toxins include major basic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, and eosinophil cationic protein. The latter 2 are ribonucleases. Free radicals produced by the eosinophilic peroxidase and the respiratory burst oxidative pathway of the infiltrating eosinophils further enhance the damage. Eosinophils amplify the inflammatory cascade by recruiting more eosinophils from secreting their own chemoattractants like eotaxin, platelet-activating factor, and the cytokine RANTES (regulated upon activation, normal T cell expressed, and secreted).

Several mechanisms have been proposed for the pathogenesis of hypereosinophilic syndrome, including overproduction of eosinophilopoietic cytokines, their enhanced activity, and defects in the normal suppressive regulation of eosinophilopoiesis. Organ damage induced by hypereosinophilic syndrome is due to the eosinophilic infiltration of the tissues accompanied by the mediator release from the eosinophil granules. Hence, the level of eosinophilia is not a true reflection of organ damage.

The most serious complication of hypereosinophilic syndrome is cardiac involvement that leads to myocardial fibrosis, congestive heart failure (CHF), and death. The mechanisms of cardiac damage are not entirely understood, but the damage is marked by severe endocardial fibrotic thickening of either ventricle or both ventricles, resulting in restrictive cardiomyopathy due to inflow obstruction.

Frequency

United States

Various sources indicate that the prevalence of true hypereosinophilic syndrome is rare. The most common cause of eosinophilia in the United States is an allergic reaction or allergic disease, but the prevalence of hypereosinophilic syndrome is far less.

International

The most common cause of eosinophilia worldwide is parasitosis. The prevalence of hypereosinophilic syndrome is far less.

Mortality/Morbidity

Hypereosinophilic syndrome is a chronic and progressive disorder that is potentially fatal. Blast transformation could occur after many years. True idiopathic hypereosinophilic syndrome is generally indolent; however, patients with characteristics that are suggestive of a myeloproliferative/neoplastic disorder and those who manifest CHF have a worse prognosis.

• An older review of 57 patients with advanced hypereosinophilic syndrome reported a mean survival of 9 months and a 3-year survival rate of 12%.⁴
• A later analysis from France noted an 80% survival at 5 years and a 42% survival at 15 years among 40 patients with hypereosinophilic syndrome.²²

Race

No racial predilection is reported for hypereosinophilic syndrome.

Sex

There is a male predominance in hypereosinophilic syndrome, with a male-to-female ratio of 9:1.

Age

Hypereosinophilic syndrome is most commonly diagnosed in patients aged 20-50 years, with a peak incidence in the 4^th decade.

• Hypereosinophilic syndrome is rare in children.
• The incidence of hypereosinophilic syndrome seems to decrease in the elderly population.

Clinical

History

Hypereosinophilic syndrome is a heterogeneous disease process; thus, multiple manifestations may occur simultaneously or individually. The presenting symptoms can be sudden and dramatic, which sometimes occur with cardiac, neurologic, or thrombotic complications, but, more often, the onset is insidious.²³ In one case series, 12% of patients with hypereosinophilic syndrome discovered it as an incidental finding.

Virtually any organ system may be involved in hypereosinophilic syndrome, but the heart, central nervous system (CNS), skin, and respiratory tract are commonly involved. Thromboembolic disease is not infrequent. Major symptoms of hypereosinophilic syndrome include the following:

