441

Current Approach to Diagnosis and

Management of Pulmonary Eosinophilic
Syndromes: Eosinophilic Pneumonias,
Eosinophilic Granulomatosis with Polyangiitis,
and Hypereosinophilic Syndrome
Amen Sergew, MD1 Evans R. Fernández Pérez, MD, MS1

1 Division of Pulmonary and Critical Care Medicine, National Jewish Address for correspondence Amen Sergew, MD, Division of
Health, Denver, Colorado Pulmonary and Critical Care Medicine, National Jewish Health, B’nai
B’rith Bldg. M336, 1400 Jackson Street, Denver, CO 80206
Semin Respir Crit Care Med 2016;37:441–456. (e-mail: sergewa@njhealth.org).

Abstract Eosinophils play a key role in orchestrating the complex clinicopathological pulmonary

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Keywords and extrapulmonary disease features in patients with eosinophilic syndromes. Eosino-
► eosinophilic lung philic pulmonary syndromes consist of a heterogeneous group of disorders character-
diseases ized by the presence of peripheral blood eosinophilia and/or eosinophilic-related
► acute eosinophilic pulmonary impairment. These disorders can present with varying degrees of organ
pneumonia involvement, and while their presentation may be similar, it is important to define the
► chronic eosinophilic disease state, as management and prognosis differ. In this article, we discuss acute and
pneumonia chronic eosinophilic pneumonias, eosinophilic granulomatosis with polyangiitis, and
► eosinophilic the hypereosinophilic syndromes. The mainstay of therapy for these disorders has been
granulomatosis with corticosteroids; however, recent and ongoing studies have provided strong grounds for
polyangiitis optimism for specific targeted treatment approaches.
► Churg–Strauss
syndrome
► allergic
granulomatosis and
angiitis
► hypereosinophilic
syndromes

Pulmonary eosinophilic syndromes (PES) encompass a het-
erogeneous group of disorders that are unified by the pres-
ence of peripheral blood eosinophilia and/or eosinophilic-
related pulmonary injury and/or dysfunction. Dysregulated
tissue eosinophil infiltration and degranulation can cause
significant organ damage and tissue remodeling.1–3 Concur-
rent peripheral blood eosinophilia may or may not be present.
Peripheral blood eosinophilia is defined as an eosinophilic
count of >500 cells
109/L. A count of 500 to 1,500 is termed
mild eosinophilia, >1,500 is marked eosinophilia, and >5,000
is massive eosinophilia.4–6
The clinical presentation and manifestations of PES can
include a broad spectrum ranging from quiescent disease to
one that is life threatening. The diagnosis of PES can be
difficult, as the clinical presentation and findings can overlap.
Differentiation is important, as treatment and prognosis can
be vastly different. ►Fig. 1 shows the diagnostic approach to
suspected eosinophilic lung diseases. The PES may be divided

Issue Theme Orphan Lung Diseases; Copyright © 2016 by Thieme Medical DOI http://dx.doi.org/
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Tel: +1(212) 584-4662.
442 Diagnosis and Management of Pulmonary Eosinophilic Syndromes Sergew, Fernández Perez

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Fig. 1 Approach to suspected pulmonary eosinophilic syndrome. ABPA, allergic bronchopulmonary aspergillosis; AEP, acute eosinophilic
pneumonia; ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasmic antibodies; anti-CCP, anticyclic citrullinated peptides; BAL,
bronchoalveolar lavage; CBC, complete blood count; CEP, chronic eosinophilic pneumonia; CMR, cardiovascular magnetic resonance; CT,
computed tomography; DDX, differential diagnosis ; ECG, electrocardiogram; EGPA, eosinophilic granulomatosis with polyangiitis; ENT, ear, nose,
and throat; F/P, FIP1-Like1 and platelet-derived growth factor receptor α fusion gene; FISH, fluorescence in situ hybridization; HES, hyper-
eosinophilic syndromes; HIV, human immunodeficiency virus; Ig, immunoglobulin; MPO, myeloperoxidase; O&P, ova and parasites; PANCA,
perinuclear antineutrophil cytoplasmic antibodies; PR3, proteinase 3; RF, rheumatoid factor; RT-PCR, reverse transcription polymerase chain
reaction; SPEP, serum protein electrophoresis; U/A, urinalysis.

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 Diagnosis and Management of Pulmonary Eosinophilic Syndromes Sergew, Fernández Perez 443

Table 1 Summary of the manifestations, work-up, and management of primary PES

AEP CEP EGPA HES

Incidence 9.1/100,000 per per- 0.23–7/100,000 per 0.9 to 2 per million per- 0.03 to 0.042/100,000
son-year person-years son-years per person-years
In asthmatics, 35 to 67
per million person-years
Demographics Smokers (age 20–40 y); Nonsmokers; age 30 to Age >50 y; asthma Myeloproliferative HES:
M>F 40 y; F > M; asthma age 20 to 50 y, M> F
Presentation Respiratory and consti- Respiratory and consti- Respiratory and consti- Respiratory and consti-
tutional symptoms to tutional symptoms tutional symptoms tutional symptoms
acute respiratory failure
Over months to year; Over months to years Over months to years
Over several days slow and progressive
Extrapulmonary None None. Atopy/allergic Allergic rhinitis/sinusitis Sinuses, cardiac skin, GI,
involvement rhinitis/sinusitis symp- with nasal polyposis; nervous system, uter-
toms common atopic disease; cardiac, ine. Less commonly he-
GI, renal, nervous sys- patic, pancreatic,
tem, skin, or joint ocular, synovial and re-
disease nal disease
Imaging X-ray: alveolar and/or X-ray: “photographic X-ray: fleeting lung X-ray: fleeting lung

