Mayo Clin Proc. 2005;80:75-83 © 2005 Mayo Foundation for Medical Education
Blood Eosinophilia: A New Paradigm in Disease Classification, Diagnosis,
From the Department of Internal Medicine and Division
of Hematology, Mayo Clinic College of Medicine, Rochester, Minn.
Address reprint requests and correspondence to Ayalew Tefferi, MD, Division
of Hematology, Mayo Clinic College of Medicine, 200 First St SW, Rochester,
MN 55905 (e-mail:
Acquired blood eosinophilia is considered either a primary or a secondary
phenomenon. Causes of secondary (ie, reactive) eosinophilia include
tissue-invasive parasitosis, allergic or inflammatory conditions, and
malignancies in which eosinophils are not considered part of the neoplastic
process. Primary eosinophilia is classified operationally into 2 categories:
clonal and idiopathic. Clonal eosinophilia stipulates the presence of either
cytogenetic evidence or bone marrow histological evidence of an otherwise
classified hematologic malignancy such as acute leukemia or a chronic myeloid
disorder. Idiopathic eosinophilia is a diagnosis of exclusion (ie, not secondary
or clonal). Hypereosinophilic syndrome is a subcategory of idiopathic
eosinophilia; diagnosis requires documentation of both sustained eosinophilia
(absolute eosinophil count =1500 cells/µL for at least 6 months) and
target organ damage (eg, involvement of the heart, lung, skin, or nerve tissue).
Genetic mutations involving the platelet-derived growth factor receptor genes
(PDGFR-a and PDGFR-ß) have been pathogenetically linked to clonal
eosinophilia, and their presence predicts treatment response to imatinib.
Accordingly, cytogenetic and/or molecular investigations for the presence
of an imatinibsensitive molecular target should accompany current evaluation
for primary eosinophilia. In the absence of such a drug target, specific
treatment is dictated by the underlying hematologic malignancy in cases of
clonal eosinophilia; however, the initial treatment of choice for symptomatic
patients with hypereosinophilic syndrome is prednisone and/or interferon
Mayo Clin Proc. 2005;80(1):75-83
|AEC = absolute eosinophil count; CEL = chronic eosinophilic
leukemia; CML = chronic myeloid leukemia; CMML = chronic myelomonocytic
leukemia; FGFR1 = fibroblast growth factor receptor 1; FISH =
fluorescence in situ hybridization; HES = hypereosinophilic
syndrome; IL = interleukin; MPD = myeloproliferative
disorder; PDGFR = platelet-derived growth factor receptor; SM =
systemic mastocytosis; SM-eos = SM associated with prominent blood
Eosinophils are derived from hematopoietic stem cells that are committed
initially to the myeloid and subsequently to the basophil-eosinophil granulocyte
lineage.1 As depicted in
Figure 1, the mature eosinophil, when examined
by standard blood-staining techniques, displays a bilobed nucleus and an
abundant cytoplasm filled with reddish-orange granules. The material in these
granules includes cationic proteins (major basic protein, eosinophilic cationic
protein, eosinophil-derived neurotoxin, eosinophil peroxidase), cytokines
(interleukins [ILs], tumor necrosis factor), and lipid mediators (leukotriene
C4).2 Interleukin 5 is considered
the major eosinophil growth and survival factor, whereas chemokines (eotaxin,
platelet-activating factor, RANTES [regulated on activation, normal T expressed
and secreted]) and endothelial adhesion molecules (integrins, vascular cell
adhesion molecules) contribute to eosinophil
Major basic protein, eosinophil cationic protein, and eosinophil-derived
neurotoxin are the primary mediators of eosinophil-associated toxicity to
microbes (parasites, protozoa, bacteria, viruses) and human tissue (myocarditis,
pneumonitis, dermatitis, neuropathy,
lung and gastrointestinal systems constitute the main residence for eosinophils.
