Eosinophil biology and causes of eosinophilia

INTRODUCTION — Eosinophils are predominantly tissue-dwelling cells whose functions in health are not entirely understood. Eosinophils in the peripheral blood or tissues can increase in a wide array of disease states, ranging in severity from mild to life-threatening, and as a result of several mechanisms. When activated, eosinophils are capable of releasing mediators and substances that can damage tissues and contribute to disease pathology.

Normal eosinophil biology, the mechanisms of eosinophilia, tissue damage by eosinophils, and the major causes of eosinophilia are discussed in this topic review. An approach to the patient with eosinophilia and the diagnosis and management of the hypereosinophilic syndromes are reviewed separately. (See "Approach to the patient with unexplained eosinophilia" and "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis" and "Hypereosinophilic syndromes: Treatment".)

EOSINOPHIL BIOLOGY — Eosinophils are white blood cells (WBCs) of the granulocytic lineage, which also includes neutrophils and basophils. The physiologic functions of eosinophils are incompletely understood, but they are involved in host immune response to infection, tissue remodeling, tumor surveillance, and maintenance of other immune cells [1,2]. Eosinophils develop and differentiate in the bone marrow under the influence of interleukin (IL) 5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). There may be distinct subsets of eosinophils that play differing roles in inflammation and homeostasis [3,4].

Normal levels and anatomic locations — Eosinophilia in peripheral blood is better defined by the absolute eosinophil count (AEC) than by a threshold percentage of eosinophils.

AEC (total WBC count multiplied by the percentage of eosinophils) up to 500 cells/microL (≤0.5 x 10⁹/L) is typically considered normal. In healthy volunteers and people with eosinophilic disorders, the AEC may vary at different times of day and on different days [5-7]; such variability is rarely large enough to impact care.

Eosinophils are primarily tissue-dwelling cells; they are several hundred-fold more abundant in tissues than in blood. In healthy individuals, eosinophils can be found in the spleen, lymph nodes, thymus, and digestive tract (although not the esophagus) [8]. Recruitment of eosinophils to these tissues is mediated mainly by eotaxins, a family of chemokines (ie, cytokines that stimulate cell migration) that bind to the eosinophil chemokine receptor CCR3.

Causes of eosinopenia — Certain common disorders result in a decrease in eosinophil numbers. Fever, bacterial and viral infections, and systemic glucocorticoid administration can all dramatically suppress blood eosinophil counts. A rare cause of a complete absence of eosinophils, occurring as part of a pure WBC aplasia, has been described in patients with thymoma (Good syndrome) [9]. (See "Clinical presentation and management of thymoma and thymic carcinoma", section on 'Thymoma'.)

Mechanisms of eosinophilia — An increase in eosinophils in the peripheral blood or tissues can result from different mechanisms:

●Polyclonal expansion – Reactive or secondary eosinophilia refers to polyclonal expansion of eosinophils from overproduction of IL-5.

Sufficient quantities of IL-5 to cause eosinophilia can be produced by T helper cell type 2 (T_h2) lymphocytes and group 2 innate lymphoid cells (ILC-2) in the setting of helminthic infections, allergen exposure, and certain organ-specific diseases like eosinophilic granulomatosis with polyangiitis (EGPA), eosinophilic gastrointestinal disorders or nasal polyposis, or constitutively by malignant cells from solid tumors (usually adenocarcinomas), T cell lymphomas, or Hodgkin lymphomas [1]. Rarely, a clonal population of nonmalignant lymphocytes can result in marked eosinophilia (lymphocytic variant hypereosinophilic syndrome) [10,11].

●Clonal expansion – Clonal expansion of eosinophils can arise in the setting of a variety of myeloid neoplasms [12]. Eosinophils may be the predominant cell type involved (eg, acute or chronic eosinophilic leukemia) or one of several proliferating cell lines (eg, chronic myelomonocytic leukemia or systemic mast cell disease).

Rarely, a clonal population of nonmalignant lymphocytes can result in marked eosinophilia (lymphocytic variant hypereosinophilic syndrome) [10,11]. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'T cell lymphocytic variants'.)

●Altered trafficking – Eosinophils normally transit from bone marrow to blood and finally to peripheral tissues in a complex process that involves multiple chemokines and adhesion molecules, including eotaxins [13] and alpha-4 and beta-7 integrins [14]. Drugs that interfere with these molecules or their ligands can cause blood eosinophilia [15,16].

●Prolonged survival – The contribution of increased eosinophil survival to blood and tissue eosinophilia is difficult to demonstrate in vivo in humans. However, IL-5 and other cytokines that promote polyclonal expansion in the bone marrow can inhibit eosinophil apoptosis in vitro [17].