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interstitial infiltrates
and Kerley B lines
HRCT: bilateral diffuse
GGO and/or air-space
consolidations, septal
thickening, and bilateral
small pleural effusions
Pathology Rarely required. Eosino-
phils filling the alveolar
spaces in a background
of interstitial
pneumonia
Prognosis Good. Rare recurrence
Differential CHF, ARDS, pneumonia;
diagnosis acute hypersensitivity
pneumonitis, acute or-
ganizing pneumonia
negative pulmonary
edema”
HRCT: patchy, bilateral,
migratory dense con-
solidations and/or GGO
Rarely required, eosino-
philic and lymphocytic
interstitial and alveolar
infiltrates
Good; but risk of
recurrence
EGPA, ABPA, drug toxic-
ity, parasitic infection,
COP
infiltrates
HRCT: CEP features.
Heterogeneous and mi-
gratory bilateral consol-
idations or GGO;
nodules; cavities; air-
ways thickening; pleural
effusions
Eosinophilic bronchitis/
pneumonia, necrotizing
granulomatous inflam-
mation, and granulo-
mas vasculitis
5-year mortality, FFS
¼ 0 is 9%, FFS ¼ 1 is
21%, FFS ¼ 2 is 40%;
worse if cardiac
involvement
GPA, MPA, eosinophilic
asthma, HES, CEP, ABPA,
DRESS
infiltrates
HRCT: CEP features.
Heterogeneous and mi-
gratory bilateral consol-
idations or GGO;
nodules; cavities; air-
ways thickening; pleural
effusions
Eosinophilic bronchitis/
pneumonia
Worse with cardiac dis-
ease or neoplastic HES;
lymphoid variant HES
has better prognosis
EGPA, HE, CEP, DRESS,
parasitic infection (e.g.,
filaria), malignancies
(e.g., CML)

Abbreviations: ABPA, allergic bronchopulmonary aspergillosis; AEP, acute eosinophilic pneumonia; ARDS, acute respiratory distress syndrome; CEP,
chronic eosinophilic pneumonia; CHF, congestive heart failure; CML, chronic myelogenous leukemia; COP, cryptogenic organizing pneumonia; DRESS,
drug reaction with eosinophilia and systemic symptoms; EGPA, eosinophilic granulomatosis with polyangiitis; FFS, five factor score; GGO, ground-glass
opacity; GI, gastrointestinal; GPO, granulomatosis with polyangiitis; HE, hypereosinophilia; HES, hypereosinophilic syndromes; HRCT, high-resolution
computed tomography; MPA, microscopic polyangiitis.

into primary (idiopathic) or secondary disorders. Secondary
causes include infections, toxins (e.g., inhalational exposures/
drug reactions), allergic bronchopulmonary aspergillosis,
connective tissue diseases (e.g., rheumatoid arthritis), and
malignancy, and are beyond the scope of this article. Primary
PES can be subdivided into lung-limited versus systemic
disorders. Chronic eosinophilic pneumonia (CEP) and acute
eosinophilic pneumonia (AEP) are lung-limited, whereas
systemic disorders include eosinophilic granulomatosis
with polyangiitis (EGPA; formerly known as Churg–Strauss
syndrome or allergic granulomatosis and angiitis) and the
hypereosinophilic syndromes (HES). In this review, we will
focus our discussions on the manifestations (►Table 1), work-
up, and management of primary PES.
Acute Eosinophilic Pneumonia
Epidemiology and Risk Factors
AEP is an uncommon disorder. The diagnosis may be missed
or delayed because the clinician may settle onto most com-
mon causes of acute lung injury or pneumonia, which can
result in the initiation of empiric corticosteroids. To date,
there is only one epidemiological study that identified 18
cases of AEP among 183,000 military personnel deployed in

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444 Diagnosis and Management of Pulmonary Eosinophilic Syndromes Sergew, Fernández Perez

or near Iraq, with an incidence of 9.1/100,000 per person-

years.7
All patients used tobacco, with 78% recently beginning to
smoke.7 In addition to new exposure to tobacco smoke,8–11 a
temporal association has been described between the devel-
opment of AEP and heavy dust exposure,12 numerous med-
ications such as antibiotics, anticonvulsants, L-tryptophan,
and illicit drugs (e.g., cocaine and heroin).13–20 Unlike CEP, a
history of asthma and atopic disease is uncommon in AEP.10

Presentation
Disease onset tends to be acute and the initial presentation
may be subclinical or fatal with patients progressing to acute
respiratory failure and requiring mechanical ventilation.10
The typical time course of AEP is progressive, presenting
generally within 7 days, and is characterized by an abrupt
onset of a febrile illness. In addition to fever, patients may
present with chest pain, shortness of breath, dry cough,
malaise, myalgias, and respiratory insufficiency.10,21

