AUTHOR AND EDITOR INFORMATION

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• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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.

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, colon cancer), pulmonary eosinophilia Loffler syndrome, 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.¹⁹

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

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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. 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.

DIFFERENTIALS

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Other Problems to Be Considered

Allergic diseases
Angiolymphoid hyperplasia with eosinophilia
Collagen vascular diseases
Dermatitis, Atopic
Drug reactions
Eosinophilic toxocariasis
Episodic angioedema with eosinophilia
Hypersensitivity diseases
Malignancy with secondary eosinophilia (eg, Hodgkin disease, AML-M4EO)
Parasitic infections

WORKUP

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Lab Studies

Laboratory workup for hypereosinophilic syndrome includes the following:

Hematologic studies

• Eosinophilia is present (>1500 cells/µL).
• The overall neutrophil count may be normal, but it is often elevated in hypereosinophilic syndrome. Many patients have absolute neutrophilia.
• Approximately 50% of the patients with hypereosinophilic syndrome are anemic at presentation, often because of anemia of chronic disease.
• Platelet counts are most often normal, but they may be elevated.
• Eosinophils in the peripheral blood are mostly mature forms. Immature eosinophilic precursors are rare in the peripheral blood.
• Morphologic abnormalities that have been described include nuclear hypersegmentation, hypo- and hypergranularity.
• Cases of hypereosinophilic syndrome with features of MPD show circulating leukocyte precursor anemia and thrombocytopenia or thrombocytosis. Teardrops and nucleated red blood cells may be seen.
• A National Institute of Health series indicated that the presence of eosinophils with vacuolization and hypogranularity is more commonly associated with cardiac disease.¹⁴
• Leukocytosis in excess of 90,000/µL carries a bad prognosis.

Chemistries

• Increased serum tryptase level gives a clue to the presence of FIP1L1-PDGFRA mutation. Always rule out C-KIT mutation, which is characteristic of systemic mastocytosis whenever serum tryptase is elevated. This distinction is clinically important because the most common form of C-KIT mutation in systemic mastocytosis, Asp 816 to Val, is not responsive to imatinib treatment.
• IL-5 is elevated in cases of hypereosinophilic syndrome that are associated with clonal T-cell disease. Interferon alpha should be considered in such cases due to its downregulating effects on IL-5 production by T-helper 2 (TH2) cells. 
• Immunoglobulin E (IgE) levels may be elevated, and hypergammaglobulinemia is common. Increased IgE levels have prognostic significance, as these patients have a lower risk of developing hypereosinophilic syndrome associated cardiovascular disease and respond well to steroid therapy.
• Serum vitamin B-12 levels may be elevated in the presence of associated myeloproliferative features.

Approach to diagnosis of hypereosinophilic syndrome

• After a thorough workup has excluded causes for secondary eosinophilia, a diagnosis of hypereosinophilic syndrome is suspected in cases of persistent eosinophilia. Any such patients with a documented AEC greater than 1500/µL on at least 2 occasions should be evaluated for hypereosinophilic syndrome, regardless of the presence of symptoms.
• Complete blood cell (CBC) count and peripheral smear
• Serum tryptase levels are elevated in FIP1LI-PDGFRA–positive hypereosinophilic syndrome, as well as SM-CEL. Hence, in such cases, workup should include the following:
• • Bone marrow tryptase levels
  • Immunophenotyping of mast cells – Mast cells in systemic mastocytosis coexpress CD117 with CD2 and/or CD25
  • Molecular genetic studies to detect FIP1L1-PDGFRA mutation (which is present in hypereosinophilic syndrome and systemic mastocytosis) and C-KIT mutation (which is present in systemic mastocytosis) are done to determine imatinib sensitivity, as mentioned above.
• Bone marrow biopsy should be evaluated for the following:
• • Morphologic examinations to look for features of MPDs and to look for dense aggregates of mass cells (greater than 15 cells) in systemic mastocytosis.
  • Special stains should include reticulin stain for myelofibrosis and tryptase staining for mast cells when serum tryptase levels are elevated.
  • Cytogenetics – Most patients with hypereosinophilic syndrome have normal karyotypes. In those who have cytogenetic changes, the changes may vary from aneuploidy to Philadelphia chromosome.
  • Molecular genetic studies should include the following:
  • • FIP1L1/PDGFRA should be evaluated in all patients with increased tryptase levels. This mutation is present in both hypereosinophilic syndrome and systemic mastocytosis.
    • C-KIT mutation should also be evaluated in patients with increased tryptase levels.
• T-cell immunophenotyping
• T-cell receptor gene rearrangement
• IL-5 levels
• Computed tomography (CT) scanning of the chest, abdomen, and pelvis to look for lymphadenopathy and splenomegaly
• Initial evaluation of suspected hypereosinophilic syndrome should include tests to look for any evidence of end-organ damage
• • Electrocardiography (ECG)
  • Echocardiography (ECHO)
  • Troponin levels: Increased levels indicate presence of cardiomyopathy and predict the onset of cardiogenic shock due to imatinib therapy.
  • Pulmonary function tests
  • Tissue biopsy may be required in symptomatic patients, but it is not always essential.

