AUTHOR AND EDITOR INFORMATION

Section 1 of 8  

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

INTRODUCTION

Section 2 of 8  

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

Background

In this article, the term eosinophilia is defined as an increase in peripheral blood eosinophilic leukocytes to more than 600 cells per microliter of blood. Emphasis is placed on the number of eosinophils circulating in the peripheral blood, although an increase in eosinophils can be observed in other body fluids (eg, cerebrospinal fluid [CSF], urine) and many body tissues (eg, skin, lung, heart, liver, intestine, bladder, bone marrow, muscle, nerve).

Eosinophils are derived from hematopoietic stem cells initially committed to the myeloid line and then to the basophil-eosinophil granulocyte lineage. Nonpathologic functions of eosinophils and the cationic enzymes of their granules include mediating parasite defense reactions, allergic response, tissue inflammation, and immune modulation.

Tissues of the pulmonary and gastrointestinal systems are the normal residence for eosinophils, but peripheral, or blood, eosinophilia (absolute eosinophil count [AEC] >600/µL) indicates an eosinophilic disorder. Untreated, the eosinophilia can be categorized as mild (AEC 600-1500/µL), moderate (AEC 1500-5000/µL) or severe (AEC >1500/µL). An increase in tissue eosinophilia may be seen with or without concurrent peripheral eosinophilia.

A secondary or reactive increase in blood eosinophils, tissue eosinophils, or both is associated with a wide variety of infections (especially helminthic parasites), allergic responses, neoplasms, connective tissue disorders, medications and endocrinopathies. Primary eosinophilia is not a reactive phenomenon and can be described as either clonal or idiopathic in nature. If an underlying molecular or cytogenetic abnormality can be identified, the eosinophilia can be designated as a clonal disorder. If reactive causes are ruled out and no underlying clonal origin is proven, the eosinophilia is described as idiopathic.

Given the broad spectrum of conditions linked to eosinophilia, this article emphasizes the diagnostic considerations that clinicians may want to focus on in patients with eosinophilia. The individual disease manifestations and therapies for the dozens of diseases associated with eosinophilia are not described in detail; other eMedicine articles specifically address these conditions.

Pathophysiology

Over the past 2 decades, substantial progress has been made in understanding the mechanisms of eosinophil production, eosinophil programmed cell death (apoptosis), and how eosinophil immunology contributes to both host defenses against infections and to tissue damage within the host in cases of allergic and autoimmune diseases.

The primary stimuli for eosinophil production are interleukin (IL)–5, IL-3, and the granulocyte-macrophage colony-stimulating factor (GM-CSF). These cytokines are also the primary signals that inhibit eosinophil programmed cell death. Thus, eosinophilia can be triggered via these 3 eosinophilopoietic cytokines by increased eosinophil production, by eosinophil longevity, or by a combination of these. In addition, an evolving number of chemotactic cytokines (ie, chemokines) have been established as causing eosinophils to migrate from their site of production in the bone marrow into the blood and then into peripheral tissues. These chemokines include eotaxin-1, eotaxin-2, and RANTES (regulated on activation normal T cell expressed and secreted).

Eosinophils are the source of a large number of cytokines, including IL-2, IL-3, IL-4, IL-5, IL-7, IL-13, IL-16, tumor necrosis factor–alpha (TNF-alpha), transforming growth factor–beta (TGF-beta), and RANTES. In addition to these cytokines, eosinophils are a source of several cationic proteins that also contribute to the immunologic responses against infectious disease agents and to tissue damage in allergic and autoimmune diseases. These cationic proteins include eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), Charcot-Leyden crystal lysophospholipase, major basic protein (MBP), and eosinophil-derived neurotoxin (EDN).

Secondary eosinophilia is a reactive phenomenon driven by eosinophilopoetic cytokine release by nonmyeloid cells. Eosinophilic differentiation occurs in the bone marrow from myeloid progenitors through the actions of GM-CSF, IL-3 and IL-5. Mature eosinophils are released into the bloodstream where they migrate quickly to peripheral tissues of the bronchial and gastrointestinal mucosa and skin. Their survival is short unless apoptosis is blocked by cytokines (GM-CSF, IL-3 and IL-5). Dysregulated production of these cytokines by various cell populations account for secondary hypereosinophilia such as seen in nonmyeloid malignancies (eg, Hodgkin lymphoma; transitional cell carcinoma [TCC] of the bladder; adenocarcinomas of the stomach, colon, and uterus; large cell undifferentiated lung carcinomas; and large cell cervical tumors), allergic reactions, parasitic infections, and other conditions.

Primary eosinophilias include both clonal and idiopathic hypereosinophilic syndrome (HES). These disorders have very heterogeneous underlying pathophysiologies, not all of which are well-defined. They are by definition eosinophilia for greater than 6 months, without evidence of reactive cause and with signs and symptoms of organ involvement.