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Clinical Evaluation
The pulmonary examination findings are nonspecific but the
most common finding is crackles on auscultation.10,11,21
Pulmonary function tests (PFTs) may show a restrictive
pattern but are rarely done given frequent acuity and severity
of the presentation. Laboratory evaluation with arterial blood
gas can reveal significant hypoxemia, and peripheral blood
counts frequently demonstrate leukocytosis.10,21 Peripheral
eosinophilia is rare at presentation but can develop during
the disease course.10 An initial presentation with peripheral
eosinophilia may be associated with milder disease.22 The
presentation and radiological appearance can be similar to
congestive heart failure, acute respiratory distress syndrome,
or community-acquired pneumonia with imaging studies
demonstrating diffuse bilateral infiltrates. The chest X-ray
commonly shows alveolo-interstitial infiltrates.10,21 High-
resolution computed tomography (HRCT) findings classically
consist of bilateral diffuse (sometimes patchy or asymmetric)
ground-glass attenuation and air-space consolidations. Also,
interlobular septal thickening and bilateral small pleural
effusions are common.10,21,23 ►Fig. 2 shows representative
CT images.
Diagnosis
An increased bronchoalveolar (BAL) eosinophil percentage (i.
e., >25%)10,21 establishes the diagnosis without the need for
open lung biopsy. Histopathologic findings of AEP are notable
for eosinophils filling the alveolar spaces in a background of
interstitial pneumonia. Eosinophilic abscesses, foci of orga-
nizing pneumonia, and features of diffuse alveolar damage
may also be seen.24 Unusual associated histopathologic find-
ings may suggest the presence of other pulmonary eosino-
philic syndromes (e.g., dirofilarial nodules, necrotizing
vasculitis in EGPA).
Treatment and Prognosis
In hospitalized patients, initial treatment involves intrave-
nous (IV) corticosteroids at high doses. The exact dosage of
Fig. 2 Acute eosinophilic pneumonia (AEP). (A) Axial CT images in
lung window shows mild ground-glass opacity and interlobular septal
thickening, particularly in the left apical lung. (B) Axial CT image in soft
tissue window shows small pleural effusions. AEP often mimics pul-
monary edema on initial presentation; a high level of clinical suspicion
is necessary to achieve an expedient diagnosis.
steroids is not standardized but typically ranges from 240 to
1,000 mg per day given in divided doses. The response to
corticosteroids is dramatic even within hours. Once disease
activity is controlled, IV corticosteroids are changed to high-
dose oral steroids with a slow taper over weeks to 3 months.
The prognosis, if the patient recovers from the acute presen-
tation, is generally good as recurrence is rare.
Chronic Eosinophilic Pneumonia
Epidemiology and Risk Factors
The epidemiology of CEP suggests it is a rare disease. A wide
range in the incidence (estimated to be 0.23–7/100,000 per
person-years) and prevalence (1–42/100,000 per person-
years) may be explained by differences in study designs
and populations.25–27 There are no known genetic predis-
positions. Similar to AEP, CEP commonly presents at the age of
30 and 40 years of age.25–27 More women have been reported
with CEP than men, and in contrast to AEP, the majority of
patients are nonsmokers.28–30 Risk factors are unknown but
most patients have an underlying history of asthma and atopy
which can develop at any point in the course of the disease.28
Presentation
The presentation of CEP occurs over several weeks or months
and can include pulmonary symptoms of cough, shortness of
breath, and dyspnea on exertion. Constitutional symptoms
are common and include chills, sweats, anorexia, and

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 Diagnosis and Management of Pulmonary Eosinophilic Syndromes Sergew, Fernández Perez 445

fatigue.28,30 Symptoms slowly develop and rarely do patients
present in respiratory failure requiring ventilator support.28
Physical exam findings may mirror those of asthma, pneu-
monia, and/or idiopathic interstitial pneumonias with find-
ings of wheezing or crackles on auscultation.28 Findings
consistent with allergic rhinitis and chronic sinusitis are
also frequently observed.28 Extrapulmonary findings such
as nephritis and central and/or peripheral nervous system
involvement may suggest the presence of a systemic
disorder.28
Clinical Evaluation
Laboratory findings are nonspecific with peripheral eosino-
philia and increased inflammatory markers. Immunoglobulin E
(IgE) elevation has been noted in some cases.28,30 CEP charac-
teristic findings on chest imaging include upper and peripheral
predominant consolidations and ground-glass opacities also
known as “photographic negative pulmonary edema.” Al-
though distinctive, these findings were only noted in a quarter
of 19 cases of CEP in one study.29 The infiltrates can be patchy,
findings. Baseline PFTs may show restrictive and/or obstructive
defects. The latter may be due, in part, to the presence of asthma
and/or emphysema.28,29
Diagnosis
BAL cell count is consistent with eosinophilia in almost all
cases and can range from 12 to 95%.28,33 One series showed
a notable increase in mast cells in almost a quarter of the
cases.28 Lung biopsy is not needed if the BAL cell count has
marked eosinophilia and the imaging and clinical informa-
tion is consistent with CEP. Endobronchial biopsies may
show eosinophilic submucosal infiltrates.28 In the case
where a lung biopsy is performed, the pathological pattern
seen is one of eosinophilic and lymphocytic interstitial and
alveolar infiltrates.28,29 Representative images are shown
in ►Fig. 3C, D.
Treatment and Prognosis
The mainstay of therapy is oral corticosteroids. Patients

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generally have almost immediate relief of their symptoms
bilateral, and migratory in nature28,31,32 (►Fig. 3A, B). Fibrotic and there is improvement in the imaging studies within
changes such as bronchiectasis and honeycombing are late days.28 We commonly start therapy with 0.5 to 1 mg/kg/

Fig. 3 (A) Chronic eosinophilic pneumonia (CEP). Axial (left) and coronal (right) images from chest CT in one patient showing upper lung
preponderant, right-greater-than-left, focal areas of consolidation, and ground-glass opacity, typical of CEP. (B) Axial (left) and coronal (right)
images from chest CT in another patient showing significant ground-glass opacity as well as consolidation in the left upper lobe.