Blood eosinophilia (absolute eosinophil count [AEC] =600 cells/µL) is
the usual initial clue for the presence of an eosinophilic disorder. The
degree of blood eosinophilia, in the absence of active treatment, can be
categorized into mild (AEC 600-1500 cells/µL), moderate (AEC 1500-5000
cells/µL), or severe (AEC >5000
cells/µL).17 Target organ damage is
unusual with mild eosinophilia, but its occurrence in association with moderate
to severe eosinophilia does not appear to depend on the specific cause of
eosinophilia (ie, in addition to the well-established association of target
organ damage with primary eosinophilia, it also has been reported to occur
in both familial and secondary
GENERAL CLASSIFICATION OF EOSINOPHILIC
Blood eosinophilia can be classified as either familial or acquired
(Table 1). Acquired eosinophilia is classified
further into a primary or a secondary process, depending on whether eosinophils
are considered integral to the underlying disease. Infectious causes and
noninfectious causes of secondary eosinophilia (Table
1) are prevalent in underdeveloped and developed countries, respectively.
Primary eosinophilia occurs primarily in males and is considered clonal in
the presence of either cytogenetic evidence or bone marrow histological evidence
of an otherwise defined neoplastic hematologic disorder. Otherwise, a working
diagnosis of idiopathic eosinophilia is made, and in the presence of both
sustained eosinophilia (AEC =1500 cells/µL for at least 6 months) and
target organ damage (eg, skin, heart, lung, nerve tissue), the process is
subclassified as hypereosinophilic syndrome
FIGURE 1. Peripheral blood smear shows an eosinophil (E), basophil (B), and
other blood cells (image courtesy of Chin-Yang Li, MD, Department of Laboratory
Medicine and Pathology, Division of Hematopathology, Mayo Clinic, Rochester,
TABLE 1. Classification and Causes of Blood
Tissue-invasive parasitosis (most common)
Bacterial or viral infections (rare)
Drugs (sulfa, carbamazepine, etc)
Toxins (associated with eosinophilia-myalgia syndrome, toxic oil syndrome,
Allergy (asthma, atopic dermatitis, etc)
Idiopathic/autoimmune inflammatory conditions
Vasculitis (Churg-Strauss, Wegener)
Systemic sclerosis or scleroderma
Polyarteritis and other CTDs
Inflammatory bowel disease
Malignancy (metastatic cancer, Hodgkin lymphoma)
Endocrinopathies (Addison disease, etc)
Acute myeloid leukemia
Acute lymphocytic leukemia
Chronic myeloid disorder
Molecularly defined chronic myeloid disorder
Bcr/Abl+ chronic myeloid leukemia
PDGFRA-rearranged eosinophilic disorder
PDGFRB-rearranged eosinophilic disorder
Kit-mutated systemic mastocytosis
Clinicopathologically defined chronic myeloid disorder
Classic myeloproliferative disorder (polycythemia vera, etc)
Atypical myeloproliferative disorder
Chronic eosinophilic leukemia
Chronic myelomonocytic leukemia
Unclassified myeloproliferative disorder
*CTD = connective tissue disease; HES = hypereosinophilic syndrome; PDGFR
= platelet-derived growth factor receptor.
PATHOGENESIS AND CLINICAL
Familial eosinophilia is rare, and its genetic basis, at least in some cases,
may be similar to that of clonal
such cases, the chromosomal region 5q31-33 has been identified as the hot
zone, although it may not involve mutations of some of the resident
genes responsible for the synthesis of known eosinophil growth factors including
IL-3, IL-5, and granulocyte-macrophage colony-stimulating
factor.22 Interestingly, one recently reported
familial case involved a translocation-associated mutation of the
platelet-derived growth factor receptor gene PDGFRB, which is known
to reside in the 5q31-33 chromosomal region and to be pathogenetically linked
to some cases of clonal
general, familial eosinophilia is an extremely rare autosomal dominant disorder
that is characterized by a stable eosinophil count and, compared with HES,
a lesser degree of eosinophil activation as well as a more benign clinical
The most common cause of secondary eosinophilia is tissue-invasive parasitosis
including schistosomiasis, visceral toxocariasis, strongyloidiasis, filariasis,
ancylostomiasis, fascioliasis, trichinellosis, and paragonimiasis
1).25-32 In general,
