Eosinophil biology and causes of eosinophiliaAuthors:

Peter F Weller, MD, FACPAmy D Klion, MD

Section Editors:Donald H Mahoney, Jr, MDBruce S Bochner, MD

Deputy Editors:Alan G Rosmarin, MDAnna M Feldweg, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Nov 2016. | This topic last updated: Nov 03, 2015.

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 [1]. The true physiologic function(s) of eosinophils remain largely unknown although they are likely involved in host immune response to infection, tissue remodeling, tumor surveillance, and maintenance of other immune cells [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) [3].

Normal levels — In peripheral blood, an absolute eosinophil count (determined by multiplying the total WBC count by the percentage of eosinophils) of 0 to 500/microL (<0.5 x 109/L) is typically considered normal. Defining the normal range by percentage of WBC can be problematic because differences in absolute neutrophil counts between ethnic groups can dramatically impact the percent of eosinophilia [4]. Blood eosinophil counts have been reported to vary within the same person at different times of day and on different days, both in individuals with eosinophilic disorders and in healthy volunteers [5-7]. However, results are inconsistent among studies, and the variability in counts 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 [8]. In healthy individuals, eosinophils can be found in the digestive tract (although not the esophagus), spleen, lymph nodes, thymus, mammary glands, and uterus [2]. 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.

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

●Polyclonal expansion – A polyclonal expansion of eosinophils may result from overproduction of IL-5. This is termed reactive or secondary eosinophilia. Sufficient quantities of IL-5 to cause eosinophilia can be produced by T helper cell type 2 (Th2) lymphocytes and group 2 innate lymphoid cells (ILC-2) in the setting of helminthic infections [9-11], 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 [2].●Clonal expansion – Less commonly, a clonal eosinophilia arises as a result of a hematopoietic stem cell mutation. In this case, eosinophils may be the only 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).

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.

Tissue damage — Tissue damage is more likely to occur when the absolute eosinophil count exceeds1500/microL but can occur even with lower blood eosinophil levels [2,12,13]. 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. Thus, organ involvement and end-organ damage cannot be predicted by a high eosinophil count, nor can they be excluded by a normal eosinophil count.  

Activated eosinophils may damage tissues in a number of mechanisms, including the following:

●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.●Production of lipid mediators, such as sulfidopeptide leukotrienes and platelet activating factor, which mediate smooth muscle contraction and recruitment of inflammatory cells.●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 mediators are generally released after entry of eosinophils into tissues, although detection of eosinophil granule proteins in the blood is considered a potential biomarker of tissue eosinophilia. In some cases, increased blood levels of eosinophil granule proteins can be detected in the absence of peripheral eosinophilia in patients with eosinophilic tissue infiltration [14].  

Target organs — Common target organs of eosinophils in disease include the skin, airway, and gastrointestinal tract. However, cardiac and nervous system damage can also occur and can be more concerning and potentially life-threatening. (See "Approach to the patient with unexplained eosinophilia".)

MAJOR CAUSES OF EOSINOPHILIA — There are various approaches to categorizing the disorders that can cause eosinophilia. In medical training, it is common to learn the mnemonic NAACP, which stands forNeoplasms, Addison's disease, Allergic diseases, Collagen vascular diseases, and Parasitic diseases. However, this approach has several limitations: Addison's disease is a rare cause but features prominently in the mnemonic; other groups of disorders, such as the eosinophilic gastrointestinal diseases and the hypereosinophilic syndromes (HES), do not fit well into any of the categories; and there are other infections besides parasitic infections that cause eosinophilia.

We prefer to divide the disorders into two groups because of differences in treatment approaches:

●Disorders presenting with signs and symptoms affecting multiple organ systems, usually accompanied by peripheral blood eosinophilia (table 1)●Disorders that typically present with eosinophilic involvement of a single organ, variably accompanied by peripheral blood eosinophilia (table 2)

However, since some individuals who appear to have single-organ involvement may subsequently develop additional clinical manifestations, the division between these two groups is imperfect.

Importance of considering many possible causes — 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 myeloproliferative neoplasm [MPN]). 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 elsewhere. (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 — Many neoplastic disorders can cause eosinophilia. Examples include the following:

●Primary (or neoplastic) hypereosinophilic syndrome (HES) – Primary (neoplastic) HES refers to an MPN that produces a predominance of mature eosinophils. These are typically associated in males with a fusion gene created from Fip1-like 1 (FIP1L1) and platelet-derived growth factor receptor alpha (PDGFRA). Other molecular abnormalities have also been implicated, including fusion genes involving platelet-derived growth factor receptor beta (PDGFRB) and fibroblast growth factor receptor (FGFR1). 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 classified as FAB M4Eo) caused by abnormalities in chromosome 16. Patients usually present with symptoms related to complications of pancytopenia (eg, severe fatigue, infection, bleeding). Immature eosinophils may be seen in the peripheral blood. (See"Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia" and "Cytogenetics in acute myeloid leukemia", section on 'Inv(16) and t(16;16)'.)●Chronic eosinophilic leukemia – Chronic eosinophilic leukemia (CEL) is a rare MPN characterized by clonal expansion of dysplastic eosinophils. Patients may be asymptomatic or have constitutional symptoms. A variety of genetic abnormalities have been described in CEL. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Chronic eosinophilic leukemia'.)●Other myeloproliferative neoplasms – Eosinophilia can be associated with a variety of other MPNs. As examples:

