Download Eosinophil biology and causes of eosinophilia Authors: Peter F

Eosinophil biology and causes of eosinophilia
Authors:
Peter F Weller, MD, FACP
Amy D Klion, MD
Section Editors:
Donald H Mahoney, Jr, MD
Bruce S Bochner, MD
Deputy Editors:
Alan G Rosmarin, MD
Anna 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 "Aspirinexacerbated 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 (ChurgStrauss)", 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.)
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