The n e w e ng l a n d j o u r na l of m e dic i n e

Clinical Problem-Solving

CarenG. Solomon, M.D., M.P.H., Editor

All That Wheezes...

Sanjay Divakaran, M.D., Paul Dellaripa, M.D., Lester Kobzik, M.D.,
Bruce Levy, M.D., and Joseph Loscalzo, M.D., Ph.D.

In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert
clinician, who responds to the information, sharing his or her reasoning with the reader (regular type).
The authors commentary follows.

A 20-year-old woman presented to her physicians office with persistent cough and From the Departments of Medicine and
shortness of breath. She had been seen 6 weeks earlier for nasal congestion, rhinor- Pathology, Brigham and Womens Hospi-
tal and Harvard Medical School, Boston.
rhea, postnasal drip, and cough. Her nasal congestion had abated on treatment with Address reprint requests to Dr. Levy at the
fluticasone nasal spray and loratadine, but her cough persisted. The cough was Department of Medicine, Brigham and
worse at night, and she could hear herself wheezing during prolonged episodes of Womens Hospital, 75 Francis St., Boston,
MA 02115, or at blevy@partners.org.
coughing. She had used her grandmothers albuterol inhaler during one of these
episodes, and the inhaler provided enough relief to allow her to go back to sleep. At N Engl J Med 2017;377:477-484.
DOI: 10.1056/NEJMcps1607526
the time of presentation, she also had some shortness of breath when walking to the Copyright 2017 Massachusetts Medical Society.
bus stop. Her symptoms occurred both at home and at work. She reported no fevers,
chills, sputum production, headache, joint pains, muscle aches, heartburn, nausea,
vomiting, or frequent throat clearing. On examination, she was noted to have an
oxygen saturation of 96% while breathing ambient air. Diffuse, high-pitched, expira-
tory wheezing could be heard on auscultation of the lungs, and there was an in-
creased ratio of expiratory to inspiratory time. The nasopharyngeal mucosa was
normal in appearance.

The differential diagnosis for cough and shortness of breath includes upper respira-
tory tract infection, pneumonia, volume overload, and asthma. Anemia can cause
shortness of breath on exertion but is not associated with cough. Seasonal aller-
gies can cause cough but should not cause shortness of breath in the absence of
concomitant asthma. Since the patients symptoms occur both at home and at work,
it is unlikely that an allergen found at only one of these sites is the cause of her
symptoms. Postnasal drip can cause chronic cough; in patients with this condi-
tion, the nasopharyngeal mucosa may have a cobblestone appearance on examina-
tion. The patients history of wheezing, the relief of symptoms after the use of a
short-acting bronchodilator, and the findings on examination strongly suggest
asthma with reversible airflow obstruction, airway hyperreactivity, and airway
inflammation.

The patient had a history of migraine headaches and allergic sinusitis, and she was
overweight. She had no history of infection with tuberculosis. Her medications in-
cluded fluticasone nasal spray daily, 10 mg of loratadine once a day as needed, and
100 mg of benzonatate up to three times a day as needed. She had no known aller-
gies. She was born in the Dominican Republic but lived in the Boston area with her
mother. She worked full time at a day-care center, and she had a pet dog. She reported

n engl j med 377;5nejm.org August 3, 2017 477

The New England Journal of Medicine
Downloaded from nejm.org on August 2, 2017. For personal use only. No other uses without permission.
Copyright 2017 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