•MPNs associated with mutation of the gene encoding the JAK2 protein kinase (eg, polycythemia vera, essential thrombocythemia, primary myelofibrosis) can present with eosinophilia; clinical features are varied. (See "Overview of the myeloproliferative neoplasms", section on 'JAK2 mutations'.)•Chronic myeloid leukemia (CML) is MPN associated with the BCR-ABL fusion gene. Many patients are asymptomatic at diagnosis; some 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'.)

●Lymphoid neoplasms – Almost any B or T cell lymphoma or leukemia can be implicated in causing eosinophilia. The mechanism may involve dysregulation of cytokine production by lymphocytes. Some lymphoid neoplasms commonly associated with eosinophilia include the following:

•B cell lymphoma – Hodgkin lymphoma and B cell non-Hodgkin lymphoma (NHL) can be associated with eosinophilia; one report suggested that eosinophilia could occur in up to 15 percent of patients with Hodgkin lymphoma and 5 percent of those with B cell NHL [15]. Patients present with lymphadenopathy with or without "B symptoms" (eg, fever, weight loss, sweats). (See "Clinical presentation and diagnosis of non-Hodgkin lymphoma".)•T cell lymphoblastic lymphoma and adult T cell leukemia/lymphoma – T cell malignancies including lymphoblastic lymphoma, T cell leukemia/lymphoma, and angioimmunoblastic T cell lymphoma (AITL) have also been associated with eosinophilia. 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".)•Sézary syndrome – Sézary syndrome is a type of cutaneous T cell lymphoma (CTCL) associated with increased serum immunoglobulin E (IgE) and eosinophilia. Patients can present with erythroderma, lymphadenopathy, and systemic symptoms. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Pathogenesis'.)•Precursor B cell acute lymphoblastic leukemia – Acute lymphoblastic leukemia (ALL) with a t(5;14) translocation has been associated with eosinophilia. This translocation caused a fusion of the immunoglobulin heavy-chain gene to the IL-3 gene promoter. Patients with ALL are generally acutely ill. (See "Clinical manifestations, pathologic features, and diagnosis of precursor B cell acute lymphoblastic leukemia/lymphoma".)

●Systemic mastocytosis – Systemic mastocytosis 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. (See "Mastocytosis (cutaneous and systemic): Evaluation and diagnosis in adults".)●Solid tumors – Nonhematologic cancers can cause eosinophilia, most notably adenocarcinomas of the gastrointestinal tract (eg, stomach, large bowel), lung, and squamous epithelium (eg, cervix, vagina, penis, skin, nasopharynx, bladder).

Parasites and other infections — Parasitic helminths (worms) are the most commonly identified infectious cause of eosinophilia [16]. Helminths that can elicit eosinophilia are listed in the tables (table 3 and table 4 andtable 5).

Some parasitic infections are associated only with specific geographical exposures. However, many parasites are endemic worldwide. Eosinophilia may increase transiently with therapy, with

the magnitude of post-treatment eosinophilia dependent on the parasite burden and host responses [17,18]. Resolution of eosinophilia following treatment of a helminthic infection may take months, possibly because killed helminths in the tissue may act as an ongoing source of antigens.

Parasites to consider in all patients — Some parasites are endemic worldwide and should be considered in all patients with eosinophilia, regardless of where the individual has resided or traveled. All of these parasites may cause symptomatic or asymptomatic infection:

●Strongyloidiasis – Strongyloides stercoralis is endemic worldwide in areas with a hot, humid climate (eg, the southeastern United States and southern Europe) and can directly penetrate the skin upon contact with soil or water contaminated with human feces. Strongyloidiasis can have a latency of years between the initial exposure and the development of symptoms, and infection easily could be overlooked if the patient or clinician were unaware of the possibility of remote exposure. (See "Strongyloidiasis".)We perform Strongyloides serology as part of the initial evaluation in all patients with a potential exposure history. Strongyloides is of greatest concern for several reasons:

•The parasite can internally reinfect, enabling ongoing infections even decades after initial exposure.•Eosinophilia of varying levels may be the only indication of a subclinical infection.•Disseminated hyperinfection can develop in patients given systemic glucocorticoids. Thus, latent infection with this parasite must be excluded or the patient empirically treated prior to the initiation of systemic glucocorticoid therapy. (See "Hypereosinophilic syndromes: Treatment" and"Hypereosinophilic syndromes: Treatment", section on 'Glucocorticoids'.)