Tissue damage — Activated eosinophils can damage tissues. This is more likely to occur when the AEC exceeds 1500/microL (hypereosinophilia) but can occur with lower blood eosinophil levels [18,19]. Conversely, hypereosinophilia does not always result in organ involvement or tissue damage [20,21]. It is important for the clinician to understand that the degree of peripheral blood eosinophilia does not always accurately predict the risk of organ damage.

Activated eosinophils may damage tissues by several different mechanisms, including the following:

●Eosinophil granule contents – Release of toxic granule products (eg, major basic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, or eosinophil cationic protein) that can damage epithelial cells and nerves.

●Lipid mediators – Production of lipid mediators, such as sulfidopeptide leukotrienes and platelet activating factor, which mediate smooth muscle contraction and recruitment of inflammatory cells.

●Cytokines – Release of cytokines such as GM-CSF, transforming growth factors (TGF)-alpha and -beta, and interleukins, which may be involved in tissue remodeling and fibrosis.

These products are generally released after entry of eosinophils into tissues. Eosinophil granule proteins, eosinophil extracellular traps (EETs), and/or Charcot-Leyden crystals in the tissue can provide a footprint indicating prior eosinophilic infiltration [22-24]. Eosinophil activation and mediator release can also occur in the blood as suggested by the presence of hypodense eosinophils and upregulation of surface markers associated with degranulation in patients with eosinophilic disorders. Increased blood levels of eosinophil granule proteins are an additional marker of eosinophil activation that can be detected in the absence of peripheral eosinophilia in some patients and may be a useful marker of eosinophilic tissue involvement [25].

Target organs — Common target organs of eosinophils in disease include the skin, airway, and gastrointestinal tract, but any organ system, including the cardiac and nervous systems, can be involved. (See "Approach to the patient with unexplained eosinophilia".)

MAJOR CAUSES OF EOSINOPHILIA

Categories of disorders — We divide eosinophilic disorders into two categories, which inform the approach to management:

●Multiple affected organs – Disorders presenting with signs and symptoms affecting multiple organ systems, usually accompanied by peripheral blood eosinophilia (table 1).

●One affected organ – Disorders that typically present with eosinophilic involvement of a single organ, accompanied by variable levels of blood eosinophilia (table 2); some of these individuals may subsequently develop additional clinical manifestations.

Importance of considering many possible causes — Except at extremes of eosinophil counts, the degree of eosinophilia is rarely helpful for identifying the underlying cause. For example, very mild eosinophilia is more likely to be seen with asthma or allergic rhinitis, while severe eosinophilia (eg, ≥20,000 eosinophils/microL) is more likely to be caused by a myeloid neoplasm (MN). Between these extremes, the list of potential causes is extensive, and the clinician should consider the entire spectrum of disorders discussed here. An approach to the evaluation is reviewed separately. (See "Approach to the patient with unexplained eosinophilia".)

The pattern of organ involvement may be helpful in suggesting the etiology of eosinophilia in some patients (eg, serpiginous skin eruptions in cutaneous larva migrans; eosinophilic hepatitis in tetracycline-induced drug hypersensitivity). However, the presence or absence of organ dysfunction cannot be used to exclude a specific diagnosis.

Neoplastic diseases — Some neoplastic disorders can cause eosinophilia, including the following:

●Primary (or neoplastic) hypereosinophilic syndrome (HES) – Primary (neoplastic) HES refers to an MN that produces a predominance of mature eosinophils.

In males, this is typically associated with an interstitial deletion resulting in FIP1L1::PDGFRA (a fusion of Fip1-like 1 [FIP1L1] and platelet-derived growth factor receptor alpha [PDGFRA]). Other molecular abnormalities involve platelet-derived growth factor receptor beta (PDGFRB) or fibroblast growth factor receptor (FGFR1) fusion genes, or point mutations or insertion/deletions involving Janus kinase 2 (JAK2) and point mutations in signal transducer and activator of transcription 5b (STAT5b) [26-29]. Depending on the stage of their disease and the organ(s) involved, patients may present with few or no clinical manifestations or as an acutely ill, hospitalized patient. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Myeloproliferative HES variants'.)

●Acute eosinophilic leukemia – Eosinophilic leukemia is a rare variant of acute myeloid leukemia (acute myelomonocytic leukemia with eosinophilia, formerly labeled FAB M4Eo) caused by abnormalities in chromosome 16. Patients usually present with symptoms related to complications of pancytopenia (eg, severe fatigue, infection, bleeding), and immature eosinophils may be seen in peripheral blood. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia" and "Acute myeloid leukemia: Cytogenetic abnormalities", section on 'inv(16) or t(16;16); CBFB::MYH11'.)