no exposure to mold, smoke, cockroaches, or mice.
She had never smoked, did not drink alcohol, and
did not use recreational drugs. Her family history
was notable for allergic rhinitis in her mother,
childhood asthma in her sister, and lymphoma in
a maternal uncle and cousin.
The patients personal and family histories sug-
gest atopy. Her place of birth raises the possibil-
ity of strongyloidiasis, which is endemic in tropical
and subtropical regions. Chronic strongyloidiasis
can cause asthmalike symptoms that usually wors-
en with glucocorticoid treatment. Her place of
work puts her at risk for recurrent upper respira-
tory symptoms. She reports no exposure to several
common allergens, but she does have a dog. It
would be important to know whether she had ac-
quired the dog recently and whether its presence
correlated with the onset of symptoms.
Given the results of the patients pulmonary-
A preliminary diagnosis of asthma was made. A function tests, she was started on therapy with
trial of an albuterol inhaler was prescribed for an inhaled glucocorticoid and a long-acting beta-
use as needed, and the patient was referred for
pulmonary-function testing to confirm the diag-
nosis.
Asthma is a chronic inflammatory disease of the
airways that is characterized by hyperresponsive-
ness to a variety of stimuli and is manifested as
episodic wheezing, dyspnea, and in some instances
(22%) to 1.67 liters. Exhaled nitric oxide was not
measured. Her flow-volume loops are shown in
Figure 1.
The patients FEV1 and ratio of FEV1 to FVC are
low and consistent with obstruction. The con-
cave contour of the flow-volume loop during
exhalation (Fig. 1) is also consistent with intra-
thoracic obstruction. The positive bronchodila-
tor response (i.e., an increase in FEV1 of at least
12% and at least 200 ml) indicates reversible
obstruction, which is one of the three main
clinical characteristics of asthma. The patient
has already shown signs and symptoms associ-
ated with the other two characteristics: her al-
lergic rhinitis suggests airway inflammation,
and her episodic symptoms suggest bronchial
hyperresponsiveness.
8 Before bronchodilator
7 After bronchodilator
6
Predicted
5
4
3
Flow (liters/sec)

2
cough. Approximately 75% of patients with asth- 1
ma receive a diagnosis before they reach 7 years 0
1
of age, but asthma may develop at any age. A
2
history of cigarette smoking (which does not ap- 3
FEV3 =1.99
ply to this patient) and atopy, such as allergic rhi- 4
FEV1 =1.37
nitis (which does apply to this patient), are poten- 5
tial risk factors for a later onset of asthma. The use 6
7
of pulmonary-function testing to document air-
8
flow obstruction that abates in response to bron- 1 2 3 4 5
chodilators would provide objective evidence to Volume (liters)
support the diagnosis. It will also be important
to rule out infection with Strongyloides stercoralis Figure 1. Flow-Volume Loop According to Results on
before the initiation of treatment with systemic Spirometry.
glucocorticoids for symptom management. Expiratory flow is shown on the y axis, and the volume
exhaled from total lung capacity (forced expiratory vol-
The patients spirometry results revealed a forced ume) is shown on the x axis. The data for the blue
curve were obtained before treatment with albuterol,
expiratory volume in 1 second (FEV1) of 1.37 liters and the data for the orange curve were obtained after
(35% of the predicted value). The ratio of FEV1 to treatment with albuterol. FEV1 denotes forced expira-
forced vital capacity (FVC) was 0.58 (67% of the tory volume in 1 second, and FEV3 forced expiratory
predicted value). After the administration of bron- volume in 3 seconds.
chodilator therapy, her FEV1 increased by 300 ml