Related Medscape topics:
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Imaging Studies

ECHO is helpful in the initial evaluation & monitoring of cardiac disease in patients suspected with hypereosinophilic syndrome. Intracardiac thrombi may be detected, as well as the fibrosis that appears not only as areas of increased echogenicity but often as posterior mitral valve leaflet thickening. Because the papillary muscles are often involved in hypereosinophilic syndrome, mitral and tricuspid dysfunction may also be detected by ECHO.

CT scanning of the chest, abdomen, and pelvis is done to look for lymphadenopathy and splenomegaly.

Procedures

• An endocardial biopsy may be performed via cardiac catheterization if any question about the diagnosis of hypereosinophilic syndrome exists.
• Perform bone marrow aspiration and biopsy, and submit samples for cytogenetic studies.
• • Occasionally, the findings may suggest an atypical presentation of chronic myelogenous leukemia.
  • Cytogenetic abnormalities or the presence of a myeloproliferative picture in the bone marrow may be indicative of more aggressive disease.
• If cutaneous involvement is present, skin biopsies may be performed to rule out other diagnoses that have similar skin presentations, such as drug eruptions, cutaneous T-cell lymphoma, Wells syndrome, immunobullous diseases, and vasculitis.

Histologic Findings

Eosinophil infiltrates are present in affected tissues in patients with hypereosinophilic syndrome. Cutaneous histologic features vary with the pattern of presentation. In patients with papular or nodular lesions, perivascular mixed cellular infiltrates (eosinophils and other cell types) are present. However, vasculitis is not present (see Lab Studies).

TREATMENT

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Medical Care

Overview of the management of hypereosinophilic syndrome

• Currently, there are no recommendations for treating asymptomatic patients with hypereosinophilic syndrome, as treatment itself is not without risks. Such patients are closely monitored with serum troponin level every 3-6 months, and ECHO and pulmonary function tests every 6-12 months.
• In contrast, cases of hypereosinophilic syndrome with myeloproliferative features, particularly those with FIP1L1/PDGFRA mutation, should be treated aggressively, as they carry worse prognosis without treatment.
• A decision to treat hypereosinophilic syndrome, therefore, depends on the clinical presentation, laboratory findings, and mutational analysis.
• Glucocorticoids are the first-line therapy in all patients without FIP1L1/PDGFRA mutation.³ About one third of patients conditions do not respond to steroids. In such patients, interferon alpha and hydroxyurea are the second-line drugs of choice.²⁰ For those individuals whose conditions do not respond to first- and second-line therapy, a high dose (400 mg) of imatinib is the treatment of choice.
• For those with FIP1L1/PDGFRA mutation, imatinib is the drug of choice with a very good response rate that approaches 100% in various studies.
• For those patients whose condition is refractory to the usual treatment of hypereosinophilic syndrome, chemotherapeutic agents that have been used with some success include chlorambucil, etoposide, vincristine, and 2-cda (2-chlorodeoxyadenosine) and cytarabine. However, alkylating agents are usually avoided in view of their potential to induce leukemias.
• In patients whose condition is refractory to treatment, particularly those resistant to imatinib therapy, hematopoietic stem cell transplantation has been shown to reverse the organ dysfunction. However, because of the limited experience and complications associated with hematopoietic stem cell transplantation, its routine use is not justified at the present time.
• Recurrent thromboembolic complications occur despite anticoagulant therapy in hypereosinophilic syndrome. Currently, there are no recommendations for prophylactic use of aspirin or Coumadin in the absence of documented thrombi in hypereosinophilic syndrome.
• Leukapheresis is indicated as an emergency therapy in hypereosinophilic syndrome to control symptoms due to hyperleukocytosis.
• Human leukocyte antigen (HLA) typing should be done early in the course of hypereosinophilic syndrome for patients with aggressive disease, cytogenetic aberration, or the FIPL1/PDGFRA fusion gene.