In some neoplastic disorders, the hypereosinophilia is part of neoplastic clonal expansion affecting the myeloid lineage. This pathophysiology would describe the eosinophilia in chronic myelogenous leukemia (CML), Ph chromosome or BCR-ABL positive; acute myelogenous leukemia (AML), including inv(16), t(16;66)(p13;q22); myeloproliferative diseases; and myelodysplastic syndromes.

A number of HES cases exhibit clonal expansion of abnormal lymphocytes. Immunophenotypically, they are characterized by aberrant and immature T cells, which exhibit abnormal cytokine production. T-cell receptor gene rearrangements are demonstrated in many. These T cells produce high levels of IL-5, thought to cause the hypereosinophilia.

Eosinophilia is further classified as clonal or idiopathic both clinically and pathologically. The World Health Organization proposed criteria to distinguish idiopathic HES from chronic eosinophil leukemia with predominant eosinophilic differentiation. The diagnosis of CEL is made if (1) cytogenetic or molecular evidence of clonality is present, (2) an increase in peripheral blasts of more than 2% or marrow blasts of more than 5% but less than 19% occurs, and (3) other causes are excluded. The underlying chromosomal abnormalities leading to CEL have been described in some cases. A deletion on chromosome band 4q12 resulting in the FIP1L1-PDGFRA (FIR1-like-1-platelet-derived growth factor receptor–alpha) fusion gene causes an abnormal constitutively activated tyrosine kinase.

These patients demonstrate CHIC2 gene deletion in peripheral blood mononuclear cells as a result of this fusion gene. Another fusion gene involving BCR-PDGFRA has been seen in CML with marked eosinophilia. Mutations involving PDGFRB rearrangements have been described, as well as FGFR1 (fibroblast growth factor receptor–1) fusions. Clinical features of eosinophil leukemia result from accumulation of leukemic cells in bone marrow, liver, and spleen. Inflammatory mediators from the eosinophils themselves cause tissue damage to the pericardium, myocardium, endocardium, and nervous system.

Finally, idiopathic HES is the diagnosis of exclusion in patients with marked prolonged (>6 mo) eosinophilia with multiple organ involvement but without identifiable cytogenetic or molecular abnormalities. Organ damage occurs from release of contents of eosinophilic granules. Some of these cases transform into identifiable entities.

Frequency

United States

In the United States, compared to developing countries, eosinophilia occurs most commonly due to allergic conditions, including drug reactions and atopic asthma. Parasitic infections are rare.

International

Helminthic infections are the most common cause of eosinophilia worldwide due to the high prevalence of helminthic parasite infections, several of which are estimated to involve hundreds of millions of people.

Mortality/Morbidity

Patient mortality and morbidity depend on the individual disease associated with eosinophilia. Many helminthic infections develop into chronic diseases that cause morbidity but not mortality. Similarly, allergic reactions and conditions associated with eosinophilia usually do not cause mortality. Eosinophilia associated with nonmyeloid malignancies does not affect their individual prognosis or rates of mortality. The mortality and morbidity associated with clonal and idiopathic causes is associated with the degree of tissue involvement, damage, or both damage at diagnosis; how quickly therapy is implemented; and treatment responsiveness.

Race

No racial predilection exists, although the occurrence of eosinophilia-associated helminthic parasitic infections is more common in certain geographic areas of the world.

Sex

No male or female predilection exists in most subtypes. However, there is a marked male predominance in clonal disorders involving the PDGFRB fusion gene and a small male predominance in clonal disorders of the FGFR1 gene.

Age

People of all ages can be affected.

CLINICAL

Section 3 of 8  

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

History

• Obtaining a travel history is critical to assess whether a patient has traveled to an area that is endemic for certain infections, including helminthic infections and coccidioidomycosis, which is the only fungal infection that is frequently associated with eosinophilia and is endemic in the southwestern United States and northern Mexico.
• Obtaining a medication and diet history is crucial to evaluate for allergic reactions associated with eosinophilia. Particularly the temporal relationship of medication changes to the onset of eosinophilia should be assessed. History of discontinued medications should also be obtained, as eosinophilia can persist long after cessation.
• Obtaining a history of symptoms associated with lymphoma, especially Hodgkin lymphoma, is important.
• A history that is suggestive of adrenal insufficiency, including the use and tapering of corticosteroid medications, can provide a clue that the observed eosinophilia is associated with adrenal insufficiency. Hypoadrenalism (ie, Addison disease) is the most common endocrine abnormality associated with eosinophilia.
• Symptom evaluation for respiratory symptoms, cardiovascular symptoms including exertional dyspnea, fatigue, fever, muscle pain, rash, visual changes, and weakness may indicate specific organ involvement.