478 n engl j med 377;5 nejm.org August 3, 2017

The New England Journal of Medicine

Downloaded from nejm.org on August 2, 2017. For personal use only. No other uses without permission.
Copyright 2017 Massachusetts Medical Society. All rights reserved.
 Clinical Problem-Solving
adrenergic agonist bronchodilator. A short-act-
ing beta-adrenergic agonist bronchodilator was
also prescribed for rescue from acute symp-
toms. Her symptoms escalated and later did not
respond to the addition of a leukotriene modifier
and a long-acting anticholinergic bronchodilator.
She presented again, 6 months after her initial
presentation, with cough, shortness of breath,
and wheezing.
Medication adherence should be addressed given
the inadequate control of symptoms after the ini-
tiation of appropriate step-up therapy for asthma.
Direct observation during a clinic visit can be help-
ful to determine whether patients need instruc-
tion on the proper use of inhalers. If adherence
is confirmed, clinicians should consider alterna-
tive diagnoses, such as strongyloidiasis or allergic
bronchopulmonary aspergillosis. In addition to
cough, shortness of breath, and wheezing, patients
with strongyloidiasis may have urticaria or pru-
ritus as well as diarrhea, nausea, and vomiting.
Patients with allergic bronchopulmonary asper-
gillosis typically present with recurrent asthma
exacerbations, but they may also have fever, a
productive cough, or even hemoptysis.
On physical examination, the temperature was
37.0C, the pulse 69 beats per minute, the blood
pressure 108/57 mm Hg, the respiratory rate 18
breaths per minute, and the oxygen saturation
97% while breathing ambient air. The patient ap-
peared anxious and uncomfortable but was not in
acute respiratory distress. The conjunctiva appeared
normal. There was no oropharyngeal erythema or
edema. The nasopharyngeal mucosa appeared nor-
mal. The sinuses showed no tenderness to palpa-
tion, and there was no discharge. There were no
allergic shiners (swelling and darkening of the
skin under the eyes), and there was no lymphade-
nopathy. Pulmonary examination was notable for
a prolonged expiratory phase with mild expirato-
ry wheezing in both lungs. There were no inspira-
tory crackles, egophony, tactile fremitus, or dull-
ness to percussion in either lung. The results of
cardiac and abdominal examinations were nor-
mal. The jugular venous pressure was not elevat-
ed. There was no clubbing, cyanosis, or edema of
the arms and legs. The cranial nerves, motor
strength, sensation, and gait were normal. There
was no skin rash or erythema.
n engl j med 377;5nejm.org August 3, 2017
The New England Journal of Medicine
Downloaded from nejm.org on August 2, 2017. For personal use only. No other uses without permission.
Copyright 2017 Massachusetts Medical Society. All rights reserved.
There is evidence of ongoing airflow obstruction
on examination. Although signs of allergy are
absent on examination, an allergic cause for the
patients symptoms cannot be ruled out. It may
be helpful to obtain a peripheral eosinophil count
to screen for airway and other allergic disorders
characterized by type 2 inflammation, such as ec-
zema, allergic conjunctivitis, and allergic rhinitis.
The electrolyte count was within normal limits.
The level of blood urea nitrogen was 8 mg per
deciliter (3 mmol per liter), and the creatinine
level was 0.79 mg per deciliter (69.8 mol per liter).
The white-cell count was 20,730 per cubic millime-
ter, with 53% eosinophils (reference range, 0 to 5).
The hemoglobin level, hematocrit, and platelet
count were normal. Tests for antinuclear antibod-
ies and antineutrophil cytoplasmic antibodies
(ANCAs) were negative. The erythrocyte sedimen-
tation rate was 31 mm per hour (reference range,
0 to 18), and the C-reactive protein level was 41.7 mg
per liter (reference range, 0 to 3.0).
The striking new information regarding the pa-
tient is her prominent peripheral eosinophilia.
There are several categories of disease associated
with eosinophilia: infectious (particularly with
invasive helminths), respiratory (e.g., asthma and
eosinophilic pneumonia), gastrointestinal (e.g., eo-
sinophilic gastroenteritis), allergic (e.g., allergic
bronchopulmonary aspergillosis, eczema, and
asthma), inflammatory vascular (e.g., eosino-
philic granulomatosis with polyangiitis, previ-
ously known as the ChurgStrauss syndrome),
and malignant (e.g., leukemia and lymphoma).
Other possibilities include adrenal insufficiency
and idiopathic hypereosinophilic syndrome. The
patients presenting symptoms, diagnosis of asth-
ma refractory to treatment, and now prominent
peripheral eosinophilia are suggestive of stron-
gyloidiasis, allergic bronchopulmonary aspergil-
losis, chronic eosinophilic pneumonia, or eosino-
philic granulomatosis with polyangiitis.
Allergic bronchopulmonary aspergillosis is
an allergic pulmonary disorder caused by a hyper-
sensitivity response to aspergillus. Chronic eosin-
ophilic pneumonia is characterized by cough,
progressive dyspnea, peripheral eosinophilia, and
the presence of peripheral opacities in both lungs
on chest imaging. Eosinophilic granulomatosis
with polyangiitis is a vasculitis of small and
479
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

Figure 2. Computed Tomographic Images of the Chest.