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446 Diagnosis and Management of Pulmonary Eosinophilic Syndromes Sergew, Fernández Perez

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Fig. 3 (C) Chronic eosinophilic pnemonia. Hematoxylin and eosin (H&E) low power: dense lung parenchyma consolidation by predominantly air
filling process. (D) H&E high power: air space filling predominantly by eosinophils, macrophages, and fibrin. There is some degree of interstitial
(septal) inflammation by a mixture of lymphocytes plasma cells and eosinophils in CEP.

day of prednisone or equivalent, followed by a slow and
gradual taper over 6 to 12 months in combination with
Pneumocystis prophylaxis. Fast tapers can result in relap-
ses.28–30,34 In one study of 62 CEP patients, 70% were on
steroids for more than a year. If steroids are still required after
this time or in those intolerant of steroids, steroid-sparing
agents may be considered. Objective data should guide
therapy, since steroid withdrawal symptoms may be confused
with disease worsening. In those with objective evidence of
disease progression, an alternative diagnosis or comorbid
complication should always be considered (e.g., other idio-
pathic interstitial pneumonia, superimpose infection or aspi-
ration, associated systemic disease). In those with asthma,
high-dose inhaled steroids should be considered and may be
the cause for a reduced numbers of relapses in comparisons to
nonasthmatics.35 Other interventions in CEP should focus on
monitoring for disease progression, and prevention and
management of complications associated with steroid thera-
py, the use of supplemental oxygen to help maintain nor-
moxia, smoking cessation, and treatment of comorbid
conditions.
Eosinophilic Granulomatosis with
Polyangiitis
Historical Perspective
EGPA was initially termed Churg–Strauss syndrome after J.
Churg and L. Strauss who first described it in 1951.36 They
published a series of 14 patients with necrotizing vasculitis
involving small- to medium-sized vessels with associated
granuloma formation and eosinophilic infiltration of various
tissues. They also noted an association with peripheral eo-
sinophilia and that almost all the patients had underlying
asthma.36

