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• Eosinophilic Disorders
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Eosinophilia is defined as a peripheral blood eosinophil count > 450/μL. Causes and associated disorders are myriad but often represent an allergic reaction or parasitic infection. Diagnosis involves selective testing directed at clinically suspected causes. Treatment is directed at the cause.

Eosinophilia has features of an immune response: an agent such as Trichinella spiralis invokes a primary response with relatively low levels of eosinophils, whereas repeated exposures result in an augmented or secondary eosinophilic response. Several compounds released by mast cells and basophils induce IgE-mediated eosinophil production. Such substances include eosinophil chemotactic factor of anaphylaxis, leukotriene B4, complement complex (C5-C6-C7), and histamine (over a narrow range of concentration).

Eosinophilia itself does not cause symptoms. However, occasionally patients with very severe eosinophilia (eg, eosinophil counts of > 100,000/μL), usually with eosinophilic leukemia, develop complications of hyperleukocytosis (see Eosinophilic Disorders: Hypereosinophilic Syndrome).

Etiology

Eosinophilia may be primary (ie, clonal proliferation of eosinophils associated with hematologic disorders such as leukemias and myeloproliferative disorders), secondary to (or associated with) numerous nonhematologic disorders (see Table 1: Eosinophilic Disorders: Important Disorders and Treatments Associated With Eosinophilia), or idiopathic (if other causes cannot be identified).

The most common cause in the US is

• Allergic or atopic disorders (typically respiratory or dermatologic)

Other common causes include

• Infections (typically parasitic)
• Certain tumors (hematologic or solid, benign or malignant)

Almost any parasitic invasion of tissues can elicit eosinophilia, but protozoa and noninvasive metazoa usually do not.

Of the tumors, Hodgkin lymphoma may elicit marked eosinophilia, whereas eosinophilia is less common in non-Hodgkin lymphoma, chronic myelocytic leukemia, and acute lymphoblastic leukemia. Ovarian cancer is the most commonly associated solid tumor.

The pulmonary infiltrates with eosinophilia syndrome comprises a spectrum of clinical manifestations characterized by peripheral eosinophilia and eosinophilic pulmonary infiltrates (see Interstitial Lung Diseases: Eosinophilic Pulmonary Diseases) but is usually of unknown cause.

Patients with eosinophilic drug reactions may be asymptomatic or have various syndromes, including interstitial nephritis, serum sickness, cholestatic jaundice, hypersensitivity vasculitis, and immunoblastic lymphadenopathy. Several hundred patients were reported to have developed an eosinophilia-myalgia syndrome after taking l-tryptophan for sedation or psychotropic support. This syndrome was probably caused by a contaminant rather than by l-tryptophan. The symptoms (severe muscle pain, tenosynovitis, muscle edema, rash) lasted weeks to months, and several deaths occurred.

Table 1
Important Disorders and Treatments Associated With Eosinophilia Cause or Associated Disorder Examples Allergic or atopic disorders Asthma Allergic bronchopulmonary aspergillosis Allergic rhinitis Atopic dermatitis Drug reactions (eg, to antibiotics or NSAIDs) Eczema Episodic angioedema with eosinophilia Milk-protein allergy Occupational lung disease Urticaria Connective tissue, vasculitic, or granulomatous disorders (especially those involving the lungs) Dressler's syndrome Eosinophilic fasciitis Idiopathic eosinophilic synovitis Inflammatory bowel disease Polyarteritis nodosa Progressive systemic sclerosis (scleroderma) RA Sarcoidosis Sjögren's syndrome SLE Endocrine disorders Adrenal hypofunction Immune disorders (often with eczema) Congenital immunodeficiency syndrome (eg, IgA deficiency, hyper-IgE syndrome, Wiskott-Aldrich syndrome) Graft-vs-host disease Myeloproliferative disorders Acute or chronic eosinophilic leukemia Acute lymphoblastic leukemia (certain types) Chronic myelocytic leukemia Hypereosinophilic syndrome Nonparasitic infections Aspergillosis Brucellosis Cat-scratch fever Chlamydial pneumonia of infancy Coccidioidomycosis (acute) Infectious lymphocytosis Infectious mononucleosis Mycobacterial disease Scarlet fever Parasitic infections (especially due to tissue-invasive metazoans) Ascariasis Clonorchiasis Cysticercosis (caused by Taenia solium) Echinococcosis Fascioliasis Filariasis Hookworm infection Paragonimiasis Pneumocystis jirovecii infection Schistosomiasis Strongyloidiasis Trichinosis Trichuriasis Visceral larva migrans Skin disorders Dermatitis herpetiformis Exfoliative dermatitis Pemphigus Psoriasis Syndromes of pulmonary infiltration with eosinophilia Allergic bronchopulmonary aspergillosis Chronic eosinophilic pneumonia Churg-Strauss syndrome Simple pulmonary eosinophilia (Löffler's syndrome) Tropical pulmonary eosinophilia Tumors Carcinomas and sarcomas of the lung, pancreas, colon, cervix, or ovary Hodgkin lymphoma Immunoblastic lymphadenopathy Non-Hodgkin lymphomas Miscellaneous Cirrhosis Familial eosinophilia Peritoneal dialysis Radiation therapy l-Tryptophan use