Scattered subpleural, consolidative opacities can be seen in both lungs (arrows, Panels A through D).

medium-sized arteries that is characterized by
chronic rhinosinusitis, peripheral and tissue eo-
sinophilia, and asthma. The patient does not
have a fever, productive sputum, or hemoptysis,
any of which may occur with allergic broncho-
pulmonary aspergillosis. The airflow obstruction
detected on spirometry is most consistent with a
diagnosis of eosinophilic granulomatosis with
polyangiitis or allergic bronchopulmonary asper-
gillosis; however, some patients with chronic eo-
sinophilic pneumonia have obstructive rather
than restrictive ventilatory defects. Symptoms
and signs of a mononeuropathy or polyneuropa-
thy or of sinus abnormalities would favor eosino-
philic granulomatosis with polyangiitis, but such
symptoms and signs are not present. The negative
test result for ANCAs does not rule out eosino-
philic granulomatosis with polyangiitis, since this
test is negative in approximately 60% of patients
with this condition.
Given the patients worsening symptoms and lab-
oratory findings, computed tomography (CT) of
the chest was performed in order to look for pul-
monary parenchymal abnormalities. The images
showed scattered subpleural, consolidative opaci-
ties in both lungs (Fig.2).
These findings on imaging are consistent with
eosinophilic granulomatosis with polyangiitis,
although such findings may also may be seen in
patients with eosinophilic pneumonia, organizing
pneumonia, or pulmonary emboli with resulting
parenchymal infarction. Given the clinical presen-

480 n engl j med 377;5nejm.org August 3, 2017

The New England Journal of Medicine

Downloaded from nejm.org on August 2, 2017. For personal use only. No other uses without permission.
Copyright 2017 Massachusetts Medical Society. All rights reserved.
 Clinical Problem-Solving

A B
*

C D

Figure 3. Biopsy Specimen from the Right Lung.

A biopsy specimen from the right lung showed airways with features of asthma (Panel A, mucus-cell hyperplasia
[asterisk], smooth-muscle hypertrophy [arrowheads], and an eosinophil-rich inflammatory infiltrate [arrows]), eosin-
ophilic pneumonia (Panel B), eosinophilic vasculitis (Panel C, vessel wall [asterisk] and eosinophils [arrowheads]),
and areas of infarction (Panel D).

tation and laboratory findings, eosinophilic granu-
lomatosis with polyangiitis is the most likely di-
agnosis. Patients with allergic bronchopulmonary
aspergillosis can have peripheral opacities simi-
lar to those seen here, but CT frequently reveals
bronchiectasis, ground-glass opacities, or both,
findings that are not present here. On the basis
of the clinical presentation and CT findings, a
diagnosis of chronic eosinophilic pneumonia
should also be considered, but this disease typi-
cally affects patients in their 30s or 40s.
After the chest CT, laboratory analyses revealed
elevated serum levels of IgE (1600 IU per milliliter
[reference range, 0 to 100]). The level of aspergil-
lus-specific IgE was less than 0.35 kU per liter
(reference range, 0 to 0.35). The results of skin
tests for aspergillus were negative. No ova or par-
asites were found in a stool sample, and a test for
strongyloides antibodies was negative. The deci-
sion was made to obtain a biopsy specimen from
one of the subpleural opacities in order to make a
definitive diagnosis. A wedge biopsy specimen from
the right lung showed airway changes related to
asthma, eosinophilic pneumonia, and eosinophilic
vasculitis with areas of infarction (Fig. 3). An in-
terferon-gamma release assay for latent tubercu-
losis infection was negative.
Conditions associated with elevated serum IgE
levels include parasitic infection, allergic broncho-
pulmonary aspergillosis, allergic asthma, several
inherited immunodeficiencies, eosinophilic granu-
lomatosis with polyangiitis, and Hodgkins lym-
phoma. The patients normal level of aspergillus-
specific IgE and the negative result on aspergillus
skin testing rule out allergic bronchopulmonary
aspergillosis. Stool examination is insensitive for
the detection of strongyloides; however, the
negative test for strongyloides antibody is incon-