●Toxocariasis – Toxocara canis and cati are endemic worldwide and can be ingested with soil or food contaminated by dog or cat feces. This is typically a concern with children who may ingest contaminated soil. Affected individuals are acutely ill. Testing by serology may be appropriate in children. (See"Toxocariasis: Visceral and ocular larva migrans".)●Trichinellosis – Trichinella species have been reported worldwide. Human infections are seen most commonly in China, Thailand, Mexico, Argentina, Bolivia, and parts of Eastern and Central Europe. Infection results from ingestion of undercooked meat, especially pork. Testing by serology may be appropriate in individuals with potential exposure. (See "Trichinellosis".)●Hookworm – Ancylostoma duodenale is found in Mediterranean countries, Iran, India, Pakistan, and Asia.Necator americanus lives in North America, South America, Central Africa, Indonesia, the South Pacific, and parts of India. These worms infect humans by larval penetration into skin. Affected individuals may have rash, cough, and gastrointestinal symptoms. Testing by stool studies is indicated in individuals with an appropriate exposure history. (See "Hookworm infection".)

Infections relevant to certain geographic areas — In contrast to parasites endemic worldwide, other parasitic infections associated with eosinophilia are more geographically limited (see "Approach to the patient with unexplained eosinophilia", section on 'Travel'):

●Filariasis – Several filarial infections can occur in several human tissues, including lymphatic, pulmonary, and subconjunctival. Transmission is via arthropod vectors (eg, mosquitoes, blackflies). Most filarial infections are endemic only in the tropics and subtropics, with the exception of zoonotic filariae (Dirofilariaand Mansonella species), which cause self-limited infections in humans that are rarely associated with peripheral blood eosinophilia. (See "Epidemiology, pathogenesis, and clinical manifestations of lymphatic filariasis" and "Tropical pulmonary eosinophilia" and "Mansonella infections".)●Schistosomiasis – Schistosome species are endemic in some regions of the tropics and Africa. Most patients are asymptomatic; however, acute symptoms localized to specific organs (eg, swimmer's itch, Katayama fever) or generalized fatigue may occur. (See "Epidemiology, pathogenesis, and clinical manifestations of schistosomiasis".)

Nonhelminthic infections — Nonhelminthic parasites and other infections are occasionally associated with eosinophilia:

●Ectoparasites (eg, scabies mites) can cause eosinophilia, especially if the infection is severe or there is an underlying immunodeficiency or skin disorder [19,20].●Some fungi can also cause eosinophilia. Aspergillus is the one most commonly implicated in the setting of allergic bronchopulmonary aspergillosis (ABPA). Coccidioidomycosis has also been associated with eosinophilia in approximately 25 percent of patients, with eosinophilia peaking during the second or third week of illness or during disseminated infection [21-23]. Basidiobolomycosis, paracoccidioidomycosis, disseminated histoplasmosis, and cryptococcosis also have been associated with eosinophilia. (See"Primary coccidioidal infection", section on 'Clinical manifestations' and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis", section on 'Differential diagnosis'.)●Retroviral infections can sometimes be accompanied by eosinophilia. Infection with the human T-lymphotropic virus HTLV-II is commonly associated with eosinophilia; HTLV-I infection may also be implicated [24,25]. Eosinophilia also may occur with human immunodeficiency virus (HIV)-1 infection, but in the setting of HIV infection, the eosinophilia is usually due to an associated condition (eg, drug reaction, adrenal insufficiency, eosinophilic folliculitis) rather than a direct result of the HIV virus. (See "Pituitary and adrenal gland dysfunction in HIV-infected patients" and "HIV-associated eosinophilic folliculitis".)●Protozoal parasites (eg, Giardia, malaria, Babesia) generally do not produce eosinophilia. Exceptions are the intestinal protozoa Isospora belli, Dientamoeba fragilis, and Sarcocystis species, which can cause peripheral eosinophilia. Sarcocystis can also cause eosinophilic myositis [26]. (See "Approach to the patient with unexplained eosinophilia", section on 'Travel'.)

Eosinophilia in a patient with fever is unlikely to be due to a bacterial or viral infection, since most acute bacterial or viral infections are associated with decreased eosinophil counts. High quality evidence is lacking for an association of eosinophilia with tuberculosis, toxoplasma, bartonellosis, or group A streptococcal infections.

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.