Evaluation

The number of possible causes and associated disorders is very large. Common causes (eg, allergic, infectious, neoplastic disorders) should be considered first, but even they are often difficult to identify; a thorough history and physical examination are always required.

History: The questions most likely to be helpful pertain to the following:

• Travel (suggesting possible parasite exposure)
• Allergies
• Drug use
• Use of herbal products and dietary supplements, including l-tryptophan
• Systemic symptoms (eg, fever, weight loss, myalgias, arthralgias, rashes, lymphadenopathy)

Systemic symptoms suggest that a minor allergic or drug cause is less likely, and a detailed evaluation for an infectious, neoplastic, connective tissue, or other systemic disorder should be done. Other important parts of the history include family history of blood dyscrasias (eg, plasma cell disorders) and a complete review of systems, including symptoms of allergic, pulmonary, cardiac, GI, and neurologic dysfunction.

Physical examination: General physical examination is done, including the heart, skin, and neurologic and pulmonary systems. Certain physical findings may suggest causes or associated disorders. Examples include rash (allergic, dermatologic, or vasculitic disorders), abnormal lung findings (asthma, lung infections, or syndromes of pulmonary infiltration with eosinophilia), and generalized lymphadenopathy or splenomegaly (myeloproliferative disorders or cancer).

Testing: Eosinophilia is typically recognized when CBC is done for other reasons. Additional testing often includes the following:

• Stool ova and parasite testing
• Other tests to detect organ damage or for specific causes based on clinical findings

When the CBC indicates eosinophilia, an absolute eosinophil count is rarely needed.

In general, if a drug or allergic cause is not clinically suspected, 3 stool specimens should be examined for ova and parasites; however, negative findings do not rule out a parasitic cause (eg, trichinosis requires a muscle biopsy; visceral larva migrans and filarial infections require other tissue biopsies; duodenal aspirates may be needed to exclude specific parasites, eg, Strongyloides sp—see Nematodes (Roundworms): Strongyloidiasis).

Other specific diagnostic tests are determined by the clinical findings (particularly travel history) and may include chest x-ray, urinalysis, liver and kidney function tests, and serologic tests for parasitic and connective tissue diseases. If patients have generalized lymphadenopathy, splenomegaly, or systemic symptoms, blood tests are done; an elevated serum vitamin B₁₂ level, low WBC alkaline phosphatase level, or abnormalities on the peripheral blood smear suggest an underlying myeloproliferative disorder, in which case a bone marrow aspirate and biopsy with cytogenetic studies may be helpful. Also, if routine evaluation does not reveal a cause, tests are done to detect organ damage. Testing can include some of the tests previously mentioned as well as LDH and liver function tests (suggesting liver damage or possibly a myeloproliferative disorder), echocardiogram, and pulmonary function tests.

Treatment

• Sometimes corticosteroids

Corticosteroid treatment of hypereosinophilic syndrome is discussed in Eosinophilic Disorders: Immediate therapy.

Drugs known to be associated with eosinophilia are stopped. Other identified causes are treated.

If no cause is detected, the patient is followed for complications. A brief trial with low-dose corticosteroids may lower the eosinophil count if eosinophilia is secondary (eg, to allergy, connective tissue disorders, or parasitic infection) rather than primary. Such a trial is indicated if eosinophilia is persistent and progressive in the absence of a treatable cause.

Hypereosinophilic Syndrome

(Idiopathic Hypereosinophilic Syndrome)

Hypereosinophilic syndrome (HES) is a condition characterized by peripheral blood eosinophilia with manifestations of organ system involvement or dysfunction directly related to eosinophilia in the absence of parasitic, allergic, or other causes of eosinophilia. Symptoms are myriad, depending on which organs are dysfunctional. Diagnosis involves excluding other causes of eosinophilia and bone marrow and genetic tests. Treatment usually begins with prednisone and, in one common subtype, includes imatinib.