parasites that are isolated in either the intestinal lumen (Cestoda,
Ascaris) or an intact cyst (Echinococcus granulosus) do not
cause blood eosinophilia unless they are introduced systemically through
tissue invasion or cyst disruption.33 In
addition to helminths, some (Toxoplasma gondii, Dientamoeba fragilis,
Isospora belli) but not other (Giardia lamblia, Entamoeba
histolytica) protozoan infections may induce blood
reports of eosinophilia-associated bacterial (borrelia) or viral (human
immunodeficiency virus) infections have been
Noninfectious causes of secondary eosinophilia include drugs (sulfa derivatives,
gold compounds, carbamazepine, myeloid growth factors, purine nucleoside
(associated with eosinophilia-myalgia syndrome, toxic oil syndrome, toxic
disorders (asthma, hay fever, atopic dermatitis, allergic bronchopulmonary
idiopathic/autoimmune inflammatory conditions (granulomatous and/or systemic
vasculitis, Churg-Strauss syndrome, Wegener granulomatosis, Kimura disease,
angiolymphoid hyperplasia with eosinophilia, bullous pemphigoid and other
cutaneous disorders, eosinophilic fasciitis, systemic sclerosis or scleroderma,
polyarteritis, sarcoidosis, inflammatory bowel disease), malignancies in
which eosinophils are not considered part of the neoplastic clone (Hodgkin
and non-Hodgkin lymphoma, metastatic
endocrinopathies including Addison disease (Table
1).58 Secondary eosinophilia in inflammatory
and malignant conditions is mediated by tissue-derived or tumor-derived
A diagnosis of clonal eosinophilia requires the presence of either cytogenetic
evidence or bone marrow morphologic evidence for either acute leukemia or
a chronic myeloid disorder (Table 1). Hematologic
disorders that can be accompanied by clonal eosinophilia include acute myeloid
leukemia,62 acute lymphocytic
leukemia,63 chronic myeloid leukemia
syndrome,65 and both classic and atypical
cases of myeloproliferative disorders
(MPDs).66,67 The atypical
MPD category includes chronic eosinophilic leukemia
(CEL),68 systemic mastocytosis
(SM),69 and chronic myelomonocytic leukemia
(CMML).70 Recent developments in the molecular
characterization of pathogenesis, in a subset of patients with clonal
eosinophilia, have identified activating mutations of 3 receptor tyrosine
kinase genes: PDGFRA, PDGFRB, and fibroblast growth factor
receptor 1 (FGFR1).71
Within the context of hematologic malignancies, PDGFRA mutations have
been connected so far with a subset of patients with SM associated with prominent
(SM-eos).72-76 In general,
SM-eos makes up approximately 20% of all cases of SM in
adults.77 Of these cases of SM-eos, approximately
half may be associated with a specific PDGFRA mutation caused by an
800 kilobase interstitial deletion involving chromosome 4q12, resulting in
juxtaposition of PDGFRA and FIP1L1 genes
The fusion gene generates a constitutively activated PDGFRA tyrosine kinase
that transforms hematopoietic cells.75 Other
cases of SM-eos are associated with a C-kit
mutation.74 Systemic mastocytosis not associated
with eosinophilia does not display the FIP1L1-PDGFRA
mutation.75 Although rare, PDGFRA
also may be activated through chromosomal translocations as in
Patients with FIP1L1-PDGFRA+ SM-eos display a
myeloproliferative clinical phenotype with organomegaly, cytopenia,
increased serum B12 levels, and bone marrow hypercellularity with
As a result, investigators use the terms myeloproliferative-variant
to describe the same disease. However, most, if not all, such patients display
bone marrow mast cell infiltration with morphologically and immunophenotypically
the term FIP1L1-PDGFRA+eosinophilic disorder
could be used to avoid confusion.73 Patients
with FIP1L1-PDGFRA+ eosinophilic disorder also are
characterized by a high risk of eosinophilic heart disease and inferior survival
compared with those with
The PDGFRB gene is located on chromosome 5q33, and its activation
through translocation to various partner chromosomes, including t(5;12)(q33;p13),
t(5;10)(q33;q21), t(5;7)(q33;q11.2), t(5;14)(q33;q13), t(5;17)(q33;p11),
and t(1;5)(q23;q33), produces a distinct MPD that usually is associated with
prominent eosinophilia and sometimes with
