Eosinophilia ?>

Eosinophilia

Eosinophilia


Introduction
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
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

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