HES is traditionally defined by peripheral blood eosinophilia > 1500/μL persisting ≥ 6 mo. HES was previously considered to be idiopathic but is now known to result from various disorders, some of which have known causes. One limitation of the traditional definition is that it does not include those patients with some of the same abnormalities (eg, genetic defects) that are known causes of HES and who do not fulfill the traditional HES diagnostic criteria for degree or duration of eosinophilia. Another limitation is that some patients with eosinophilia and organ damage that characterize HES require treatment earlier than the 6 mo necessary to confirm the traditional diagnostic criteria.

HES is rare, has an unknown prevalence, and most often affects people age 20 through 50. Only some patients with prolonged eosinophilia develop organ dysfunction that characterizes hypereosinophilic syndrome. Although any organ may be involved, the heart, lungs, spleen, skin, and nervous system are typically affected. Cardiac involvement often causes morbidity and mortality.

Subtypes: There are two broad subtypes (see Table 2: Eosinophilic Disorders: Subtypes of Hypereosinophilic Syndrome):

• Myeloproliferative variant
• Lymphoproliferative variant

The myeloproliferative variant is often associated with a small interstitial deletion in chromosome 4 and the FIPILI/PDGFRA-associated fusion gene (reflecting tyrosine kinase activity that can transform hematopoietic cells). Patients often have

• Splenomegaly
• Thrombocytopenia
• Anemia
• Elevated serum vitamin B₁₂ levels
• Hypogranular or vacuolated eosinophils
• Myelofibrosis

Patients with this subtype often develop endomyocardial fibrosis and may rarely develop acute myeloid or lymphoblastic leukemia. Patients with the FIPILI/PDGFRA-associated fusion gene are more often males and may be responsive to imatinibSome Trade Names
GLEEVEC
Click for Drug Monograph
.

The lymphoproliferative variant is associated with a clonal population of T cells with aberrant phenotype. Patients more often have

• Angioedema, skin abnormalities, or both
• Hypergammaglobulinemia (especially IgE)
• Circulating immune complexes (sometimes with serum sickness)

They also more often respond favorably to corticosteroids and occasionally develop T-cell lymphoma.

Other HES variants include chronic eosinophilic leukemia, Gleich's syndrome (cyclical eosinophilia and angioedema), familial hypereosinophilic syndrome mapped to 5q 31-33, and other organ-specific syndromes. Hyperleukocytosis may occur in patients with eosinophilic leukemia and very high eosinophil counts (eg, > 100,000 cells/μL). Eosinophils can form aggregates that occlude small blood vessels, causing tissue ischemia and microinfarctions. Common manifestations include brain or lung hypoxia (eg, encephalopathy, dyspnea or respiratory failure).

Table 2
Subtypes of Hypereosinophilic Syndrome Feature Myeloproliferative Variant Lymphoproliferative Variant Genetics Small interstitial deletion in chromosome 4 FIPILI/PDGFRA-associated fusion gene Clonal population of T cells with aberrant phenotype Clinical manifestations and laboratory findings Anemia Elevated serum vitamin B12 levels Endomyocardial fibrosis Hypogranular or vacuolated eosinophils Myelofibrosis Splenomegaly Thrombocytopenia Angioedema Circulating immune complexes (sometimes with serum sickness) Hypergammaglobulinemia (especially IgE) Skin abnormalities Increased risk of future disorder Acute lymphoblastic leukemia Acute myeloid leukemia T-cell lymphoma Responsiveness to drugs ImatinibSome Trade Names GLEEVEC Click for Drug Monograph and other tyrosine kinase inhibitors Corticosteroids

Symptoms and Signs

Symptoms are diverse and depend on which organs are dysfunctional (see Table 3: Eosinophilic Disorders: Abnormalities in Patients With Hypereosinophilic Syndrome).

Table 3
Abnormalities in Patients With Hypereosinophilic Syndrome System Prevalence Manifestations Constitutional ≈ 50% Anorexia Fatigue Fever Myalgias Weakness Weight loss Cardiopulmonary > 70% Mural thrombi with emboli Restrictive or infiltrative cardiomyopathy or mitral or tricuspid regurgitation with cough, dyspnea, heart failure, arrhythmias, endomyocardial disease, pulmonary infiltrates, and pleural effusions Dermatologic > 50% Angioedema Dermatographism Pruritus Rashes (including eczema and urticaria) Hematologic > 50% Anemia Lymphadenopathy Splenomegaly Thromboembolic phenomena Thrombocytopenia Neurologic > 50% Cerebral emboli with focal deficits Diffuse encephalopathy with altered behavior and cognitive function and spasticity Peripheral neuropathy GI > 40% Abdominal cramps Diarrhea Nausea Immunologic ≈ 40% Circulating immune complexes with serum sickness Elevated immunoglobulins (especially IgE)

Occasionally, patients with very severe eosinophilia (eg, eosinophil counts of > 100,000/μL) develop complications of hyperleukocytosis, such as manifestations of brain or lung hypoxia (eg, encephalopathy, dyspnea or respiratory failure).