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 Diagnosis and Management of Pulmonary Eosinophilic Syndromes
Epidemiology
The incidence has been reported to be 0.9 to 2 per million
person-years and the prevalence 11.3 per million person-
years.37–41 In those with asthma, the incidence is estimated to
be 35 to 67 cases per million person-years.42,43 There is also
an increased incidence associated with age greater than
50 years.40,41
Pathogenesis
The pathogenesis of this disease is still under study. Epige-
netic and genetic factors may play a role in the disease
pathogenesis. One case report presented two sisters with
asthma and antineutrophil cytoplasmic antibody (ANCA)–
negative EGPA, and in another report, a father with EGPA
and a son with GPA (granulomatosis with polyangiitis).44,45
Clinical Presentation, Laboratory Tests and Chest
Imaging
There are three distinct clinical stages for patients with
EGPA46 that are not necessarily progressive and may overlap.
The first stage described is the prodromal allergic/atopic
phase and consists of atopic disease, allergic rhinitis, nasal
polyposis, and asthma. More than 95% of patients with EGPA
have asthma, which is usually severe and requires ste-
roids.47,48 Sinusitis in EGPA commonly does not demonstrate
the destructive sinus changes sometimes observed in other
vasculitides.47–49 The eosinophilic phase is marked by pe-
ripheral eosinophilia and sometimes pulmonary, cardiac, and
gastrointestinal (GI) infiltration of eosinophils. Pulmonary
manifestations may include fleeting lung infiltrates, nodules,
or cavities. Cardiac involvement has been reported in as high
as 62% of EGPA patients.50 Manifestations include pericarditis
or effusion, endomyocarditis, arrhythmias, valvular disease,
mural thrombus, heart failure, and myocardial infarct from
coronary arteritis.50–53 Electrocardiogram (ECG) and cardiac
imaging should be done to evaluate even for preclinical
involvement. GI manifestations are marked by eosinophilic
esophagitis, gastroenteritis, and colitis.48,49 The final phase is
the vasculitic phase which can be life threatening and is
similar to other ANCA-associated vasculitides.
Peripheral blood eosinophilia and elevated serum IgE, C-
reactive protein, and erythrocyte sedimentation rate are
commonly observed. ANCA is important in assessing for
vasculitis. The antibody is known to promote neutrophil
migration and degranulation in tissue. As the name suggests,
the antibodies are against antigens in the cytoplasmic gran-
ules of neutrophil and also monocytes. There are two tests
frequently used, indirect immunofluorescence assay, which is
more sensitive, and the enzyme-linked immunosorbent assay
(ELISA), which is more specific. Indirect immunofluorescence
staining patterns have been characterized as cytoplasmic (c-
ANCA), perinuclear (p-ANCA), or atypical (a-ANCA). If the
screening test is positive, the ELISA test is conducted. This test
targets the serine proteinase 3 (PR3) and myeloperoxidase
(MPO), which are located in the azurophilic granules of
neutrophils and peroxidase-positive monocyte lysosomes.
PR3 is typically associated with a c-ANCA pattern, while
MPO is associated with p-ANCA.54,55 ANCA positivity is
Sergew, Fernández Perez 447
variable in frequency in EGPA, ranging from 38 to 78%, usually
in p-ANCA pattern and MPO positive.47–49,56–58 ANCA nega-
tivity does not rule out the presence of EGPA. Similar to HES,
ANCA-negative EGPA is significantly more likely to have an
eosinophilic phenotype with cardiac and lung involvement,
whereas ANCA-positive EGPA is more likely to have disease
manifestations associated with small-vessel vasculitis such as
necrotizing glomerulonephritis, mononeuritis multiplex, and
purpura. ANCA positivity is influenced by organ involvement
and if the disease state is active or untreated. One study of 116
patients with EGPA found that in those with renal involve-
ment 75% were ANCA positive, while in those without renal
involvement ANCA was positive in only 26%.59 Another study
of 93 patients with EGPA found an overall ANCA positivity in
38% of patients. ANCA was positive in 51% of those with renal
disease in comparison to 12% in those without renal disease
and positive in 20% of those with alveolar capillaritis versus
none in those without pulmonary hemorrhage. To a lesser
extent, this has also been described in patients with purpura
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(ANCA positive 26% in those with purpura vs. 7% in those
without), as well as in mononeuritis multiplex (ANCA positive
51% in those with vs. 24% in those without). However, in those
with cardiac involvement, ANCA positivity was lower (6%) in
comparison to those without cardiac involvement (22%) and
also in those with lung involvement outside of alveolar
hemorrhage (34%) versus those without (60%).56
Radiologic manifestations of pulmonary involvement in
EGPA are observed in 70 to 100% of patients.46,60–63 Imaging
findings are heterogeneous and commonly include migratory,
patchy, bilateral ground-glass opacities and/or air-space con-
solidations. Other findings include pulmonary nodules, air-
ways thickening, or pleural effusions.47,60,61,64 A
representative image is show in ►Fig. 4A. ECG abnormalities
have been reported in as high as 66% of patients, and about
half of EGPA patients have been noted to have echocardio-
gram abnormalities.50 Histopathological findings can show
eosinophilic pneumonia, necrotizing granulomas, and small
or medium vessel vasculitis.65 Representative images are
shown in ►Fig. 4B, C.
Diagnosis
The diagnosis of EGPA requires the correlation of clinical,
laboratory, radiologic, and histopathologic findings. Repeat-
ed clinical and serologic evaluations may help confirm the
diagnosis. Given the rarity and the complexity of the disease
presentation, accuracy of the diagnosis increases with a
multidisciplinary discussion among experience clinicians.
Early referral to an interstitial lung disease center is recom-
mended. Various diagnostic schemes have been proposed.
The Lanham criteria was proposed in 1984 and includes:
asthma, peripheral eosinophilia  1,500 cells/µL, and evi-
dence of vasculitis in at least two extrapulmonary organs.46
In 1990, the American College of Rheumatology (ACR) estab-
lished six criteria: asthma, peripheral eosinophilia > 10%,
neurologic manifestations (such as mononeuritis multiplex
and polyneuropathy), fleeting pulmonary infiltrates on lung
imaging, paranasal sinus abnormality, and biopsy of a blood
vessel demonstrating eosinophilic infiltration in
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 3/2016
448 Diagnosis and Management of Pulmonary Eosinophilic Syndromes
extravascular areas.66 Four criteria out of the six are sugges-
tive of EGPA. The ACR criteria for EGPA have a specificity of
99.7% and a sensitivity 85.0%.66 In 1994, the Chapel Hill
International Consensus Conference (CHCC) sought to stan-
dardize the nomenclature and definition of vasculitis. EGPA
was identified as a necrotizing vasculitis affecting small- and
medium-sized vessels, granulomatous and eosinophilic in-
flammations involving the respiratory tract and presenting
in the setting of asthma, and peripheral blood eosinophilia.67
None of the three diagnostic criteria captured all EGPA or
forme fruste cases.68 In 2007, the European Medicines Agen-
cy published a classification of a methodology that validated
a classification scheme for ANCA-associated vasculitides.69
This uses the Lanham criteria, ACR, and CHCC as well as ANCA
status.69
Management of Eosinophilic Granulomatosis
with Polyangiitis
EGPA should be managed in collaboration with or in
specialized referral centers. Treatment of EGPA is tailored
to disease extent, severity, and patient’s response to thera-
py. The European Vasculitis Study Group (EUVAS) is a
commonly utilized classification system that stratified
Fig. 4 Eosinophilic granulomatosis with polyangiitis. (A) Axial image from chest CT shows patchy ground-glass opacity and consolidation in the
upper lobe and superior segment of the left lower lobe consistent with EGPA in this patient with asthma, sinusitis, and peripheral eosinophilia.
Seminars in Respiratory and Critical Care Medicine Vol. 37
Sergew, Fernández Perez
ANCA-associated vasculitis patients by disease extent and
severity into the following categories: (1) limited: upper
respiratory tract disease without any other systemic in-
volvement or constitutional symptoms; (2) early general-
ized: end-organ involvement, without organ-threatening
or life-threatening disease; (3) generalized active: end-
organ involvement with evidence of significant im-
pairment; (4) severe: immediate threat of organ failure or
death; (5) refractory: progressive disease unresponsive to
glucocorticoids and cyclophosphamide (CYC); and (6) re-
mission: no evidence of ongoing vasculitic activity. Alter-
natively, the French Vasculitis Study Group five-factor score
(FFS) can been used as a scoring system to identify patients
who may benefit from immunosuppression with cytotoxic
agents.70 The first four factors include age > 65 years,
kidney involvement, heart involvement, and GI involve-
ment. The presence of each of these predictors marks a poor
prognosis and is given one point. For example, in the
absence of cardiac involvement, comprehensive and expert
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disease management of EGPA is associated with increased
life expectancy. Cardiac involvement such as cardiomyop-
athy, vasculitis involving the coronary arteries, and peri-
cardial disease carries a significant mortality.71–74
Therefore, a thorough cardiac evaluation is required
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Fig. 4 Eosinophilic granulomatosis with polyangiitis. (B) H&E high power: necrotizing vasculitis involving a small muscular pulmonary arteries
with numerous eosinophils. (C) H&E high power: lung parenchyma with features of eosinophilic pneumonia.