Organ-specific allergic disorders — 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 6). 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 and picture 3 and picture 4). Additional systemic symptoms 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 weeks following discontinuation of the implicated drug. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

Adrenal insufficiency — Adrenal insufficiency has been associated with eosinophilia, especially in acutely ill patients. This is believed to be due to loss of endogenous glucocorticoids. Severe adrenal insufficiency presenting as isolated eosinophilia in an otherwise healthy individual is rare. In contrast, eosinophilia may be a marker of 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. In these rare cases, we obtain a cortisol level and/or ACTH stimulation test. (See "Clinical manifestations of adrenal insufficiency in adults" and "Diagnosis of adrenal insufficiency in adults".)

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

•Dermatomyositis•Severe rheumatoid arthritis•Progressive systemic sclerosis•Sjögren's syndrome•Thromboangiitis obliterans with eosinophilia of the temporal arteries•Granulomatosis with polyangiitis (Wegener's syndrome)•Eosinophilic fasciitis•Systemic lupus erythematosus•Behçet's syndrome•IgG4-related disease

These conditions are discussed in separate topic reviews.

Other rare causes — Other rare causes include cholesterol embolization, autoimmune lymphoproliferative syndrome (ALPS), and several primary or secondary forms of immunodeficiency.

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) [27]. (See "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)".)

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 [28]. (See "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis" and "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)

Some primary immunodeficiency syndromes are associated with eosinophilia, including:

●Hyperimmunoglobulin E syndrome (also called Job syndrome, due to STAT3 or DOCK8 deficiency), which is characterized by chronic dermatitis, recurrent bacterial infections, and elevated serum immunoglobulin E (IgE). Hyperimmunoglobulin E syndrome is most often diagnosed in older children or adults with staphylococcal pneumonias or recurrent abscesses and chronic eczema. (See "Autosomal dominant hyperimmunoglobulin E syndrome" and "Combined immunodeficiencies", section on 'Dedicator of cytokinesis 8 deficiency'.)●Omenn syndrome, 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, a rare X-linked immune dysregulatory disorder involving the transcription factor FOXP3 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, which usually presents within the first two years of life with recurrent infections and sometimes also chronic diarrhea and/or failure to thrive, similar to SCID. Some patients have eosinophilia [29]. (See "ZAP-70 deficiency".)

Acquired forms of immunodeficiency and/or inflammation may also be associated with eosinophilia, including the following [30]:

●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)

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 relatively infrequent in this disorder. Marked eosinophilia, dramatic elevation of serum immunoglobulin E (IgE), recurrent infections, or other atypical features should prompt evaluation for other causes of eosinophilia. (See "Pathogenesis, clinical manifestations, and diagnosis of atopic dermatitis (eczema)".)●Eosinophilic panniculitis – Eosinophilic panniculitis is characterized by a prominent eosinophil infiltration of subcutaneous fat [31]. Lesions often are nodular but may present as plaques or vesicles. This pathology is commonly associated with gnathostomiasis, leukocytoclastic vasculitis, and erythema nodosum [31-33]. Eosinophilic panniculitis can also develop in response to injected medications [34-36].●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 [37-39]. One report described a series of 21 cases of Kimura disease in the United States, the majority of which had eosinophilia [39]. The posterior auricular or cervical lymph nodes were most often involved. Consistent histologic features included follicular hyperplasia, eosinophilic infiltrates, and proliferation of postcapillary venules. Treatment usually consists of surgical resection. In addition, some case reports suggest a beneficial effect from glucocorticoids [40], the selective H1 receptor antagonistcetirizine [41], radiotherapy [42,43], topical tacrolimus [44], and thalidomide [45].●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 5). 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 6) [46,47]. There are several different clinical variants [47]. 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 [48]. 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 [49-51].●Eosinophilic pustular folliculitis – Human immunodeficiency virus (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 7 and picture 8). 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 [52]. However, it can also be seen in infants in a self-limited form [53]. (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 [54-56]. 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 [57-60].●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 [61], the pregnancy-related dermatosis pruritic urticarial papules and plaques syndrome (PUPPS), and in orbital pseudotumors [62]. 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 [63].

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 elsewhere. (See "Causes 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 "Causes of pulmonary eosinophilia", section on 'Transpulmonary passage of helminth larvae (Löffler syndrome)'.)  Asthma-associated eosinophilia is usually mild to moderate (eg, <1500/microL) [64]. 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 syndrome, 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 "Causes 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 laboratories may demonstrate a peripheral 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".)●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 gastroenteritis".)●Other disorders – Local tissue infiltration may be noted in patients with gastroesophageal acid reflux disease [65,66], Helicobacter pylori infection [67], inflammatory bowel disease [68], celiac disease, and collagenous colitis [69]. 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 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 [70], hypereosinophilic syndrome [71,72], sclerosing cholangitis [73], eosinophilic cholangitis [74], and eosinophilic cholecystitis [75].●Transplant rejection – Following liver transplant, eosinophilic infiltrate of the portal tract on biopsy may be a warning sign of rejection. (See "Liver transplantation: Diagnosis of acute cellular rejection", section on 'Liver biopsy'.)