●Other myeloid neoplasms – Eosinophilia can be associated with a variety of other MNs. As examples:

•Chronic myeloid leukemia (CML) – CML is a myeloproliferative neoplasm associated with the BCR-ABL1 fusion gene. Patients may be asymptomatic at diagnosis, while others present with fatigue, weight loss, or abdominal fullness due to splenomegaly. The predominant hematologic finding is an abundance of neutrophils and neutrophil precursor cells, but increased numbers of eosinophils are also commonly seen. It is rare for CML to present with a predominance of eosinophils over neutrophils. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Peripheral blood'.)

•Systemic mastocytosis – Systemic mastocytosis (SM) is a clonal proliferation of mast cells that can infiltrate various organs including the skin, liver, spleen, bone marrow, and lymph nodes. Aggressive and indolent forms exist. Patients may present with signs and symptoms of recurrent "allergic" reactions caused by episodic release of mast cell mediators or with organomegaly, hematologic, or cutaneous abnormalities (most commonly urticaria pigmentosa) (picture 1). Peripheral blood eosinophilia is seen in up to 20 percent of cases and can be associated with clinical manifestations. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

●Lymphoid neoplasms – Almost any B or T cell lymphoma or leukemia can be associated with eosinophilia. In a single institution study, 21 patients out of 2642 who were evaluated for eosinophilia were found to have a lymphoid neoplasm (12 T cell-derived lymphomas, 4 B cell-derived lymphomas, 4 chronic lymphocytic leukemias) [30]. Eosinophilia has also been reported following chemotherapy for lymphoid neoplasia. Some lymphoid neoplasms commonly associated with eosinophilia include the following:

•T cell lymphoblastic lymphoma and adult T cell leukemia/lymphoma – Peripheral eosinophilia can be associated with T cell leukemia/lymphoma, occurring in up to 30 percent of patients depending on the series and specific diagnosis [31]. Production of interleukin (IL) 3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and/or IL-5 by neoplastic T cells has been demonstrated and is presumed to drive the eosinophilia in most cases. Patients are generally acutely ill. (See "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified", section on 'Clinical features' and "Clinical manifestations, pathologic features, and diagnosis of angioimmunoblastic T cell lymphoma".)

•Cutaneous T cell lymphoma (CTCL) – Both Sézary syndrome and mycosis fungoides can be associated with increased serum immunoglobulin E (IgE) and eosinophilia in up to 20 percent of cases. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Pathophysiology'.)

•B cell lymphoma – Tissue eosinophilia is common in Hodgkin lymphoma and B cell non-Hodgkin lymphoma, but peripheral eosinophilia is generally mild. In one series of 1620 patients with classic Hodgkin lymphoma, only 1 percent had >1000 eosinophils/microL [32]. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma".)

•Precursor B cell acute lymphoblastic leukemia – Acute lymphoblastic leukemia (ALL) has been associated with eosinophilia, particularly in cases with a t(5;14) translocation. This translocation causes fusion of the immunoglobulin heavy-chain gene to the IL3 gene promoter. Eosinophilia may be an early presenting sign prior to the development of clinical manifestations [33,34]. Patients with ALL are generally acutely ill. (See "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma".)

●Solid tumors – In rare cases, eosinophilia can result from secretion of IL-5 by nonhematologic tumors. This is most commonly reported in adenocarcinomas of the gastrointestinal tract (eg, stomach, large bowel), lung, and squamous epithelium (eg, cervix, vagina, penis, skin, nasopharynx, bladder) [35], although IL-5 secretion by benign tumors has been described [36].

Parasites and other infections — Parasitic helminths (worms) are the most commonly identified infectious cause of eosinophilia. Infectious causes of eosinophilia are discussed separately. (See "Infectious causes of peripheral eosinophilia".)

Allergic disorders — A variety of allergic disorders are associated with eosinophilia. In general, these disorders cause mild eosinophilia. Thus, the presence of severe eosinophilia (ie, eosinophils >5000/microL) and sometimes moderate eosinophilia (1500 to 5000/microL) should prompt a more extensive evaluation.

There is significant overlap between the different categorization systems of disorders causing eosinophilia. Several allergic disorders predominantly affect one organ system, including allergic rhinitis, chronic rhinosinusitis, asthma, and atopic dermatitis. Some eosinophilic gastrointestinal disorders appear to have a significant allergic component. These are discussed below. (See 'Disorders with eosinophilic involvement of specific organs' below.)