when EGPA is suspected.75 The fifth factor (ear, nose, and
throat involvement) is associated with better prognosis,
and the absence of upper airway manifestations is given
one point. In the scoring system, the greater the score, the
higher the 5-year mortality: FFS score of 0 is 9%, 1 is 21%,
and 2 is 40%.70 Since the patient disease activity may
change during follow-up, restaging and therapy interven-
tions may need to be modified accordingly. A patient with
an FFS score of 0 can be treated with oral steroids alone at
0.5 to 1 mg/kg. Methotrexate (10–30 mg/week, with folic
acid replacement) and azathioprine (2 mg/kg/day) can also
be considered as steroid-sparing agents if the patient could
not have their prednisone taper due to refractory disease.
The Churg–Strauss Syndrome and Polyarteritis Nodosa 2
(CHUSPAN 2) trial is currently evaluating whether a com-
bination of corticosteroids and azathioprine can achieve a
higher remission rate and a lower subsequent relapse rate
in patients with FFS ¼ 0 EGPA as compared with cortico-
steroids alone. For an FFS of 0 to 1, cytotoxic agents such as
intermittent IV CYC are recommended in addition to

Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 3/2016

450 Diagnosis and Management of Pulmonary Eosinophilic Syndromes
steroids. IV formulation tends to have lower drug toxicity
and is preferable to oral CYC. A trial of 48 patients with
EGPA were treated with 6 versus 12 cycles of CYC, and the
longer course had few relapses noted, with 41% in the 12
cycle group and 94% in the 6 cycle group relapsing.76
Similarly, in patients with an FFS of 1 to 2, CYC and steroids
are initiated. In ANCA-positive patients with renal involve-
ment intolerant to or unresponsive to cytotoxic agents,
rituximab can be an alternative. Rituximab, an anti-CD 20
monoclonal antibody, has been shown in a prospective,
multicenter trial to be as effective as CYC in inducing
remission at 6 months in ANCA-positive GPA and micro-
scopic polyangiitis and may in fact have lower rates of
relapse than CYC.77 There have also been many case reports
and case series that have demonstrated its effect in steroid-
recalcitrant EGPA.78–81 In a multicenter survey of rituxi-
mab therapy for refractory ANCA-associated vasculitis
(EPGA, GPA, and microscopic polyangiitis) in 65 patients,
complete remission was described in 75%, partial remission
in 23%, and no response in 2%.82 In those with life-threat-
ening disease from diffuse alveolar hemorrhage (very rare
and less prevalent complication in contrast to GPA and
microscopic polyangiitis) and glomerulonephritis (i.e., pul-
monary-renal syndrome) and FFS > 2, plasma exchange in
combination with steroids and CYC or rituximab can be
considered.83,84 Azathioprine, methotrexate, and lefluno-
mide are also recommended for remission maintenance for
patients with life- and/or organ-threatening disease man-
ifestations after a remission induction therapy.
Biologics are under study in EGPA. An open-label study of
seven patients with steroid-dependent EGPA showed
monthly mepolizumab, anti–interleukin 5 (IL-5) monoclo-
nal antibodies, given four times leads to the reduction of
steroid need.85 Another study of 10 patients with refractory
or relapsing disease on steroids and immunosuppression
showed 8 of the patients had remission and were able to
taper steroids after nine treatments of monthly mepolizu-
mab.86 These studies demonstrate a greater potential for the
role of biologics in EGPA.87 At present, the efficacy of
mepolizumab compared with placebo has been evaluated
over a 52-week study treatment period in subjects with
relapsing or refractory EGPA receiving standard of care
therapy including background corticosteroid therapy with
or without immunosuppressive therapy, but results are not
yet available. Other medications that have been evaluated in
observational studies for EGPA include α-interferon,88 IV
immune globulin,89 anti–tumor necrosis factor agents,90
and anti-IgE therapy.91
ENT manifestations should be treated promptly and just
as aggressively as asthma. Asthma management is impor-
tant in EGPA as it is typically severe and often requires high-
potency inhaled corticosteroids and a long-acting β-ago-
nist. Leukotriene antagonists have previously been linked
to EGPA and likely are involved in unmasking disease rather
than being causative. The data support the use of leukotri-
ene antagonists in asthma as they reduce the need for oral
corticosteroids and these agents should be used in asth-
matics who require oral steroids. Asthmatics who qualify
Seminars in Respiratory and Critical Care Medicine Vol. 37
Sergew, Fernández Perez
should be initiated on omalizumab, a monoclonal antibody
that binds IgE. A recently published case study of a patient
with severe asthma and EGPA had significant symptomatic
reduction of her asthma exacerbations and hospitalizations
as well as a reduction in peripheral eosinophils and serum
IgE after initiation with omalizumab.92
Interventions for EGPA center on patient educational pro-
grams, therapy adjustments according to disease activity and
to prevent clinically significant side effects treatment of
opportunistic infections and comorbid conditions, smoking
cessation, and providing vaccinations against pneumococcal
disease and influenza.
Hypereosinophilic Syndromes
Historical Perspective
The term HES was first coined in 1968 by Hardy and Anderson
who reported three cases of patients with hypereosinophilia
(HE), hepatosplenomegaly, and cardiac or pulmonary manifes-
tations.94 Since the first diagnostic criteria proposed in 1975
Downloaded by: Imperial College London. Copyrighted material.
(peripheral eosinophilia 1.5
109/L persisting for > 6
months, no known cause of HE, and eosinophil-mediated organ
dysfunction),95 several different HES classifications have been
described. In 2011, a Working Conference of Eosinophil Disor-
ders and Syndromes came up with a consensus statement to
update and refine the diagnostic criteria of eosinophilic and
associated disorders.96
Epidemiology
The incidence of HES has been reported to be 0.03 to 0.042/
100,000 per person-years and a prevalence of 0.315 to 6.3/
100,000 persons.97
Diagnosis
HE is defined as an eosinophilic count of >1,500 cells
109/
L that presents at least on two occasions over a span of
greater than a month and/or evidence of tissue infiltration
by eosinophils. Tissue infiltration can include one or more of
the following: bone marrow eosinophils of >20% of nucleat-
ed cells (normal values range, 1–6%), pathologic evidence of
tissue infiltration, or evidence of degranulated contents of
eosinophil granules. Immunostaining for eosinophilic cat-
ionic protein, major basic protein, and eosinophilic protein X
can be helpful to prove eosinophilic degranulation in biop-
sied tissue.98 HES is defined as HE and evidence of organ