n engl j med 377;5 nejm.org August 3, 2017 481

The New England Journal of Medicine
Downloaded from nejm.org on August 2, 2017. For personal use only. No other uses without permission.
Copyright 2017 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
sistent with the diagnosis. The patients clinical
presentation and biopsy results are most consis-
tent with a diagnosis of eosinophilic granuloma-
tosis with polyangiitis, although she does not
currently appear to have extrapulmonary mani-
festations of the disease. Glucocorticoid therapy
is indicated, and a test for latent tuberculosis in-
fection would be recommended before the treat-
ment is started.
The patient received a diagnosis of eosinophilic
granulomatosis with polyangiitis and was started
on 60 mg of prednisone daily. The results of a
purified protein derivative skin test were negative.
She was discharged home and seen in clinic 3 days
later, where she reported resolution of dyspnea
and wheezing. Her absolute peripheral eosinophil
count at this visit was 1630 per microliter (as com-
pared with 10,990 per microliter at presentation)
and transiently decreased to a level within normal
limits 2 weeks later. However, within a few weeks
her eosinophil count became elevated again. Aza-
thioprine was started, initially at a dose of 100 mg
daily. During the next month, the dose was in-
creased to 150 mg daily as a slow tapering of pred-
nisone was initiated. Prednisone treatment was
discontinued after 13 months. Eighteen months
after receiving her diagnosis, the patient contin-
ued to do well while taking 150 mg of azathio-
prine daily.
C om men ta r y
The patient presented with an atopic history and
symptoms and signs of asthma, but her symptoms
progressed despite appropriate step-up therapy.
Her marked peripheral-blood eosinophilia and
pulmonary consolidations put allergic broncho-
pulmonary aspergillosis high on the differential
diagnosis. The working group of the International
Society for Human and Animal Mycology has pub-
lished diagnostic criteria in which either skin-
test positivity for aspergillus or detectable levels
of IgE against Aspergillus fumigatus must be pres-
ent to make a diagnosis of allergic bronchopul-
monary aspergillosis.1 This patient had negative
test results on both counts.
Wedge biopsy of the lung showed airway
changes related to asthma, eosinophilic pneu-
monia, and eosinophilic vasculitis with areas of
infarction that were consistent with eosinophilic
482 n engl j med 377;5nejm.org August 3, 2017
The New England Journal of Medicine
Downloaded from nejm.org on August 2, 2017. For personal use only. No other uses without permission.
Copyright 2017 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
granulomatosis with polyangiitis. The American
College of Rheumatology has established that
eosinophilic granulomatosis with polyangiitis is
probable when four of the following six criteria
are present: asthma, peripheral eosinophilia great-
er than 10% on the differential white-cell count,
mononeuropathy (including mononeuropathy mul-
tiplex) or polyneuropathy, migratory or transient
radiographic pulmonary opacities, paranasal sinus
abnormality, and extravascular eosinophil infiltra-
tion on biopsy.2 In a study involving 20 patients
with eosinophilic granulomatosis with polyangi-
itis and 787 control patients with other forms of
vasculitis, the presence of four or more of the six
criteria yielded a sensitivity of 85% and a speci-
ficity of 99.7% for the diagnosis of this condi-
tion.2 The initial presentation in patients with
eosinophilic granulomatosis with polyangiitis of-
ten includes symptoms resembling those of asth-
ma, allergic rhinitis, and atopic disease. Subse-
quent phases of the syndrome are characterized
by peripheral-blood eosinophilia and eosinophilic
infiltration of the organs, followed by necrotizing
vasculitis of small and medium-sized vessels with
granuloma formation.
In addition to pulmonary disease, the major
manifestations of eosinophilic granulomatosis
with polyangiitis include peripheral neuropathy,
skin lesions, cardiomyopathy, and involvement
of the ear, nose, and throat.3 Other manifestations
can include eosinophilic gastroenteritis, peritoni-
tis, or colitis, necrotizing glomerulonephritis, hy-
pertension, and venous thromboembolic disease.4
A long-term follow-up study of a cohort of
101 patients with eosinophilic granulomatosis
with polyangiitis showed that 80% of patients
had a first remission but that 81% had relapse
over a median follow-up of 6 years.5 Overall sur-
vival was 93% over the same median follow-up
period.5 The five-factor score which is based
on an age greater than 65 years, cardiac symp-
toms, gastrointestinal involvement, renal insuf-
ficiency, and the absence of symptoms related to
the ear, nose, and throat (one point for each
factor, for five points in total) has been used
to predict prognosis at the time of diagnosis.6,7
In a study involving 1108 consecutive patients,
scores of 0, 1, and 2 or higher were associated
with respective 5-year mortality rates of 9%, 21%,
and 40%.7 ANCA positivity, present in approxi-
mately 40% of patients with eosinophilic granu-
 Clinical Problem-Solving