Physical

• A complete physical examination is required because diseases associated with eosinophilia can involve any part of the body, including the skin, brain, eyes, lymph nodes, lungs, heart, liver, spleen, intestine, bone, and nervous system.
• Cholesterol emboli due to atherosclerotic disease, with or without recent vascular catheterization, can present with eosinophilia and end-organ damage to the kidneys, skin, and lower extremities (causing blue/purple toes).

Causes

The mnemonic device CHINA (ie, connective tissue diseases, helminthic infections, idiopathic HES, neoplasia, allergies) describes the categories of diseases that sometimes are associated with blood eosinophilia.

• Connective tissue diseases
• • Churg-Strauss vasculitis
  • Rheumatoid arthritis
  • Eosinophilic fasciitis
  • Eosinophilia-myalgia syndrome (due to tryptophan in the United States in 1989)
  • Toxic-oil syndrome (due to contaminated rapeseed oil in Spain in 1981)
  • Coccidioidomycosis fungal infection
• Helminthic (ie, worm) parasitic infections
• • Ascariasis
  • Schistosomiasis
  • Trichinosis
  • Visceral larva migrans
  • Gnathostomiasis
  • Strongyloidiasis
  • Fascioliasis
  • Paragonimiasis
• Idiopathic hypereosinophilic syndrome
• Neoplasia
• • Lymphoma (eg, Hodgkin lymphoma, non-Hodgkin lymphoma)
  • Human T-cell lymphotropic virus I (HTLV-I)
  • Adult T-cell leukemia/lymphoma (ATLL)
  • Eosinophilic leukemia (very rare)
  • Gastric or lung carcinoma (ie, paraneoplastic eosinophilia)
• Allergic/atopic diseases
  • Asthma
  • Allergic rhinitis

WORKUP

Section 4 of 8  

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

Lab Studies

• Complete blood count with differential to quantitate percent eosinophils and absolute number of eosinophils.
• Blood chemistries can indicate specific organ involvement (ie, liver, kidney).
• Spinal fluid examination to assess CSF eosinophilia due to worm infections (eg, Angiostrongylus cantonensis), drug reactions, and coccidioidomycosis fungal meningitis.
• Patients with allergic symptoms should have a nasal smear for eosinophilia and Gram stain. Patients with asthma symptoms should have sputum examination for eosinophilia.
• In suspected cases of medication and some parasitic infections, evaluation of urine sediment may be helpful. Stool samples should be evaluated for ova and parasites if indicated by history.
• If reactive causes are unlikely, a bone marrow biopsy should be done. Clues of clonality in peripheral blood include macrocytosis, thrombocytosis, left-shifted granulopoiesis and circulating blasts. In the bone marrow, myeloproliferation with dyshematopoiesis and reticulin fibrosis are suggestive of clonality. Staining for tryptase and immunophenotyping should be done. If primary eosinophilia is suspected, fluorescent in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) is sent to detect fusion genes. FISH for the CHIC2 gene deletion can also give presumptive diagnosis of a fusion gene. T-cell receptor gene rearrangement can be evaluated by flow cytometry. Elevated serum levels of tryptase (seen in systemic mastocytosis [SM]), IL-5 (common in clonal t-cell disorders) and IgE can also be measured for elevation.

Imaging Studies

• CT scan
• • CT scans of the lungs, abdomen, pelvis, and brain evaluate for focal defects due to diverse causes of eosinophilia.
  • Worm infections of the liver (eg, Fasciola hepatica) can cause focal hepatic lesions.
  • A coccidioidomycosis fungal infection can cause focal lesions in the lung, which are visible on a chest radiograph or CT scan.
  • Hodgkin or non-Hodgkin lymphoma can cause adenopathy in the abdomen, which is visualized on a CT scan.
• Echocardiogram to assess for thrombi (eg, mural, endocardial) due to HES

Procedures

• A bone marrow biopsy may be helpful (see Lab Studies).
• A lumbar puncture may be performed to evaluate spinal fluid for CSF eosinophilia. CSF eosinophilia may be due to worm infections (eg, A cantonensis), drug reactions, or coccidioidomycosis fungal meningitis.
• Schistosoma hematobium typically causes eosinophilia and hematuria due to infection of the bladder. All patients with blood eosinophilia who have lived or traveled in Africa and have either gross or microscopic hematuria should have their urine examined for the eggs of S hematobium. Cystoscopy is usually necessary to make the diagnosis because the terminal-spined eggs of this species of schistosome can often be found in the urine if specifically sought.

TREATMENT

Section 5 of 8  

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

Medical Care

A detailed discussion of therapeutics for the many individual causes of eosinophilia, including parasitic and malignancy-associated forms, are beyond the scope of this article. General guidelines only are addressed here.