damage due to eosinophilic infiltration and exclusion of
other causes of organ damage. HE-related organ damage
can include the sinuses, heart, skin, lung, GI tract, and
nervous system.96,99 Pulmonary manifestations may include
AEP, CEP, and/or eosinophilic bronchitis/bronchiolitis. When
evaluating patients with HES, the difficulty may lie in
determining whether the eosinophilia was a direct cause
of organ damage. Additionally, the presentation of HES can
be varied from those with asymptomatic disease to those
who present with life-threatening disease. For these rea-
sons, the diagnosis and management of HES requires fre-
quent reevaluations, multidisciplinary discussion, and
referral to an expert center.
No. 3/2016
 Diagnosis and Management of Pulmonary Eosinophilic Syndromes
The definition and classification of HES may be modified as
more is learned about the biology of the disease. Currently,
HES can be categorized as primary (neoplastic), secondary
(reactive), and other variants (e.g., familial). Idiopathic HES is
considered once other etiologies such as clonal and/or reac-
tive causes have been ruled out.
Primary Hypereosinophilic Syndromes
Primary HES (clonal/neoplastic) is due to a myeloid or
lymphoid neoplasm with eosinophilia. When primary HES
has myeloproliferative features, it is termed myeloprolifera-
tive HES (MHES). MHES presents between 20 and 50 years of
age and is a male-predominant disease. The features of
myelodysplasia include increased serum B12 level, anemia,
thrombocytopenia, splenomegaly, and increased circulating
myeloid precursors and a hypercellular bone marrow with
increased atypical mast cells and fibrosis.100 An increased
tryptase level has been shown to be a sensitive marker of
MHES and correlates with increase end-organ fibrosis (en-
domyocardial fibrosis, mucosal ulcerations, and restrictive
lung disease), poor prognosis, and responsiveness to
imatinib.101
FIP1L1-PDGFRα (F/P) is the most frequent gene rear-
rangement found in MHES102 and results from an intersti-
tial deletion in chromosome 4q12 leading to the fusion of
two genes: FIP1-Like1 (FIP1L1) and platelet-derived growth
factor receptor α (PDGFRA).103 This fusion gene can be
found in 3 to 11% of patients with HES104,105 and can be
detected by reverse transcriptase-polymerase chain reac-
tion (or fluorescence in situ hybridization of peripheral
blood or bone marrow aspirate). A subset of F/P-negative
MHES has been shown to have PDGFRA and PDGFRB
mutations.106–108
Like in EGPA, cardiac involvement in patients with MHES
purports a poor prognosis.109 There are no clinical markers
that can predict the development and the severity of
cardiac manifestations and there is no direct correlation
with the level of eosinophilia. Patients with HES who
have cardiac manifestations can present with congestive
heart failure, mural thrombosis and/or embolic events,
arrhythmias, myocardial ischemia, and less frequently
pericarditis.110,111
Secondary Hypereosinophilic Syndromes
Secondary HES may result from a nonclonal proliferation of
eosinophils. The lymphoid variant HES (LHES) is the best
known subtype105 and is characterized by the expansion of
abnormal T cell phenotypes (e.g., CD3  CD4 þ , CD3 þ
CD4 þ CD7  , and CD3 þ CD4  CD8  TCRαβþ T cells)
which produce eosinophilopoietic cytokines such as IL-5,
IL-4, and IL-13.6,112–116 In some cases, the aberrant T
cell population is clonal. In addition to T cell abnormalities,
patients can have increased IgE levels, and increased
serum thymus and activation-regulated chemokine
levels. Atopic skin manifestations such as urticaria and
angioedema are common. Cardiac manifestations in LHES
are rare.
Sergew, Fernández Perez 451
Treatment of Hypereosinophilic Syndromes
Systemic steroids are the mainstay therapy for most HES
variants, in particular in those with life-threatening disease
(e.g., cardiac and neurologic manifestations). Before initiation
of steroids, infection should be rule out and/or treated prompt-
ly. Patients with a history of exposure to endemic areas of
Strongyloides should be empirically treated with ivermectin
200 ug/kg, orally daily for 2 days. Use of alternative therapy (e.
g., cytotoxic drugs, nonmyeloablative allogeneic bone marrow
transplantation) should be considered on a case-by-case basis,
according to the HES variant, extent, and severity of organ
involvement and in corticosteroid-refractory disease.
Imatinib mesylate is the treatment of choice for those with
the F/P gene mutation at doses of 100 to 400 mg dai-
ly.100,101,103,117 Cardiac decompensation and acute drug-
induced myopathy have been described after imatinib thera-
py in patients with known cardiac manifestations of
HES.118–120 Systemic corticosteroid treatment before and
during imatinib therapy has been recommended for HES
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patients with cardiac involvement. Imatinib resistance in F/
P positive patients is rare and other tyrosine kinase inhibitors
such as dasatinib, sorafenib, and nilotinib have been used
with mixed results.121–127
Mepolizumab has been shown to result in corticosteroid
sparing in F/P-negative HES patients. Currently, in addition of
mepolizumab, there are studies recruiting to assess the safety
and efficacy of dexpramipexole (a synthetic aminobenzothia-
zole which has been shown to reduce eosinophilia in amyo-
trophic lateral sclerosis) and benralizumab (a biologic agent
that blocks IL-5 receptor) in HES.
In conjunction with a multidisciplinary team, an experi-
enced hematologist should guide serial monitoring as well as
immunomodulatory and cytotoxic therapy as dictated by
World Health Organization disease-specific algorithms and
guidelines. As with CEP and EGPA, it is paramount to screen,
prevent, and treat all steroid-related side effects.
Future Therapies
The treatment for the PES continues to evolve. Growing
understanding of the PES pathogenesis, in particular EGPA
and HES, is resulting in new therapeutic options beyond
glucocorticoids therapy and standard immunosuppressive
therapies. ►Fig. 5 demonstrates the eosinophil pathway
and the targets of emerging biologic therapies.
Conclusion
PES (AEP, CEP, EGPA, HES) are a heterogeneous group of
diseases characterized by the presence of peripheral blood
eosinophilia and/or eosinophilic-related pulmonary im-
pairment. These disorders may be idiopathic, lung-limited,
or systemic in nature. A thorough clinical evaluation in a
multidisciplinary setting is key to achieve an accurate diag-
nosis and appropriate therapeutic interventions. Although
corticosteroids remain the mainstay of therapy, new treat-
ments options are emerging as alternatives.
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 3/2016
452 Diagnosis and Management of Pulmonary Eosinophilic Syndromes Sergew, Fernández Perez