Pathologic diagnosis in previously described cases of
PDGFRB+ clonal eosinophilia have included CEL, atypical
CML or MPD, and
The gene for FGFR1 is located on chromosome 8p11, and its activation through
translocation to different chromosome partners, including t(8;13)(p11;q12),
t(8;9)(p11;q33), t(6;8)(q27;p11), and t(8;22)(p11;q22), produces a
myeloproliferative syndrome with eosinophilia, lymphadenopathy, and a high
incidence of T-cell non-Hodgkin lymphoma with progression to acute myeloid
leukemia.84 Other karyotypic variants involving
FGFR1, including t(8;17)(p11;q25), t(8;11)(p11;p15), t(8;12)(p11;q15),
and ins(12;8)(p11;p11; p21), have been associated with SM, acute leukemia,
or MPD associated with both T-cell lymphoma and marrow
When both clinical and laboratory evaluations do not clearly identify either
a secondary or a clonal cause, a working diagnosis of idiopathic eosinophilia
is reasonable. For now, HES is considered a subcategory of idiopathic
eosinophilia that requires documentation of both target organ damage and
an AEC of 1500 cells/µL or greater for at least 6
review articles have described the clinical manifestations and natural history
These and other case reports have shown that some cases evolve into either
acute leukemia or an aggressive disease phenotype that is indistinguishable
MPD.89-91 This information
has long suggested that HES may represent a clonal hematologic disorder.
This contention was supported by clonality studies that used X-linked DNA
analysis.92 In contrast, the presence of
clonal TH2 lymphocytes in a subset of patients with HES
suggests a pathogenetic heterogeneity that may include an IL-5mediated
secondary eosinophilia in the
mix.93,94 In a study
of 60 patients with HES, 16 (27%) had T cells with an aberrant immunophenotype,
and T-cell clonality was suggested in half of these 16
As in clonal eosinophilia, more than 90% of patients with HES are males.
The reason for male predominance in HES and in clonal eosinophilia is unknown.
Clinical manifestations can be either nonspecific (cough, nocturnal sweating,
fatigue, anorexia, weight loss, gastrointestinal
symptoms)96 or directly related to an affected
target organ including the skin (pruritus, erythematous papules, nodules,
urticaria, angioedema, mucosal ulcers, eosinophilic cellulitis or Wells
(mural thrombus, endocardial fibrosis, cardiomyopathy, elevated serum troponin
nervous system (sensory and motor neuropathy, mononeuritis multiplex, isolated
vasculitis of central nervous system, eosinophilic meningitis, transverse
lung (pulmonary infiltrates, lung nodules, acute respiratory distress
or gastrointestinal system (gastroenteritis, inflammatory bowel disease,
Thromboembolic complications, including Budd-Chiari syndrome, are not infrequent
and in isolated reports, HES has been associated with retinal vein occlusions,
polymyositis, arthritis, and renal
A thorough patient history is the most important part of the evaluation for
blood eosinophilia, and it should guide the extent and type of laboratory
tests performed. The initial focus should be on international travel history
and a review of current and recent medications. In the absence of possible
drug association, a stool test should be performed in all cases to look for
ova and larvae of intestinal worms (ascaris, schistosoma, ancylostoma, cestodes,
fasciola, strongyloides). Next, depending on the travel history, the following
tests and procedures should be performed: urine sediment tests (schistosoma),
blood concentration tests (filaria), serology (strongyloides, filaria,
trichinosis, visceral larva migrans, schistosomiasis), sputum examination
(paragonimiasis, visceral larva migrans), chest radiography (paragonimiasis,
ascariasis), computed tomography (echinococcus, cysticercosis), small bowel
biopsy (isosporiasis, strongyloidosis), or muscle biopsy (trichinosis). However,
work-up beyond stool examination is recommended only if history dictates.
Similarly, a good history and basic laboratory tests should be adequate to
address the possibility of a noninfectious cause of secondary eosinophilia,
and only in the presence of historical clues should more invasive and costly
interventions be pursued.