• Cardiac symptoms
  • The cardiac system is one of the most frequently involved systems, and cardiac complications are a leading cause of mortality.
  • Damage typically occurs in 3 stages: (1) initial acute necrosis early in the disease process that typically has no clinical manifestations but may occasionally be severe enough to cause symptoms; (2) thrombotic phase; and (3) endomyocardial fibrosis. Common symptoms in these phases include chest pain, dyspnea, or orthopnea.
• Hematologic symptoms
  • Hematologic symptoms are largely nonspecific and may include fatigue, which may be due to the anemia that is occasionally observed with hypereosinophilic syndrome.
  • Left upper quadrant pain may indicate splenomegaly, which occurs in about 40% of patients.
  • Thrombotic episodes occur frequently and often present as neurologic symptoms. The thrombotic events may occur solely due to cardiac disease, or they may be caused by hypercoagulability. The mechanism of hypercoagulability is unknown.
• Neurologic symptoms
  • Embolic or thrombotic strokes or transient ischemic episodes may occur and are often the initial manifestations of hypereosinophilic syndrome.
  • Some patients with hypereosinophilic syndrome experience an encephalopathy caused by CNS dysfunction.
  • Blurred vision and slurred speech have been reported.
  • Peripheral neuropathies account for about 50% of all neurologic symptoms in hypereosinophilic syndrome. Their etiology is poorly understood, but the symptoms may present as symmetric or asymmetric sensory changes, pure motor deficits, or mixed sensory and motor complaints.
• Pulmonary symptoms
  • The most benign variant of hypereosinophilic syndrome involves eosinophilic infiltrates in the bases and periphery of the lungs, according to one source.
  • Patients often have recurrent angioedema.
  • A chronic, persistent cough, usually nonproductive, is the most common respiratory symptom reported in hypereosinophilic syndrome.
  • Dyspnea may occur due to CHF or pleural effusions (which are not always secondary to CHF).
  • Less frequently, pulmonary fibrosis occurs after prolonged disease and often accompanies cardiac fibrosis.
  • Bronchospasm and asthmatic symptoms are infrequent.
  • Rhinitis is sometimes a presenting symptom.
• Rheumatologic symptoms
  • Arthralgias and myalgias are frequent complaints.
  • Raynaud phenomenon occurs but is infrequent.
• Dermatologic symptoms
  • Skin involvement is common and nonspecific.
  • The most common symptom is pruritus.
  • Dermatographism and angioedema are also frequently present.
• Gastrointestinal symptoms
  • Diarrhea is a relatively common complaint, occurring in approximately 20% of patients with hypereosinophilic syndrome.
  • Nausea and abdominal pain are also common complaints.
  • Occasionally, small bowel necrosis due to microthrombi can occur.
  • Some patients present with sclerosing cholangitis.
• Constitutional symptoms
  • Many patients experience fever and night sweats.
  • Some sources identify anorexia and weight loss as common presenting symptoms; however, other sources report that these symptoms do not usually occur unless underlying cardiac disease is present.

Physical

The physical findings of hypereosinophilic syndrome are varied and parallel the clinical history.

• Cardiac findings
  • Evidence of CHF becomes prominent with advanced hypereosinophilic syndrome and is an ominous sign.
  • Various murmurs may be heard, especially mitral or tricuspid regurgitation.
  • Splinter hemorrhages are often observed with cardiac involvement.
  • Physical findings typical of restrictive heart disease can be expected.
• Hematologic findings include splenomegaly in approximately 40% of patients.
• Neurologic findings
  • Physical findings associated with stroke and transient ischemic attacks can be observed.
  • When peripheral neuropathy is present, findings may be purely sensory, entirely motor, or a combination of both.
  • Deficits are often symmetric.
  • Mononeuritis multiplex and muscle atrophy due to radiculopathy are sometimes encountered.
  • Generalized weakness is observed but is less specific.
• Pulmonary findings
  • Rales may accompany infiltrates and fibrosis.
  • Findings typical of CHF with effusion may also be encountered.
  • Angioedema is often a prominent feature associated with pulmonary involvement.
• Rheumatologic findings
  • Large joint effusions can occur.
  • Digital necrosis is rare but sometimes observed with associated Raynaud phenomenon.
• Dermatologic findings
  • The skin is among the most common organ systems involved in hypereosinophilic syndrome; more than half of all patients have cutaneous involvement. In a minority of reports, skin involvement is the only manifestation of hypereosinophilic syndrome.
  • Most skin eruptions fall into 2 patterns. One pattern is angioedematous or urticarial and associated with a benign prognosis. The other pattern is erythematous, pruritic papules, plaques, and nodules, with or without ulceration.
  • A special form of urticaria is dermatographism, which occurs in up to 75% of affected patients.
  • Other less common cutaneous manifestations include erythroderma, erythema annulare centrifugum, erythema gyratum repens, and mucosal ulcerations.
• Gastrointestinal findings
  • Hepatomegaly may occur with chronic active hepatitis due to hypereosinophilic syndrome.
  • Hepatomegaly may also occur with Budd-Chiari syndrome, which may infrequently be a thrombotic complication of hypereosinophilic syndrome.

• Search for CME/CE on This Topic »

• Hypereosinophilic Syndrome (Pediatrics: General Medicine)
• Hypereosinophilic Syndrome (Dermatology)
• Eosinophilia (Hematology)
• Loeffler Endocarditis (Cardiology)

• Lasker Awards Honor Leukemia Researchers

• FLT3 Inhibitors in Acute Myeloid Leukemia
• T670X KIT Mutations in Gastrointestinal Stromal Tumors: Making Sense of Missense
• Budd-Chiari Syndrome