Downloaded by: Imperial College London. Copyrighted material.

Fig. 5 Eosinophils are leukocytes produced in the bone marrow from granulocytic lineage. Cytokines such as interleukin 5 (IL-5), interleukin 3 (IL-
3), and granulocyte macrophage colony-stimulating factor (GM-CSF) promote their production, maturation, and activation.97,128,129 These
cytokines are produced predominantly by activated T-helper 2 (Th2) cells. IL-5 is specific to promoting eosinophil production, differentiation,
survival, and function, while IL-3 and GM-CSF are more pleotropic. 128 IL-5 attaches to eosinophils via IL-5Rα receptor. Mepolizumab and reslizumab
are anti-IL-5 antibodies, which target IL-5 and inhibit its interaction with the α-chain of the IL-5Rα receptor. 130 Benralizumab is a novel monoclonal
antibody that binds to a distinct epitope within the extracellular domain of recombinant human IL-5Rα and directly targets eosinophils.130
IL-4 and IL-13 are also produced by Th2 cells and play an important role in eosinophil accumulation and IgE production.131,132 They attach to the IL-
4Rα receptor on eosinophils and B cells. Lebrikizumab and tralokinumab are anti-IL-13 antibodies. 133 Dupilumab is a monoclonal antibody to the IL-
4Rα/IL-13Rα1 receptor complex that inhibits both IL-4 and IL-13 signaling. 134 Pitrakinra is a recombinant human IL-4 variant that inhibits the IL-4Rα
receptor complex and blocks the actions of IL-4 and IL-13. 130 Activated B cells induce plasma cells to make antibodies such as IgE, which leads
to mast cell activation. 130 Alemtuzumab targets CD52, which is expressed on T and B lymphocyte cell membrane. Omalizumab is a biologic that
targets IgE.130

Financial Disclosure References

None.
Conflict of Interest
None.
Acknowledgments
We gratefully acknowledge Dr. Jonathan Chung, Dr. Jona-
than Richards, and Dr. Rosane Achcar at National Jewish
Health, Denver, Colorado, for providing several of the CT
images and photomicrographs. We are also particularly
indebted to Dr. Joanne E Yi, Mayo Clinic, Rochester, Min-
nesota, who kindly provided the photomicrographs of
EGPA.
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