Cardiac — Endomyocardial fibrosis and intraventricular thrombosis may occur following a variety of eosinophilic syndromes including hypersensitivity myocarditis [76], parasitic infections [71,77], hypereosinophilic syndrome [71,77], eosinophilic leukemia, sarcomas, carcinomas, lymphomas [78], granulocyte-macrophage colony-stimulating factor (GM-CSF) administration [79], and prolonged drug-induced eosinophilia. (See"Etiology and pathogenesis of myocarditis", section on 'Hypersensitivity myocarditis' and "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Cardiac disease'.)

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 [80], eosinophilic prostatitis [81], eosinophilic cystitis, renal transplant rejection, bladder cancer [82], cholesterol embolization, and schistosomiasis [83,84]. (See "The significance of urinary eosinophils".)

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, indinavir, 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 [85]. It occurs more often in children than adults and is of unknown etiology [86]. Cystoscopy reveals diffusely hyperemic mucosa with nodular areas of prominent eosinophilic infiltration [87]. 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 [88]. A variety of treatments can be considered including fulguration, analgesics, or glucocorticoids [89].  ●Dialysis – Patients on hemodialysis may have mild eosinophilia [90]. Initiation of peritoneal dialysis leads to episodes of peritoneal eosinophilia with or without blood eosinophilia [91,92]. Although this eosinophilic peritonitis is usually self-limited, treatment with montelukast has been described [93].  ●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 "Clinical manifestations and diagnosis of acute renal 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

●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.)●In peripheral blood, an absolute eosinophil count (determined by multiplying the total white blood cell count by the percentage of eosinophils) of 0 to 500/microL (<0.5 x 109/L) is typically considered normal. (See'Normal levels' above.)●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.)●Tissue damage is more likely to occur when the absolute eosinophil count exceeds 1500/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.)●In eosinophilic diseases, the skin, airways, and gastrointestinal tract are 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 may be divided into those 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 myeloproliferative neoplasm). Between these two extremes, there is a wide differential of potential etiologies. (See 'Importance of considering many possible causes' above.)

Use of UpToDate is subject to the Subscription and License Agreement.REFERENCES

1. Gleich GJ, Klion AD, Lee JJ, Weller PF. The consequences of not having eosinophils. Allergy 2013; 68:829.

2. Roufosse F, Weller PF. Practical approach to the patient with hypereosinophilia. J Allergy Clin Immunol 2010; 126:39.

3. Ackerman SJ, Bochner BS. Mechanisms of eosinophilia in the pathogenesis of hypereosinophilic disorders. Immunol Allergy Clin North Am 2007; 27:357.

4. Hsieh MM, Everhart JE, Byrd-Holt DD, et al. Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences. Ann Intern Med 2007; 146:486.

5. Spector SL, Tan RA. Is a single blood eosinophil count a reliable marker for "eosinophilic asthma?". J Asthma 2012; 49:807.

6. Statland BE, Winkel P, Harris SC, et al. Evaluation of biologic sources of variation of leukocyte counts and other hematologic quantities using very precise automated analyzers. Am J Clin Pathol 1978; 69:48.

7. Sennels HP, Jørgensen HL, Hansen AL, et al. Diurnal variation of hematology parameters in healthy young males: the Bispebjerg study of diurnal variations. Scand J Clin Lab Invest 2011; 71:532.

8. Weller PF. The immunobiology of eosinophils. N Engl J Med 1991; 324:1110. 9. Liu Z, Liu Q, Pesce J, et al. Requirements for the development of IL-4-producing T cells

during intestinal nematode infections: what it takes to make a Th2 cell in vivo. Immunol Rev 2004; 201:57.

10. Moore TA, Nutman TB. Eosinophilia in the returning traveler. Infect Dis Clin North Am 1998; 12:503.

11. Roediger B, Weninger W. Group 2 innate lymphoid cells in the regulation of immune responses. Adv Immunol 2015; 125:111.

12. Chen YY, Khoury P, Ware JM, et al. Marked and persistent eosinophilia in the absence of clinical manifestations. J Allergy Clin Immunol 2014; 133:1195.

13. Helbig G, Hus M, Francuz T, et al. Characteristics and clinical outcome of patients with hypereosinophilia of undetermined significance. Med Oncol 2014; 31:815.

14. Makiya MA, Herrick JA, Khoury P, et al. Development of a suspension array assay in multiplex for the simultaneous measurement of serum levels of four eosinophil granule proteins. J Immunol Methods 2014; 411:11.

15. Navarro-Román L, Medeiros LJ, Kingma DW, et al. Malignant lymphomas of B-cell lineage with marked tissue eosinophilia. A report of five cases. Am J Surg Pathol 1994; 18:347.

16. Wilson ME, Weller PF. Eosinophilia. In: Tropical Infectious Diseases: Principles, Pathogens and Practice, 3rd ed, Guerrant RL, Walker DH, Weller PF (Eds), Saunders Elsevier, Philadelphia 2011. p.939.