All patients with suspected primary eosinophilia should undergo bone marrow
examination with cytogenetics. Also, my colleagues and I encourage use of
bone marrow immunohistochemical stains for tryptase and mast cell
immunophenotyping (neoplastic but not normal or reactive mast cells express
CD25) to test for SM. The following PDGFRB rearrangements currently
are detected by conventional cytogenetics: t(5;12)(q33;p13), t(5;10)(q33;q21),
t(5;7)(q33;q11.2), t(5;14)(q33;q13), t(5;17)(q33;p11), and t(1;5)(q23;q33).
In contrast, standard cytogenetic methods do not detect the usual
PDGFRA rearrangement that is a result of an interstitial 4q12 deletion.
This must be sought with either a fluorescence in situ hybridization
(FISH)based or a reverse transcriptase polymerase chain
technique.73 At present, we perform 3 laboratory
tests (bone marrow biopsy, bone marrow cytogenetics, peripheral blood FISH
for FIP1L1-PDGFRA) in all patients with primary eosinophilia because
of the important therapeutic implications (Figure
Finally, in addition to looking for the cause of eosinophilia, laboratory
tests to assess possible eosinophilic tissue damage may be required and include
echocardiography, chest radiography, pulmonary function tests, and, in the
presence of symptoms, tissue biopsy.
TREATMENT OF PRIMARY
In general, the underlying hematologic malignancy dictates treatment in clonal
eosinophilia. In acute leukemia, for example, standard induction chemotherapy
is used.119 In CML, imatinib is the drug
of choice.120 Imatinib works in CML by
inhibiting the leukemogenic bcr-abl gene product, which is a
constitutively activated Abl tyrosine
relatively selective in its action, imatinib inhibits other receptor tyrosine
kinases including PDGFR and
Kit.124,125 The mechanism
of action involves a competitive occupation of an adenosine
triphosphatebinding site of the catalytic domain of the kinase by a
The in vitro demonstration of imatinib-induced inhibition of both PDGFR-
and Kit-associated signal transduction formed the rationale for using the
drug in clonal eosinophilia associated with SM (SM-eos). This is because
(1) Kit ligand and Kit-associated signaling are key for the growth and
development of human mast cells127 and (2)
approximately 50% of patients with SM-eos may carry a constitutively activated
PDGFRA mutation, as discussed
vitro, imatinib effectively inhibits normal mast cell growth and
development128 as well as the growth of
human mast cell lines and primary cells that carry certain (Val560Gly) but
not other (Asp816Val) c-kit
Consistent with these in vitro observations, imatinib has been shown effective
in a subset of patients with SM-eos who carry the FIP1L1-PDGFRA mutation
but not the c-kit Asp816Val
mutation.131 Patients with SM-eos and the
FIP1L1-PDGFRA mutation experience both molecular and mast cell
immunophenotypic remissions with relatively low doses of imatinib (100
investigators refer to FIP1L1-PDGFRA+ SM-eos as
either myeloproliferative-variant HES,
FIP1L1-PDGFRA+ CEL, or
FIP1L1-PDGFRA+ HES and have reported equally impressive
results.75,78,79,133-135 Imatinib therapy produces
complete clinical, pathologic, and molecular remissions in clonal eosinophilia
connected with PDGFRB mutations that are usually associated with a
chronic myeloid disorder that phenotypically resembles CEL, CMML, or atypical
FIGURE 2. A diagnostic and treatment algorithm for blood eosinophilia. FISH
= fluorescence in situ hybridization; RT-PCR = reverse transcriptase polymerase
IDIOPATHIC EOSINOPHILIA INCLUDING HES
Most patients with symptomatic HES respond to prednisone alone or in combination
Patients with HES refractory to corticosteroids have been reported to respond
or etoposide.146 My preference during
symptomatic disease is to use interferon alfa early either by itself or combined
with low doses of prednisone. For patients in whom first-line treatment with
corticosteroids, hydroxyurea, and interferon alfa fails, the choice of
second-line treatment is currently arbitrary, and any of the aforementioned
agents can be used before an aggressive approach such as allogeneic hematopoietic
stem cell transplantation is considered seriously. Because of the documentation
of imatinib-induced partial remissions in approximately 50% of patients with
true HES (ie, FIP1L1-PDGFRA), it is reasonable
to try the specific drug as a second-line
therapy.75 However, it should be noted that
patients with true HES are unlikely to respond to low-dose imatinib (100
mg/d), and a higher dose of the drug (400 mg/d) should be used in this instance
(Figure 2). In patients with HES refractory to
drugs, both myeloablative and non-myeloablative allogeneic hematopoietic
stem cell transplantation have been used successfully and can be
Currently, the role of novel drug treatment approaches to HES, including
the use of
and monoclonal antibodies to either
IL-5151-153 or CD52
(alemtuzumab),154 is being defined.