lomatosis with polyangiitis, may also correlate
with disease manifestations and prognosis.8 In
one study, patients with positive test results for
ANCAs were more likely to have manifestations
related to the ear, nose, and throat, peripheral
neuropathy, and renal involvement but less likely
to have cardiac manifestations than patients with
negative results for ANCAs.3 In that study, pa-
tients with ANCA positivity were also more
likely to have a relapse of vasculitis.3 In another
study, ANCA positivity was not related to a higher
rate of relapse but was associated with more se-
vere disease, including the presence of mono-
neuritis and renal involvement.5
Glucocorticoids are considered to be the first-
line therapy for eosinophilic granulomatosis with
polyangiitis.4 Cyclophosphamide can be added to
the treatment regimen when patients have a re-
lapse or as an adjuvant therapy when there is
substantial vasculitic end-organ involvement.4
Azathioprine is typically used after the induction
of remission with cyclophosphamide or as a
glucocorticoid-sparing agent in patients requir-
ing long-term treatment with prednisone at a
dose of 15 mg per day or more.4 Case reports and
series have described improvement after interven-
tions including plasma exchange or the admin-
istration of intravenous immune globulin or of
rituximab, an anti-CD20 monoclonal antibody
that is licensed for the treatment of granuloma-
tosis with polyangiitis and microscopic polyan-
giitis.3-5 The use of omalizumab, a monoclonal
antibody that inhibits IgE binding to the IgE re-
ceptor on mast cells and basophils, has also been
associated with the abatement of symptoms of
asthma, a decrease in eosinophilia, and reduction
in requirements for glucocorticoids in patients
with eosinophilic granulomatosis with polyangi-
itis and moderate-to-severe asthma.9 Mepolizu
mab, an inhibitor of interleukin 5 (a driver of
eosinophilic inflammation), was associated with
a significantly lower frequency of asthma exacer-
bations than placebo in a randomized trial of
patients with severe eosinophilic asthma.10 Re-
cently, in a multicenter phase 3 trial involving
mepolizumab in patients with eosinophilic gran-
ulomatosis with polyangiitis, mepolizumab was
associated with a remission of longer duration
than placebo, and a higher proportion of patients
receiving mepolizumab had remission.11
Eosinophilic granulomatosis with polyangi-
itis can be clinically indistinguishable from se-
vere asthma. This observation was exemplified
in a case series of patients with glucocorticoid-
dependent asthma who received zafirlukast, a
cysteinylleukotriene type 1 receptor antagonist.
As glucocorticoids were withdrawn, eosinophilic
granulomatosis with polyangiitis developed.12 The
syndrome improved with the discontinuation of
zafirlukast and the reinitiation of glucocorticoids
or the addition of cyclophosphamide.12
The present case underscores the importance
of considering alternative diagnoses when appro-
priate treatment for an initially diagnosed condi-
tion does not result in improvement. In patients
with a diagnosis of asthma who do not have a
response to step-up therapy and who are adherent
to their medication regimen, an asthma-plus
syndrome, such as eosinophilic granulomatosis
with polyangiitis, allergic bronchopulmonary as-
pergillosis, or strongyloidiasis should be consid-
ered, particularly in patients with eosinophilia.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