17. Ottesen EA, Weller PF. Eosinophilia following treatment of patients with schistosomiasis mansoni and Bancroft's filariasis. J Infect Dis 1979; 139:343.

18. Reimert CM, Fitzsimmons CM, Joseph S, et al. Eosinophil activity in Schistosoma mansoni infections in vivo and in vitro in relation to plasma cytokine profile pre- and posttreatment with praziquantel. Clin Vaccine Immunol 2006; 13:584.

19. Sluzevich JC, Sheth AP, Lucky AW. Persistent eosinophilia as a presenting sign of scabies in patients with disorders of keratinization. Arch Dermatol 2007; 143:670.

20. Roberts LJ, Huffam SE, Walton SF, Currie BJ. Crusted scabies: clinical and immunological findings in seventy-eight patients and a review of the literature. J Infect 2005; 50:375.

21. Harley WB, Blaser MJ. Disseminated coccidioidomycosis associated with extreme eosinophilia. Clin Infect Dis 1994; 18:627.

22. Malo J, Luraschi-Monjagatta C, Wolk DM, et al. Update on the diagnosis of pulmonary coccidioidomycosis. Ann Am Thorac Soc 2014; 11:243.

23. Simons CM, Stratton CW, Kim AS. Peripheral blood eosinophilia as a clue to the diagnosis of an occult Coccidioides infection. Hum Pathol 2011; 42:449.

24. Kaplan MH, Hall WW, Susin M, et al. Syndrome of severe skin disease, eosinophilia, and dermatopathic lymphadenopathy in patients with HTLV-II complicating human immunodeficiency virus infection. Am J Med 1991; 91:300.

25. Plumelle Y, Gonin C, Edouard A, et al. Effect of Strongyloides stercoralis infection and eosinophilia on age at onset and prognosis of adult T-cell leukemia. Am J Clin Pathol 1997; 107:81.

26. Esposito DH, Stich A, Epelboin L, et al. Acute muscular sarcocystosis: an international investigation among ill travelers returning from Tioman Island, Malaysia, 2011-2012. Clin Infect Dis 2014; 59:1401.

27. Saric M, Kronzon I. Cholesterol embolization syndrome. Curr Opin Cardiol 2011; 26:472. 28. Kim YJ, Dale JK, Noel P, et al. Eosinophilia is associated with a higher mortality rate

among patients with autoimmune lymphoproliferative syndrome. Am J Hematol 2007; 82:615.29. Turul T, Tezcan I, Artac H, et al. Clinical heterogeneity can hamper the diagnosis of

patients with ZAP70 deficiency. Eur J Pediatr 2009; 168:87.30. Klion A. Hypereosinophilic syndrome: current approach to diagnosis and treatment.

Annu Rev Med 2009; 60:293.31. Adame J, Cohen PR. Eosinophilic panniculitis: diagnostic considerations and evaluation.

J Am Acad Dermatol 1996; 34:229.32. Glass LA, Zaghloul AB, Solomon AR. Eosinophilic panniculitis associated with chronic

recurrent parotitis. Am J Dermatopathol 1989; 11:555.33. Kato N. Eosinophilic panniculitis. J Dermatol 1993; 20:185. 34. Shan SJ, Guo Y. Exenatide-induced eosinophilic sclerosing lipogranuloma at the

injection site. Am J Dermatopathol 2014; 36:510.35. Batalla A, Rosón E, Posada C, Flórez A. Eosinophilic panniculitis after subcutaneous

administration of sodium heparin. Indian J Dermatol Venereol Leprol 2013; 79:849.36. Masferrer E, Martin-Ezquerra G, Martínez-Escala E, et al. Eosinophilic panniculitis

triggered by intramuscular penicillin and occupational setting. Allergy 2011; 66:436.37. Don DM, Ishiyama A, Johnstone AK, et al. Angiolymphoid hyperplasia with eosinophilia

and vascular tumors of the head and neck. Am J Otolaryngol 1996; 17:240.38. Helander SD, Peters MS, Kuo TT, Su WP. Kimura's disease and angiolymphoid

hyperplasia with eosinophilia: new observations from immunohistochemical studies of lymphocyte markers, endothelial antigens, and granulocyte proteins. J Cutan Pathol 1995; 22:319.

39. Chen H, Thompson LD, Aguilera NS, Abbondanzo SL. Kimura disease: a clinicopathologic study of 21 cases. Am J Surg Pathol 2004; 28:505.

40. Ma XR, Xin SJ, Ouyang TX, et al. Successful treatment of Kimura's disease with leflunomide and methylprednisolone: a case report. Int J Clin Exp Med 2014; 7:2219.