Drug reactions — A variety of drug reactions are associated with peripheral blood eosinophilia; some drugs are more commonly associated with specific syndromes (table 3), but eosinophilia can be caused by almost any prescription or nonprescription drug, herbal remedy, or dietary supplement. Associated clinical findings may be helpful in identifying an implicated drug. A temporal relationship between drug initiation and development of eosinophilia should be determined, if possible. However, the latency between exposure and eosinophilia can range from days to years.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a potentially life-threatening systemic hypersensitivity reaction. The latency period between drug exposure and development of symptoms may be relatively long (eg, two to six weeks). Fever, malaise, lymphadenopathy, and skin eruption are the most common initial symptoms, but they are not invariably present. The morbilliform eruption can become confluent and progress to exfoliative dermatitis in some patients (picture 2). Additional systemic morbidity may be related to visceral involvement of liver, kidneys, lungs, or other organs. Hematologic abnormalities include leukocytosis with eosinophilia and/or atypical lymphocytosis. Symptoms can persist for up to several years following discontinuation of the implicated drug. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Adrenal insufficiency — Adrenal insufficiency has been associated with eosinophilia, which is believed to be due to loss of endogenous glucocorticoids. It is rare for isolated eosinophilia to be associated with adrenal insufficiency in an otherwise healthy individual. In contrast, eosinophilia may be associated with adrenal insufficiency in some high-risk settings (eg, tuberculosis, opportunistic infections in a patient with HIV infection, tapering or discontinuation of glucocorticoids, acute adrenal hemorrhage, necrosis, or infarction). In these settings, eosinophilia does not typically cause end-organ damage. (See "Clinical manifestations of adrenal insufficiency in adults" and "Determining the etiology of adrenal insufficiency in adults".)

Connective tissue/rheumatologic diseases — Eosinophilia may be found in the following systemic connective tissue diseases:

●Eosinophilic granulomatosis with polyangiitis – Eosinophilic granulomatosis with polyangiitis (EGPA, previously called Churg-Strauss syndrome) is the major vasculitis syndrome associated with eosinophilia. Patients typically present with asthma and other lung and upper airway findings; vasculitic symptoms typically develop years later. Moderate to severe peripheral blood eosinophilia is common although use of steroids may suppress eosinophil production. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

●Toxin-induced syndromes – Syndromes caused by toxic ingestions include the eosinophilia-myalgia syndrome, attributed to ingestion of a contaminated preparation of L-tryptophan, and toxic oil syndrome, caused by ingestion of edible oil adulterated with denatured rapeseed oil. Both of these entities are chronic, persistent, multisystem diseases. Few new cases have been reported since the offending agents were recognized. (See "Risk factors for and possible causes of systemic sclerosis (scleroderma)", section on 'L-tryptophan' and "Risk factors for and possible causes of systemic sclerosis (scleroderma)", section on 'Contaminated rapeseed oil'.)

●Other connective tissue disorders – Less commonly, eosinophilia may accompany other connective tissue disorders, including:

•IgG4-related disease

•Dermatomyositis

•Severe rheumatoid arthritis

•Progressive systemic sclerosis

•Sjögren's disease

•Thromboangiitis obliterans with eosinophilia of the temporal arteries

•Systemic lupus erythematosus

•Behçet syndrome

Other rare causes — Other rare causes of eosinophilia include cholesterol embolization, radiation exposure, autoimmune lymphoproliferative syndrome (ALPS), certain primary or secondary forms of immunodeficiency, and familial eosinophilia.

●Cholesterol embolization – Cholesterol embolization may occasionally manifest as isolated blood eosinophilia. More typically, there are other suggestive findings (eg, livido reticularis, purple toes, renal insufficiency) and hematologic changes (eg, increased erythrocyte sedimentation rate, hypocomplementemia, thrombocytopenia) [37]. (See "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)".)

●Radiation exposure – Eosinophilia and eosinophilic disorders, including eosinophilic pneumonia, have been reported following radiation therapy and exposure to ionizing radiation [38]. The mechanism underlying this relationship is unclear.

●ALPS – ALPS is a hereditary disorder characterized by immune dysregulation and lymphoproliferation. Asymptomatic eosinophilia occurs in approximately 10 percent of patients with ALPS and is associated with poor outcome [39]. (See "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis" and "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)

●Primary immunodeficiency syndromes – Examples of some of the primary immunodeficiency syndromes that are associated with eosinophilia include [40]:

•Hyperimmunoglobulin E syndrome – This condition, also called Job syndrome, is characterized by chronic dermatitis, recurrent bacterial infections, and elevated serum IgE; it typically presents with staphylococcal pneumonias or recurrent abscesses and chronic eczema. Most cases are associated with abnormalities of STAT3 or DOCK8. Severe forms (eg, DOCK8 deficiency) are generally diagnosed early in life, while STAT3 deficiency may present later in life. (See "Autosomal dominant hyperimmunoglobulin E syndrome" and "Combined immunodeficiencies: Specific defects", section on 'DOCK8 deficiency'.)