• Most cases of secondary eosinophilia are treated based on their underlying causes. Allergic and connective tissue disorders may be amenable to corticosteroid treatment. Parasitic and fungal infections can be worsened or disseminated by use of steroids and should be ruled out if they are indicated by patient history.
• In patients with primary eosinophilia without organ involvement, no treatment may be necessary. Cardiac function should be evaluated at regular intervals, however, since peripheral eosinophilia does not necessarily correlate with organ involvement. Steroid responsiveness should be evaluated, both for prognosis (steroid-responsive patients do better) and to guide treatment when needed.
• Choices for systemic treatment of primary eosinophilia with organ involvement initially include corticosteroids and IFN-alpha for steroid resistant disease. Other agents for steroid resistant disease include hydroxyurea, chlorambucil, vincristine, cytarabine, 2-CdA, and etoposide. These are usually given as chronic maintenance regimens to control organ involvement. In the presence of PDGFRA and PDGFRB mutations imatinib has achieved complete and durable remissions. In refractory cases, many investigational combinations of chemotherapeutic agents, tyrosine kinase inhibitors and monoclonal antibodies are being studied. Nonmyeloablative allogenic hematopoietic stem cell transplantation (HSCT) can also be considered in drug-refractory cases.

Surgical Care

Surgical care may be indicated, depending on the specific diagnosis.

Consultations

Consultation with infectious disease and hematology-oncology physicians can help determine the cause and treatment of eosinophilia.

MEDICATION

Section 6 of 8  

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

Specific medications for the many infectious, allergic, and hematologic-oncologic diseases associated with eosinophilia are beyond the scope of this article, which focuses on the causes of eosinophilia. A brief overview is provided under the heading of medical care.

FOLLOW-UP

Section 7 of 8  

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

Prognosis

• Prognosis depends on the associated condition. Many helminthic infections develop into chronic diseases that cause morbidity but not mortality. Similarly, many allergic reactions and conditions associated with eosinophilia usually do not cause mortality.
• The prognosis of primary eosinophilias is determined by their degree of organ involvement at diagnosis, the timeliness of treatment, responsiveness to treatment, and underlying cytogenetic and molecular pathophysiology.

REFERENCES

Section 8 of 8

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

• Allen JN, Davis WB. Eosinophilic lung diseases. Am J Respir Crit Care Med. Nov 1994;150(5 Pt 1):1423-38. [Medline].
• Bain Barbara J. Relationship Between Idiopathic Hypereosinophilic Syndrome, Eosinophilic Leukemia, and Systemic Mastocytosi. American Journal of Hematology. 2004;77:82-85.
• Bain Barbara J. Eosinophilic Leukemia. Clinical Hematology. 2006;497-504.
• Cohen AJ, Steigbigel RT. Eosinophilia in patients infected with human immunodeficiency virus. J Infect Dis. Sep 1996;174(3):615-8. [Medline].
• Cortes J, Ault P, Koller C, Thomas D, et al. Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic syndrome. Blood. Jun 15 2003;101(12):4714-6.
• Gotlib Jason. Molecular Classification and Pathogenesis of Eosinophilic Disorders: 2005 Update. Acta Haematologica. 2005;114:7-25.
• Gotlib Jason, Cools Jan, Malone III James M. The FIP1L1-PDGFRA fusion tyrosine kinase in hypereosinophilia syndrome and chronic eosinophilic leukemia: implications for diagnosis and classification. Blood. April 2004;103, number 8:2979-2891.
• Lucey DR, Clerici M, Shearer GM. Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases. Clin Microbiol Rev. Oct 1996;9(4):532-62. [Medline].
• Roufosse Florence, Goldman Michel, Cogan Elie. Hypereosinophilic Syndrome: Lymphoproliferative and Myeloproliferative Variants. Seminars in Respiratory and Critical Care Medicine. 2006;27:2006.
• Spry, CJF. Eosinophils: A Comprehensive Review and Guide to the Scientific and Medical Literature. Oxford, England:. Oxford Medical Publications;1988.
• Teffari A. Modern Diagnosis and Treatment of Primary Eosinophilia. Acta Haematologica. 2005;114:52-60.
• Teffari Ayalew, Pardanani Animesh. Imatinib Therapy in Clonal Eosinophilic Disorders, Including Systemic Mastocytosis. International Journal of Hematology. 2004;79:441-447.
• Teffari Ayalew, Patnaik Mrinal M., Pardanani Animesh. Eosinophilia: secondary, clonal and idiopathic. British Journal of Haematology. 2006;133:468-492.
• Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood. May 15 1994;83(10):2759-79. [Medline].
• Weller PF. Eosinophilia in travelers. Med Clin North Am. Nov 1992;76(6):1413-32. [Medline].

Article Last Updated: Dec 18, 2006