CURRENT ALGORITHM FOR THE DIAGNOSIS AND TREATMENT OF EOSINOPHILIC
Figure 2 outlines a proposed algorithm for the
diagnosis and treatment of eosinophilic disorders. To begin treatment of
a patient with blood eosinophilia, the possibility of secondary eosinophilia
must be excluded. Once this is accomplished, I recommend obtaining a set
of blood and bone marrow studies. The blood studies should include serum
tryptase (an increased level suggests SM), T-cell receptor gene rearrangement
analysis (positive test results suggest an underlying clonal T-cell disorder),
and serum IL-5 (an elevated level requires careful evaluation of bone marrow
studies and T-cell gene rearrangement studies for the presence of a clonal
T-cell disease). Bone marrow examination should include cytogenetic studies,
tryptase immunostains, and FISH or reverse transcriptase polymerase chain
reaction to screen for FIP1L1-PDGFRA. The last-mentioned test also
can be performed on peripheral blood.
If this work-up reveals an imatinib-sensitive molecular target (PDGFRA
or PDGFRB mutations), then treatment with low-dose imatinib (100 mg/d)
is recommended, and a complete and durable remission can be expected. We
currently recommend an initial imatinib dosage of 100 mg/d for
FIP1L1-PDGFRA+ clonal eosinophilia because this
specific dosage, as discussed previously, has been associated with molecular
disease remission.73 It is reasonable to
consider treatment even in the absence of symptoms for
FIP1L1-PDGFRA+ clonal eosinophilia in hopes of
preventing serious cardiovascular complications that may or may not be amenable
to imatinib therapy once they
In the absence of an imatinib-sensitive molecular target, the physician first
must decide whether treatment is indicated and if so, choose a first-line
treatment that is suitable for the underlying clonal process or, in cases
of HES, treat with interferon alfa and/or prednisone. Imatinib is unlikely
to benefit patients with clonal eosinophilia who do not have a known
drug-sensitive mutation. Similarly, although some patients with true HES
experience partial remission with imatinib therapy at 400
mg/d,72 the long-term benefit of single-agent
imatinib therapy in FIP1L1-PDGFRA HES is unknown.
Finally, we and others have described life-threatening cardiogenic shock
associated with imatinib therapy for
this potentially fatal complication responds well to systemic corticosteroid
therapy and may be predicted by elevated serum troponin levels before
treatment.157 For patients with either baseline
elevation of serum troponin level or echocardiographic evidence for eosinophilic
heart disease, we recommend concomitant prednisone therapy (1 mg/kg) during
the first week of treatment with imatinib. Prednisone can be tapered during
the second week of therapy.
The clinical observation158 that some patients
with HES responded to treatment with imatinib, which is a small
molecule inhibitor of certain receptor tyrosine
kinases,73 led to the recent discovery of
the association between blood eosinophilia and a cytogenetically occult genetic
mutation (FIP1L1-PDGFRA).75 Such molecular
characterizations may ultimately result in HES becoming a nonentity in the
spectrum of primary eosinophilic disorders. More importantly, the identification
of disease-causing mutations is an essential step toward the development
and application of rational drug therapy. At present, approximately 10% to
20% of patients with primary eosinophilia are known to harbor a molecular
target that predicts an excellent response to imatinib
a subset of patients with HES without known imatinib targets also has been
reported to respond to the
observations raise the exciting prospect of discovering new drug targets
in eosinophilic disorders as well as future therapeutic successes with the
use of second-generation kinase inhibitors that are more potent than imatinib
and have a broader spectrum of
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