•Omenn syndrome – Omenn syndrome is a form of severe combined immunodeficiency (SCID) characterized by exudative rash, lymphadenopathy, hepatosplenomegaly, eosinophilia, elevated serum IgE, chronic diarrhea, and failure to thrive. Children usually present before three months of age.

•IPEX – IPEX is a rare form of X-linked immune dysregulation involving FOXP3 transcription factor that typically presents during infancy with a triad of enteropathy, autoimmune endocrinopathy, and dermatitis. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)

•ZAP-70 deficiency – ZAP-70 deficiency is similar to SCID and usually presents within the first two years of life with recurrent infections with or without chronic diarrhea and/or failure to thrive. Some patients have eosinophilia [41]. (See "ZAP-70 deficiency".)

●Secondary immunodeficiencies – Acquired disorders of immune dysregulation and/or inflammation may also be associated with eosinophilia, including [42]:

•Graft-versus-host disease following hematopoietic cell transplantation

•Inflammatory bowel disease

•Sarcoidosis

•Bullous pemphigoid

•Dermatitis herpetiformis

•Rejection of a transplanted solid organ

•Irritation of serosal surfaces (mechanical, chemical, or radiation-induced)

●Familial eosinophilia – This is a rare autosomal dominant condition associated with hypereosinophilia (absolute eosinophil count >1500/microL) and a benign clinical course in most cases [43]. Studies in two kindreds linked familial eosinophilia with dysregulation of IL-5 transcription [44].

DISORDERS WITH EOSINOPHILIC INVOLVEMENT OF SPECIFIC ORGANS — In the disorders listed in this section, involvement of specific tissues or organ systems may bring the patient to medical attention. Biopsy then reveals eosinophilic infiltration, allowing for a more focused diagnostic work-up. Accompanying blood eosinophilia is variable, since tissue eosinophilia can occur with or without eosinophilia in the peripheral blood.

Dermatologic — Eosinophils participate in the inflammatory infiltrate in numerous dermatologic conditions.

●Atopic dermatitis – Atopic dermatitis (ie, eczema) is a chronic inflammatory skin condition due to impaired epidermal barrier function and/or immune dysfunction that may be accompanied by blood and tissue eosinophilia. However, eosinophil counts >1500/microL are uncommon in this disorder. Marked eosinophilia, dramatic elevation of serum IgE, recurrent infections, or other atypical features should prompt evaluation for other causes of eosinophilia. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

●Eosinophilic panniculitis – Eosinophilic panniculitis is characterized by a prominent eosinophil infiltration of subcutaneous fat [45]. Lesions often are nodular but may present as plaques or vesicles. This pathology is commonly associated with gnathostomiasis, leukocytoclastic vasculitis, and erythema nodosum [45-47]. Eosinophilic panniculitis can also develop in response to injected medications [48-50].

●Episodic angioedema with eosinophilia – Although blood eosinophilia does not usually accompany angioedema, the entity of episodic angioedema with eosinophilia (Gleich syndrome) is characterized by recurrent episodes of angioedema, urticaria, pruritus, fever, weight gain, elevated serum immunoglobulin M (IgM), and leukocytosis with marked blood eosinophilia. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Episodic angioedema with eosinophilia (Gleich syndrome)'.)

●Kimura disease and angiolymphoid hyperplasia with eosinophilia – Kimura disease presents as large subcutaneous masses on the head or neck of East Asian males, whereas angiolymphoid hyperplasia with eosinophilia (also known as epithelioid hemangioma) occurs in all races and is characterized by generally smaller and more superficial lesions. Eosinophilia is common to both conditions, which are of unknown origin [51-53]. One report described a series of 21 cases of Kimura disease in the United States, the majority of which had eosinophilia [53]. The posterior auricular or cervical lymph nodes were most often involved. Consistent histologic features included follicular hyperplasia, eosinophilic infiltrates, and proliferation of postcapillary venules. (See "Angiolymphoid hyperplasia with eosinophilia and Kimura disease".)

●Eosinophilic fasciitis – Eosinophilic fasciitis, also known as Shulman's syndrome, is characterized by symmetrical induration of the skin. The onset is typically acute, and findings include erythema, swelling, and induration of the extremities that is accompanied by eosinophilia in up to two-thirds of patients. A subacute course may also occur. The thickening and hide-bound quality of the affected skin is somewhat similar to that seen with the scleroderma-spectrum disorders. However, the irregular, woody, peau d'orange texture of eosinophilic fasciitis is distinct from the smooth, shiny skin surface seen in patients with systemic sclerosis or localized scleroderma (picture 3). Skin involvement most commonly occurs on the extremities, neck, and trunk. (See "Eosinophilic fasciitis".)