Glucocorticoids

• Due to rapidity and reliability of its effect, a 5-day course of prednisone 1 mg/kg/d or 60 mg/d is the initial treatment of choice for all FIP1L1/PGDFRA–negative patients. Eosinopenia occurs within hours of steroid administration. Then, the daily dose of prednisone is tapered to the lowest dose required on alternate days to maintain disease control.
• Glucocorticoids decrease eosinophilopoiesis by suppressing the transcription of genes for IL-3, IL-5 and GM-CSF. These agents also inhibit cytokine-dependent survival of eosinophils, resulting in their increased apoptosis. It is also believed that steroids increase rapid sequestration of eosinophils.
• Almost 70% of the cases of hypereosinophilic syndrome respond well to steroid therapy, especially those that present with urticaria and high IgE levels. Cases of hypereosinophilic syndrome that respond to steroids have a better prognosis.
• A course of steroid therapy is also given to asymptomatic patients to establish hypereosinophilic syndrome responsiveness to steroids in case rapidly progressive organ involvement develops in future.
• Steroids are also used in the management of imatinib-induced cardiogenic shock. In such circumstances, steroids are started when there is an elevation of the serum troponin level or an abnormal ECHO study.

Tyrosine kinase inhibitors

• A tyrosine kinase inhibitor, imatinib mesylate (Gleevac) is the drug of choice for hypereosinophilic syndrome with FIP1L1/PDGFRA. It’s also a potent inhibitor of other mutations like BCR-ABL, C-KIT, and PDGFRβ.
• In patients with hypereosinophilic syndrome with FIP1L1/PDGFRA, imatinib induces clinical hematologic and molecular remission in the majority of the patients. Resolution of symptoms and normalization of eosinophil count occur within 1-2 weeks. Bone marrow abnormalities including myelofibrosis resolve within 1–2 months. In contrast, structural abnormalities in the cardiovascular system and fixed neurologic deficit may not improve with imatinib therapy. However, imatinib is shown to arrest progression of endomyocardial fibrosis if therapy is initiated before the onset of structural abnormalities.
• However, in true idiopathic hypereosinophilic syndrome (FIP1L1/PDGFRA–negative), low-dose imatinib (100 mg/d) may not produce a durable remission. Response rates vary from 20% to 80%. This is thought to be due to alternate PDGFRA fusion partners. A higher dose (400 mg/d) is likely to produce partial to complete remission.
• In addition, experience with imatinib in chronic myelogenous leukemia shows that it is not effective in eliminating the early progenitor cells in chronic myelogenous leukemia. Extrapolating these results to hypereosinophilic syndrome, a lifelong therapy with imatinib is required in majority of the patients. Because FIP1L1/PDGFRA–positive hypereosinophilic syndrome is predominantly a disease of young men and oligospermia is a complication of imatinib, sperm banking before initiation of therapy should be considered.
• Other complications of imatinib include neutropenia, life-threatening eosinophilic myocarditis, peripheral edema, nausea, muscle cramps, bone pains, and rash.
• A few cases of hypereosinophilic syndrome with acquired resistance to imatinib have been reported in the literature. These cases have been associated with single-base (T6741) substitution. A newer agent PKC-412 (N-benzoyl-staurosporine) has been shown to have efficacy against T6741 mutation in animal models and in vitro. It competes for binding to the adenosine triphosphate (ATP) site on the protein kinase C (PKC) family of serine-threonine kinases. Bone marrow transplantation is an alternative in imatinib-resistant cases.
• Molecular responsiveness to imatinib is assessed by screening for the PDGFRA mutation in the peripheral blood by fluorescent in situ hybridization (FISH) or reverse transcriptase–polymerase chain reaction (RT-PCR) at 3-6 month intervals in the first year and at 6-12 months intervals thereafter.

• As mentioned above interferon alpha is a second-line drug of choice for patients whose conditions do not respond to glucocorticoids. Patients with hypereosinophilic syndrome with associated abnormal T-cell clones should also receive some other agent in addition to interferon alpha. It’s believed that interferon alpha inhibits eosinophil differentiation, proliferation, and degranulation.