Diagnosis

• Exclusion of secondary eosinophilia
• Tests to identify organ damage
• Bone marrow examination with cytogenetics

Evaluation for HES should be considered in patients who have peripheral blood eosinophilia > 1500/μL present on more than one occasion that is unexplained, particularly when there are manifestations of organ damage. Testing to exclude disorders causing eosinophilia should be done (see Eosinophilic Disorders: Testing). Further evaluation should include blood chemistries (including liver enzymes, creatine kinase, renal function, and troponin), ECG; echocardiography; pulmonary function tests; and CT of the chest, abdomen, and pelvis. Bone marrow aspirate and biopsy with flow cytometry, cytogenetics, and reverse transcriptase-PCR or fluorescence in situ hybridization (FISH) is done to identify the FIPILI/PDGFRA-associated fusion gene and other possible causes of eosinophilia (eg, BCR-ABL abnormalities characteristic of chronic myelogenous leukemia).

Prognosis

Death usually results from organ, particularly heart, dysfunction. Cardiac involvement is not predicted by the degree or duration of eosinophilia. Prognosis varies depending on response to therapy. Response to imatinibSome Trade Names
GLEEVEC
Click for Drug Monograph
improves the prognosis among patients with the FIPILI/PDGFRA-associated fusion gene. Current therapy has improved prognosis.

Treatment

• Corticosteroids for hypereosinophilia and often for ongoing treatment of organ damage
• ImatinibSome Trade Names
  GLEEVEC
  Click for Drug Monograph
  for patients with the FIPILI/PDGFRA-associated fusion gene
• Supportive therapy

Treatments include immediate therapy, definitive therapies (treatments directed at the disorder itself), and supportive therapies.

Immediate therapy: For patients with very severe eosinophilia, complications of hyperleukocytosis, or both (usually patients with eosinophilic leukemia), high-dose IV corticosteroids (eg, prednisoneSome Trade Names
DELTASONE
Click for Drug Monograph
1 mg/kg or equivalent) should be initiated as soon as possible. If the eosinophil count is much lower (eg, by ≥ 50%) after 24 h, corticosteroid dose can be repeated daily; if not, an alternative treatment (eg, vincristineSome Trade Names
ONCOVIN
Click for Drug Monograph
, imatinibSome Trade Names
GLEEVEC
Click for Drug Monograph
, leukapheresis) is begun.

Definitive therapy: Patients with the FIPILI/PDGFRA-associated fusion gene are usually treated with imatinibSome Trade Names
GLEEVEC
Click for Drug Monograph
and, particularly if heart damage is suspected, corticosteroids. If imatinibSome Trade Names
GLEEVEC
Click for Drug Monograph
is ineffective or poorly tolerated, another tyrosine kinase inhibitor (eg, dasatinib, nilotinib, sorafenib) can be used, or allogenic hematopoietic stem cell transplantation can be tried.

Patients without the FIPILI/PDGFRA-associated fusion gene, even if asymptomatic, are often given one dose of prednisoneSome Trade Names
DELTASONE
Click for Drug Monograph
60 mg (or 1 mg/kg) po to determine corticosteroid responsiveness (ie, a decrease in the eosinophil count). In patients with symptoms or organ damage, prednisoneSome Trade Names
DELTASONE
Click for Drug Monograph
is continued at the same dose for 2 wk, then tapered. Patients without symptoms and organ damage are monitored for at least 6 mo for these complications. If corticosteroids cannot be easily tapered, a corticosteroid-sparing drug (eg, hydroxyureaSome Trade Names
HYDREA
Click for Drug Monograph
, interferon alfa) can be used.

Supportive therapy: Supportive drug therapy and surgery may be required for cardiac manifestations (eg, infiltrative cardiomyopathy, valvular lesions, heart failure). Thrombotic complications may require the use of antiplatelet drugs (eg, aspirinSome Trade Names
BUFFERIN
ECOTRIN
GENACOTE
Click for Drug Monograph
, clopidogrelSome Trade Names
PLAVIX
Click for Drug Monograph
, ticlopidineSome Trade Names
TICLID
Click for Drug Monograph
); anticoagulation is indicated if a left ventricular mural thrombus is present or if transient ischemic attacks persist despite use of aspirinSome Trade Names
BUFFERIN
ECOTRIN
GENACOTE
Click for Drug Monograph
.

Last full review/revision November 2009 by Mary Lynn R. Nierodzik, MD

Content last modified November 2009