●Eosinophilic cellulitis – Eosinophilic cellulitis, also known as Wells syndrome, is marked by recurrent lesions on the extremities; blood eosinophilia is present in 50 percent of cases (picture 4) [54,55]. There are several different clinical variants [55]. Involved skin appears cellulitic but is not tender or warm; the diagnosis may be suspected when patients do not respond to appropriate antibiotic treatment for bacterial cellulitis. Histology of a lesion in the acute stage shows edematous dermis infiltrated by eosinophils in a perivascular pattern. In the chronic stage, distinctive "flame figures" composed of masses of collagen and intact and degranulated eosinophils may be seen [56]. The skin findings usually resolve in two to eight weeks. Wells syndrome may be idiopathic, drug-related, or associated with myeloproliferative, immunologic, or infectious disorders [57-59].

●Eosinophilic pustular folliculitis – HIV-associated eosinophilic pustular folliculitis is characterized by recurrent, pruritic crops of discrete, erythematous, urticarial follicular papules and rare pustules, with a diameter of 3 to 5 mm (picture 5 and picture 6). The most common areas of involvement are the scalp, face, neck, and upper trunk; all are areas with a high concentration of sebaceous glands. It is found primarily in HIV-positive patients, patients undergoing treatment for hematologic malignancies and bone marrow transplant recipients [60]. However, it can also be seen in infants in a self-limited form [61]. (See "HIV-associated eosinophilic folliculitis".)

●Recurrent cutaneous necrotizing eosinophilic vasculitis – In this distinct vasculitis of small dermal vessels, skin biopsies show necrotizing vasculitis with minimal or absent leukocytoclasis and an almost exclusive eosinophilic infiltration in vessel walls and lumen [62-64]. Patients usually respond to systemic glucocorticoid treatment and pursue a chronic but relatively benign course.

●Eosinophilic ulcer of the oral mucosa – These ulcerated lesions appear to result from trauma, are usually tender and multiple, and often involve the tongue. Eosinophilic infiltration is prominent, and the lesions usually heal spontaneously over several weeks [65-68].

●Other dermatologic conditions – Tissue eosinophilia may be seen in blistering diseases such as bullous pemphigoid, pemphigus vulgaris, dermatitis herpetiformis, and herpes gestationis. Eosinophils or deposited eosinophil granule proteins can also be prominent in drug-induced lesions, chronic urticaria, solar urticaria, delayed pressure urticaria [69], the pregnancy-related dermatosis pruritic urticarial papules and plaques syndrome (PUPPS), and in orbital pseudotumors [70]. An uncommon disorder, characterized by the association of nodules, eosinophilia, rheumatism, dermatitis, and swelling (NERDS), includes prominent para-articular nodules, recurrent urticaria with angioedema, and tissue and blood eosinophilia [71].

Sinonasal and pulmonary — A variety of pulmonary diseases can be associated with eosinophilic inflammation of the airways and pleura. These are described briefly here and reviewed in detail separately. (See "Overview of pulmonary eosinophilia" and "Tropical pulmonary eosinophilia" and "Pleural fluid eosinophilia" and "Chronic eosinophilic pneumonia".)

●Allergic rhinitis – Allergic rhinitis is a common disorder that presents with sneezing, rhinorrhea, and nasal congestion. If present, blood eosinophilia is usually mild to moderate. (See "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis", section on 'Routine laboratory findings'.)

●Chronic rhinosinusitis – Eosinophilia of involved tissues is frequent in several forms of chronic rhinosinusitis. Specific disorders that may be accompanied by blood and tissue eosinophilia include allergic fungal rhinosinusitis, chronic rhinosinusitis with nasal polyposis, often associated with aspirin sensitivity, and the sinusitis of eosinophilic granulomatosis with polyangiitis ([EGPA] previously called Churg-Strauss syndrome). (See "Allergic fungal rhinosinusitis" and "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'CRS with nasal polyposis' and "Aspirin-exacerbated respiratory disease" and "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

●Asthma – Asthma can cause eosinophilia, and other causes of eosinophilia (eg, helminthic infection, fungal infection) can present with bronchospasm mimicking asthma. Thus, it is helpful to establish the temporal relationship between development of asthma symptoms and eosinophilia, if possible. Helminthic infections that can cause wheezing are reviewed separately. (See "Overview of pulmonary eosinophilia", section on 'Transpulmonary passage of helminth larvae (Löffler syndrome)'.)