• A humanized anti–IL-5 monoclonal antibody (eg, mepolizumab [Bosatria]) and an anti-CD52 antibody (alemtuzumab [Campath]) have been shown to control symptoms as well as eosinophilia. However, durable remission was seen with maintenance therapy with alemtuzumab (30 mg q3wk) compared with single-dose therapy (1 mg/kg) with mepolizumab.

Surgical Care

Management of cardiovascular disease

Valve replacement with bioprosthetic valves may be required in patients with hypereosinophilic syndrome and regurgitant lesions. Risk of thrombosis with mechanical valves is very high in patients with hypereosinophilic syndrome despite therapeutic anticoagulation.

Endocardectomy may be required for patients with endomyocardial fibrosis, and thrombectomy may be required for individuals with thrombosis. 

Splenectomy

Evidence of hypersplenism or pain due to splenic infarction are indications for splenectomy. 

Consultations

Consult a hematologist to assist with the diagnosis, management, and follow-up care of patients with unexplained eosinophilia.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications in patients with hypereosinophilic syndrome.

Drug Category: Corticosteroids

Corticosteroids often cause a rapid reduction in level of the eosinophilia. The mechanisms for this are not entirely clear.

Drug Category: Antineoplastic Agents

Chemotherapeutic agents may be used in patients whose conditions are refractory to steroid treatment. As a group, antineoplastic agents interfere with the production of eosinophils, but they may also cause toxicity to normal tissues, especially the bone marrow.

Drug Category: Immunomodulators

Immunomodulators are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha, beta, and gamma interferons may be given topically, systemically, and intralesionally. These agents have demonstrated efficacy in small trials.

FOLLOW-UP

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Further Outpatient Care

• Periodically observe patients with hypereosinophilic syndrome to confirm that the eosinophilia is controlled and that no evidence of new or worsening organ involvement occurs.
• Follow up patients with hypereosinophilic syndrome with serum troponin levels every 3 months, as well as with ECHO and pulmonary function tests every 6 months.

Deterrence/Prevention

• No known method of prevention for hypereosinophilic syndrome exists.

Complications

• Many varied complications of hypereosinophilic syndrome depend entirely on the organ systems that are involved in the disease process (see Clinical and Pathophysiology).
• The most serious complication of hypereosinophilic syndrome is cardiac involvement that leads to myocardial fibrosis, CHF, and death (see Pathophysiology).

Prognosis

• Hypereosinophilic syndrome carries a variable prognosis. It is a chronic and progressive disorder which is potentially fatal if left untreated. Blast transformation could occur after many years.
• Although initial studies for hypereosinophilic syndrome showed a very poor prognosis (a 3-y survival rate of 12%),⁴ management of cardiovascular disease by early monitoring via ECHO and advances in medical and surgical therapies have improved the overall survival. A study of 40 cases by Lefebcve et al showed a 5-year survival of 80% and a 15-year survival of 42%.¹⁹

  As discussed above, due to the availability of tyrosine kinase inhibitors, which prevent progression of cardiac disease and other organ damage—particularly in FIP1L1/PGDFRA–positive cases—these agents will likely further improve the prognosis of hypereosinophilic syndrome (see Treatment, Medical Care, Tyrosine kinase inhibitors). However, FIP1L1/PGDFRA–negative cases of hypereosinophilic syndrome that are resistant to corticosteroids have not been shown to have a durable response to imatinib.

  Lastly, additional insight into the molecular pathogenesis of such cases of hypereosinophilic syndrome is required to develop effective targeted therapies.

• Features that indicate a favorable prognosis in hypereosinophilic syndrome include angioedema, urticaria, an elevated serum IgE level, a sustained response to corticosteroids, early diagnosis, and intensive management.
• The presence of features that are suggestive of MPD and luekocytosis >90,000 carry a worse prognosis in hypereosinophilic syndrome.

Patient Education

• Individuals with hypereosinophilic syndrome should report any new or worsening symptoms.
• Hypereosinophilic syndrome may involve almost any organ system, and the prognosis is variable.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to make the diagnosis of hypereosinophilic syndrome is a pitfall. Because the onset of hypereosinophilic syndrome is often insidious, the diagnosis may be overlooked until significant end-organ impairment has occurred.

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MULTIMEDIA

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Media file 1:  Indurated edematous plaques of hypereosinophilic syndrome on a patient's legs.
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Media file 2:  Erythroderma in a patient with hypereosinophilic syndrome.
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REFERENCES

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• References

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Article Last Updated: Oct 7, 2008