41. Ben-Chetrit E, Amir G, Shalit M. Cetirizine: An effective agent in Kimura's disease. Arthritis Rheum 2005; 53:117.

42. Chang AR, Kim K, Kim HJ, et al. Outcomes of Kimura's disease after radiotherapy or nonradiotherapeutic treatment modalities. Int J Radiat Oncol Biol Phys 2006; 65:1233.

43. Singh S, Dayal M, Walia R, et al. Intralesional radiofrequency ablation for nodular angiolymphoid hyperplasia on forehead: a minimally invasive approach. Indian J Dermatol Venereol Leprol 2014; 80:419.

44. Nouchi A, Hickman G, Battistella M, et al. [Treatment of angiolymphoid hyperplasia with eosinophilia (ALHE) using topical tacrolimus: Two cases]. Ann Dermatol Venereol 2015; 142:360.

45. Rongioletti F, Cecchi F, Pastorino C, Scaparro M. Successful management of refractory angiolymphoid hyperplasia with eosinophilia with thalidomide. J Eur Acad Dermatol Venereol 2016; 30:527.

46. Aberer W, Konrad K, Wolff K. Wells' syndrome is a distinctive disease entity and not a histologic diagnosis. J Am Acad Dermatol 1988; 18:105.

47. Caputo R, Marzano AV, Vezzoli P, Lunardon L. Wells syndrome in adults and children: a report of 19 cases. Arch Dermatol 2006; 142:1157.

48. Beer TW, Langtry JA, Phillips WG, Wojnarowska F. Flame figures in bullous pemphigoid. Dermatology 1994; 188:310.

49. Falagas ME, Vergidis PI. Narrative review: diseases that masquerade as infectious cellulitis. Ann Intern Med 2005; 142:47.

50. Sinno H, Lacroix JP, Lee J, et al. Diagnosis and management of eosinophilic cellulitis (Wells' syndrome): A case series and literature review. Can J Plast Surg 2012; 20:91.

51. Singanayagam A, Lamb L, Makinde JE, et al. Systemic cytokine storm in severe eosinophilic dermatitis. QJM 2015; 108:907.

52. Ota M, Shimizu T, Hashino S, Shimizu H. Eosinophilic folliculitis in a patient after allogeneic bone marrow transplantation: case report and review of the literature. Am J Hematol 2004; 76:295.

53. Hernández-Martín Á, Nuño-González A, Colmenero I, Torrelo A. Eosinophilic pustular folliculitis of infancy: a series of 15 cases and review of the literature. J Am Acad Dermatol 2013; 68:150.

54. Chen KR, Su WP, Pittelkow MR, Leiferman KM. Eosinophilic vasculitis syndrome: recurrent cutaneous eosinophilic necrotizing vasculitis. Semin Dermatol 1995; 14:106.

55. Li W, Cao W, Song H, et al. Recurrent cutaneous necrotizing eosinophilic vasculitis: a case report and review of the literature. Diagn Pathol 2013; 8:185.

56. Launay D, Delaporte E, Gillot JM, et al. An unusual cause of vascular purpura: recurrent cutaneous eosinophilic necrotizing vasculitis. Acta Derm Venereol 2000; 80:394.

57. el-Mofty SK, Swanson PE, Wick MR, Miller AS. Eosinophilic ulcer of the oral mucosa. Report of 38 new cases with immunohistochemical observations. Oral Surg Oral Med Oral Pathol 1993; 75:716.

58. Damevska K, Gocev G, Nikolovska S. Eosinophilic ulcer of the oral mucosa: report of a case with multiple synchronous lesions. Am J Dermatopathol 2014; 36:594.

59. Segura S, Pujol RM. Eosinophilic ulcer of the oral mucosa: a distinct entity or a non- specific reactive pattern? Oral Dis 2008; 14:287.

60. Segura S, Romero D, Mascaró JM Jr, et al. Eosinophilic ulcer of the oral mucosa: another histological simulator of CD30+ lymphoproliferative disorders. Br J Dermatol 2006; 155:460.

61. McEvoy MT, Peterson EA, Kobza-Black A, et al. Immunohistological comparison of granulated cell proteins in induced immediate urticarial dermographism and delayed pressure urticaria lesions. Br J Dermatol 1995; 133:853.

62. Noguchi H, Kephart GM, Campbell RJ, et al. Tissue eosinophilia and eosinophil degranulation in orbital pseudotumor. Ophthalmology 1991; 98:928.

63. Zenarola P, Melillo L, Bisceglia M, et al. NERDS syndrome: an additional case report. Dermatology 1995; 191:133.

64. Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma. N Engl J Med 1990; 323:1033.

65. Winter HS, Madara JL, Stafford RJ, et al. Intraepithelial eosinophils: a new diagnostic criterion for reflux esophagitis. Gastroenterology 1982; 83:818.

66. Brown LF, Goldman H, Antonioli DA. Intraepithelial eosinophils in endoscopic biopsies of adults with reflux esophagitis. Am J Surg Pathol 1984; 8:899.