Asthma-associated eosinophilia is usually mild to moderate (eg, <1500/microL) [72]. Therefore, eosinophilia ≥1500/microL should prompt consideration of other eosinophilic pulmonary conditions (eg, allergic bronchopulmonary aspergillosis [ABPA], EGPA, nasal polyposis). (See "Evaluation of severe asthma in adolescents and adults" and "Evaluation of wheezing illnesses other than asthma in adults" and "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

●Other pulmonary diseases – Abnormally high numbers of eosinophils may be seen in the pulmonary parenchyma in many conditions. These include parasitic infections, drug reactions, asthma, allergic bronchopulmonary aspergillosis, acute and chronic eosinophilic pneumonias, the hypereosinophilic syndrome, and EGPA.

Less commonly, pulmonary eosinophilia occurs in association with bronchiolitis obliterans organizing pneumonia, rheumatoid arthritis, Sjögren's disease, sarcoidosis, malignancy, eosinophilic granuloma, post-radiation therapy, graft-versus-host disease, and systemic sclerosis. Coccidioidal infection is in the differential diagnosis of eosinophilic pneumonia because organisms may be absent from cultures and open lung biopsy specimens. (See "Overview of pulmonary eosinophilia".)

●Pleural diseases – Pleural fluid eosinophilia is commonly associated with air or blood in the pleural space and usually has a benign, self-limited course. (See "Pleural fluid eosinophilia".)

Gastrointestinal and hepatobiliary — Tissue eosinophilia develops with a number of gastrointestinal and hepatobiliary disorders, and symptoms are related to eosinophil infiltration. Blood eosinophilia is present less frequently. Gastrointestinal eosinophilia elicited by intestinal parasites or by a hypersensitivity reaction to medications must be excluded in patients with the following eosinophilic conditions.

●Eosinophilic esophagitis – Eosinophilic esophagitis is a disorder associated with esophageal eosinophilia. Adults typically present with dysphagia and/or food impaction while children have a more variable presentation depending, in part, upon their age. Patients often have a history of allergies, and peripheral blood may demonstrate eosinophilia. Strictures may be seen on endoscopy; histopathology reveals mucosal infiltration with eosinophils. Blood eosinophilia may or may not be present. (See "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)".)

●Eosinophilic gastroenteritis – Eosinophilic gastroenteritis is an uncommon disorder characterized by gastrointestinal symptoms, blood eosinophilia, and eosinophilic infiltration of the gastrointestinal wall; peak onset is in the third decade of life. Although allergies to foods contribute to this disease in some children, allergic etiologies are not common in adults. This disorder is reviewed in detail separately. (See "Eosinophilic gastrointestinal diseases".)

●Other disorders – Local tissue infiltration may be noted in patients with gastroesophageal acid reflux disease [73,74], Helicobacter pylori infection [75], inflammatory bowel disease [76], celiac disease, and collagenous colitis [77]. Patients with inflammatory bowel disease and celiac disease may also have peripheral blood eosinophilia.

●Hepatobiliary diseases – Hepatic eosinophilia develops in response to some medications such as semisynthetic penicillins and tetracyclines. Hepatitis is also a feature of drug reaction with eosinophilia and systemic symptoms (DRESS). (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Helminthic parasites that affect the liver include schistosomes (whose eggs embolize into the portal system and elicit eosinophil-enriched granulomas and fibrosis), migrating larvae (eg, visceral larva migrans), and hepatobiliary parasites (eg, Clonorchis). (See 'Parasites and other infections' above.)

Other disorders that may present with hepatic disease include primary biliary cirrhosis [78], hypereosinophilic syndrome [79,80], sclerosing cholangitis [81], eosinophilic cholangitis [82], and eosinophilic cholecystitis [83].

●Transplant rejection – Following liver transplant, eosinophilic infiltrate of the portal tract on biopsy may be a warning sign of rejection. (See "Liver transplantation in adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft", section on 'Establishing the diagnosis'.)

Cardiac — Endomyocardial fibrosis and intraventricular thrombosis may occur following a variety of eosinophilic syndromes including hypersensitivity myocarditis [84], parasitic infections [79,85], hypereosinophilic syndrome [79,85], eosinophilic leukemia, sarcomas, carcinomas, lymphomas [86], granulocyte-macrophage colony-stimulating factor (GM-CSF) administration [87], and prolonged drug-induced eosinophilia. (See "Myocarditis: Causes and pathogenesis", section on 'Hypersensitivity myocarditis' and "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Clinical features'.)

Eosinophilic coronary arteritis, usually limited to the small vessels, may be seen in EGPA. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Cardiovascular'.)

Renal — A number of conditions can result either in eosinophiluria or eosinophilic infiltration of the kidneys or urinary tract. Eosinophiluria may be found in patients with drug-induced acute interstitial nephritis, rapidly progressive and acute poststreptococcal glomerulonephritis [88], eosinophilic prostatitis [89], eosinophilic cystitis, renal transplant rejection, bladder cancer [90], cholesterol embolization, and schistosomiasis [91,92].