References
1. Agarwal R, Chakrabarti A, Shah A, et
al. Allergic bronchopulmonary aspergil-
losis: review of literature and proposal of
new diagnostic and classification criteria.
Clin Exp Allergy 2013;43:850-73.
2. Masi AT, Hunder GG, Lie JT, et al. The
American College of Rheumatology 1990
criteria for the classification of Churg-
Strauss syndrome (allergic granulomato-
sis and angiitis). Arthritis Rheum 1990;
33:1094-100.
3. Comarmond C, Pagnoux C, Khellaf
M, et al. Eosinophilic granulomatosis
with polyangiitis (Churg-Strauss): clinical
characteristics and long-term followup of
the 383 patients enrolled in the French
Vasculitis Study Group cohort. Arthritis
Rheum 2013;65:270-81.
4. Noth I, Strek ME, Leff AR. Churg-
Strauss syndrome. Lancet 2003;361:587-
94.
5. Durel CA, Berthiller J, Caboni S, Jayne
D, Ninet J, Hot A. Long-term followup of
a multicenter cohort of 101 patients with
eosinophilic granulomatosis with polyan-
giitis (Churg-Strauss). Arthritis Care Res
(Hoboken) 2016;68:374-87.
6. Guillevin L, Lhote F, Gayraud M, et al.
Prognostic factors in polyarteritis nodosa
and Churg-Strauss syndrome: a prospec-
tive study in 342 patients. Medicine (Bal-
timore) 1996;75:17-28.
7. Guillevin L, Pagnoux C, Seror R,
Mahr A, Mouthon L, Le Toumelin P. The
Five-Factor Score revisited: assessment of
prognoses of systemic necrotizing vascu-
litides based on the French Vasculitis
Study Group (FVSG) cohort. Medicine
(Baltimore) 2011;90:19-27.
8. Sinico RA, Di Toma L, Maggiore U, et
al. Prevalence and clinical significance of
antineutrophil cytoplasmic antibodies in

n engl j med 377;5nejm.org August 3, 2017 483

The New England Journal of Medicine
Downloaded from nejm.org on August 2, 2017. For personal use only. No other uses without permission.
Copyright 2017 Massachusetts Medical Society. All rights reserved.
 Clinical Problem-Solving

Churg-Strauss syndrome. Arthritis Rheum
2005;52:2926-35.
9. Detoraki A, Di Capua L, Varricchi G,
Genovese A, Marone G, Spadaro G. Omal-
izumab in patients with eosinophilic gran-
ulomatosis with polyangiitis: a 36-month
follow-up study. J Asthma 2016;53:201-6.
10. Ortega HG, Liu MC, Pavord ID, et al.
Mepolizumab treatment in patients with
severe eosinophilic asthma. N Engl J Med
2014;371:1198-207.
11. Wechsler ME, Akuthota P, Jayne D, et
al. Mepolizumab or placebo for eosino-
philic granulomatosis with polyangiitis.
N Engl J Med 2017;376:1921-32.
12. Wechsler ME, Garpestad E, Flier SR,
et al. Pulmonary infiltrates, eosinophilia,
and cardiomyopathy following corticoste-
roid withdrawal in patients with asthma
receiving zafirlukast. JAMA 1998;279:455-
7.
Copyright 2017 Massachusetts Medical Society.

484 n engl j med 377;5nejm.org August 3, 2017

The New England Journal of Medicine

Downloaded from nejm.org on August 2, 2017. For personal use only. No other uses without permission.
Copyright 2017 Massachusetts Medical Society. All rights reserved.