67. Karttunen TJ, Niemelä S, Kerola T. Blood leukocyte differential in Helicobacter pylori infection. Dig Dis Sci 1996; 41:1332.

68. Bischoff SC, Wedemeyer J, Herrmann A, et al. Quantitative assessment of intestinal eosinophils and mast cells in inflammatory bowel disease. Histopathology 1996; 28:1.

69. Ettinghausen SE. Collagenous colitis, eosinophilic colitis, and neutropenic colitis. Surg Clin North Am 1993; 73:993.

70. Yamazaki K, Nakadate I, Suzuki K, et al. Eosinophilia in primary biliary cirrhosis. Am J Gastroenterol 1996; 91:516.

71. Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood 1994; 83:2759. 72. Dillon JF, Finlayson ND. Idiopathic hypereosinophilic syndrome presenting as

intrahepatic cholestatic jaundice. Am J Gastroenterol 1994; 89:1254.73. Grauer L, Padilla VM 3rd, Bouza L, Barkin JS. Eosinophilic sclerosing cholangitis

associated with hypereosinophilic syndrome. Am J Gastroenterol 1993; 88:1764.74. Rosengart TK, Rotterdam H, Ranson JH. Eosinophilic cholangitis: a self-limited cause of

extrahepatic biliary obstruction. Am J Gastroenterol 1990; 85:582.75. Dabbs DJ. Eosinophilic and lymphoeosinophilic cholecystitis. Am J Surg Pathol 1993;

17:497.76. Kendell KR, Day JD, Hruban RH, et al. Intimate association of eosinophils to collagen

bundles in eosinophilic myocarditis and ranitidine-induced hypersensitivity myocarditis. Arch Pathol Lab Med 1995; 119:1154.

77. Spry CJF. A Comprehensive Review and Guide to the Scientific and Medical Literature, Oxford Medical Publications, Oxford 1988.

78. Monsuez JJ, de Kerviler E, Barboteu M, et al. Non-Hodgkin's lymphoma related eosinophilic endomyocardial disease. Eur Heart J 1994; 15:1423.

79. Donhuijsen K, Haedicke C, Hattenberger S, et al. Granulocyte-macrophage colony- stimulating factor-related eosinophilia and Loeffler's endocarditis. Blood 1992; 79:2798.

80. Date A, Jacob M, Johny KV. Eosinophilic leukocytes in diffuse proliferative and exudative glomerulonephritis. Am J Trop Med Hyg 1977; 26:1028.

81. Liu S, Miller PD, Holmes SA, et al. Eosinophilic prostatitis and prostatic specific antigen. Br J Urol 1992; 69:61.

82. Lowe D, Fletcher CD, Gower RL. Tumour-associated eosinophilia in the bladder. J Clin Pathol 1984; 37:500.

83. Nolan CR 3rd, Anger MS, Kelleher SP. Eosinophiluria--a new method of detection and definition of the clinical spectrum. N Engl J Med 1986; 315:1516.

84. Eltoum IA, Ghalib HW, Sualaiman S, et al. Significance of eosinophiluria in urinary schistosomiasis. A study using Hansel's stain and electron microscopy. Am J Clin Pathol 1989; 92:329.

85. Mosholt KS, Dahl C, Azawi NH. Eosinophilic cystitis: three cases, and a review over 10 years. BMJ Case Rep 2014; 2014.

86. Fuller TW, Dangle P, Reese JN, et al. Inflammatory myofibroblastic tumor of the bladder masquerading as eosinophilic cystitis: case report and review of the literature. Urology 2015; 85:921.

87. Li G, Cai B, Song H, Yang Z. Clinical and radiological character of eosinophilic cystitis. Int J Clin Exp Med 2015; 8:533.

88. Itano NM, Malek RS. Eosinophilic cystitis in adults. J Urol 2001; 165:805. 89. Kiliç S, Erguvan R, Ipek D, et al. Eosinophilic cystitis. A rare inflammatory pathology

mimicking bladder neoplasms. Urol Int 2003; 71:285.90. Lee CC, Leu ML, Kuo HP, Huang CC. Hypereosinophilia in hemodialysis patients.

Changgeng Yi Xue Za Zhi 1995; 18:20.91. Chan MK, Chow L, Lam SS, Jones B. Peritoneal eosinophilia in patients on continuous

ambulatory peritoneal dialysis: a prospective study. Am J Kidney Dis 1988; 11:180.92. Patel UO, Fox SR, Moy JN, Korbet SM. Pruritic rash and eosinophilia in a patient

receiving peritoneal dialysis. Semin Dial 2011; 24:338.93. Forbes TA, Lunn AJ. Montelukast: a novel therapeutic option in eosinophilic peritonitis.

Pediatr Nephrol 2014; 29:1279.