Eosinophilic infiltration of the kidneys or urinary tract may be seen with the following disorders:

●Drug-induced acute interstitial nephritis – Acute interstitial nephritis (AIN) is a renal condition that causes a decline in creatinine clearance and is characterized by an inflammatory infiltrate in the kidney interstitium. Drugs are the most common cause of AIN. Implicated drugs include nonsteroidal anti-inflammatory drugs ([NSAIDs] including selective cyclooxygenase [COX]-2 inhibitors), penicillins and cephalosporins, rifampin, antimicrobial sulfonamides, ciprofloxacin and other quinolones, diuretics, cimetidine, allopurinol, proton pump inhibitors, and 5-aminosalicylates. Patients generally present with a rise in the plasma creatinine concentration, which (if drug induced) is temporally related to administration of the offending drug. They may have fever, rash, and peripheral blood eosinophilia. Urine sediment usually reveals white cells, red cells, and white cell casts. Urinary eosinophils may be present, but this test lacks the specificity and sensitivity to either exclude or diagnose AIN. (See "Clinical manifestations and diagnosis of acute interstitial nephritis".)

●Eosinophilic cystitis – Eosinophilic cystitis presents with hematuria, urinary frequency, dysuria, and suprapubic pain [93]. It occurs more often in children than adults and is of unknown etiology [94]. Cystoscopy reveals diffusely hyperemic mucosa with nodular areas of prominent eosinophilic infiltration [95]. The diagnosis is confirmed histologically; bladder carcinoma is the principal alternative diagnosis. Although most patients have a benign course with spontaneous resolution, some chronic cases progress to bladder destruction and renal failure [96]. A variety of treatments can be considered including fulguration, analgesics, or glucocorticoids [97].

●Dialysis – Patients on hemodialysis may have mild eosinophilia [98]. Initiation of peritoneal dialysis leads to episodes of peritoneal eosinophilia with or without blood eosinophilia [99,100]. Although this eosinophilic peritonitis is usually self-limited, treatment with montelukast has been described [101].

●Transplant rejection – Infiltration of eosinophils may accompany rejection of transplanted kidneys, and blood and urinary eosinophil counts are variably monitored as indicators of rejection. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection".)

Neurologic — The combination of neurologic findings and eosinophilia may be seen in the hypereosinophilic syndromes, EGPA, and with eosinophilic meningitis. (See "Eosinophilic meningitis".)

SUMMARY

●Description – Eosinophils are predominantly tissue-dwelling cells whose functions in health are not entirely understood. Eosinophil numbers increase in a variety disease states, ranging in severity from mild to life-threatening. When activated, eosinophils can release mediators and substances that can damage tissues and contribute to disease pathology. (See 'Eosinophil biology' above.)

●Normal eosinophil count – In peripheral blood, an absolute eosinophil count (AEC; determined by multiplying the total white blood cell count by the percentage of eosinophils) of 0 to 500 cells/microL (<0.5 x 10⁹/L) is typically considered normal. (See 'Normal levels and anatomic locations' above.)

●Eosinophilia – An increase in eosinophils in the peripheral blood or tissues most commonly represents a reactive or secondary expansion of a polyclonal eosinophil population. Less commonly, eosinophilia can be clonal, resulting from a hematopoietic stem cell mutation. (See 'Mechanisms of eosinophilia' above.)

●Consequences of eosinophilia – Tissue damage is more likely to occur when the AEC is >1500 cells/microL, but it can also occur with lower blood eosinophil levels. It is important to understand that the degree of peripheral blood eosinophilia does not always accurately predict the risk of organ damage. (See 'Tissue damage' above.)

●Target organs – Any organ can be involved, but the skin, airways, and gastrointestinal tract are the most common target organs. The heart and nervous system can also be infiltrated, and damage to these organs is potentially life-threatening. (See 'Target organs' above.)

●Causes of eosinophilia – Causes may be divided into disorders that cause signs and symptoms in multiple organ systems, accompanied by peripheral eosinophilia (table 1), and those disorders that predominantly affect one organ system, with variable peripheral eosinophilia (table 2). (See 'Major causes of eosinophilia' above and 'Disorders with eosinophilic involvement of specific organs' above.)

The degree of eosinophilia is rarely helpful for identifying the cause, except at extremes of eosinophil counts (eg, very mild eosinophilia is more likely to be seen with asthma or allergic rhinitis; very severe eosinophilia [ie, ≥20,000 eosinophils/microL] is more likely to be caused by a myeloid neoplasm). Between these two extremes, there is a wide differential of potential etiologies. (See 'Importance of considering many possible causes' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.