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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
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

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

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

cough. Approximately 75% of patients with asth- 1
ma receive a diagnosis before they reach 7 years 0
of age, but asthma may develop at any age. A
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
of pulmonary-function testing to document air-
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

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Clinical Problem-Solving

adrenergic agonist bronchodilator. A short-act- There is evidence of ongoing airflow obstruction

ing beta-adrenergic agonist bronchodilator was on examination. Although signs of allergy are
also prescribed for rescue from acute symp- absent on examination, an allergic cause for the
toms. Her symptoms escalated and later did not patients symptoms cannot be ruled out. It may
respond to the addition of a leukotriene modifier be helpful to obtain a peripheral eosinophil count
and a long-acting anticholinergic bronchodilator. to screen for airway and other allergic disorders
She presented again, 6 months after her initial characterized by type 2 inflammation, such as ec-
presentation, with cough, shortness of breath, zema, allergic conjunctivitis, and allergic rhinitis.
and wheezing.
The electrolyte count was within normal limits.
Medication adherence should be addressed given The level of blood urea nitrogen was 8 mg per
the inadequate control of symptoms after the ini- deciliter (3 mmol per liter), and the creatinine
tiation of appropriate step-up therapy for asthma. level was 0.79 mg per deciliter (69.8 mol per liter).
Direct observation during a clinic visit can be help- The white-cell count was 20,730 per cubic millime-
ful to determine whether patients need instruc- ter, with 53% eosinophils (reference range, 0 to 5).
tion on the proper use of inhalers. If adherence The hemoglobin level, hematocrit, and platelet
is confirmed, clinicians should consider alterna- count were normal. Tests for antinuclear antibod-
tive diagnoses, such as strongyloidiasis or allergic ies and antineutrophil cytoplasmic antibodies
bronchopulmonary aspergillosis. In addition to (ANCAs) were negative. The erythrocyte sedimen-
cough, shortness of breath, and wheezing, patients tation rate was 31 mm per hour (reference range,
with strongyloidiasis may have urticaria or pru- 0 to 18), and the C-reactive protein level was 41.7 mg
ritus as well as diarrhea, nausea, and vomiting. per liter (reference range, 0 to 3.0).
Patients with allergic bronchopulmonary asper-
gillosis typically present with recurrent asthma The striking new information regarding the pa-
exacerbations, but they may also have fever, a tient is her prominent peripheral eosinophilia.
productive cough, or even hemoptysis. There are several categories of disease associated
with eosinophilia: infectious (particularly with
On physical examination, the temperature was invasive helminths), respiratory (e.g., asthma and
37.0C, the pulse 69 beats per minute, the blood eosinophilic pneumonia), gastrointestinal (e.g., eo-
pressure 108/57 mm Hg, the respiratory rate 18 sinophilic gastroenteritis), allergic (e.g., allergic
breaths per minute, and the oxygen saturation bronchopulmonary aspergillosis, eczema, and
97% while breathing ambient air. The patient ap- asthma), inflammatory vascular (e.g., eosino-
peared anxious and uncomfortable but was not in philic granulomatosis with polyangiitis, previ-
acute respiratory distress. The conjunctiva appeared ously known as the ChurgStrauss syndrome),
normal. There was no oropharyngeal erythema or and malignant (e.g., leukemia and lymphoma).
edema. The nasopharyngeal mucosa appeared nor- Other possibilities include adrenal insufficiency
mal. The sinuses showed no tenderness to palpa- and idiopathic hypereosinophilic syndrome. The
tion, and there was no discharge. There were no patients presenting symptoms, diagnosis of asth-
allergic shiners (swelling and darkening of the ma refractory to treatment, and now prominent
skin under the eyes), and there was no lymphade- peripheral eosinophilia are suggestive of stron-
nopathy. Pulmonary examination was notable for gyloidiasis, allergic bronchopulmonary aspergil-
a prolonged expiratory phase with mild expirato- losis, chronic eosinophilic pneumonia, or eosino-
ry wheezing in both lungs. There were no inspira- philic granulomatosis with polyangiitis.
tory crackles, egophony, tactile fremitus, or dull- Allergic bronchopulmonary aspergillosis is
ness to percussion in either lung. The results of an allergic pulmonary disorder caused by a hyper-
cardiac and abdominal examinations were nor- sensitivity response to aspergillus. Chronic eosin-
mal. The jugular venous pressure was not elevat- ophilic pneumonia is characterized by cough,
ed. There was no clubbing, cyanosis, or edema of progressive dyspnea, peripheral eosinophilia, and
the arms and legs. The cranial nerves, motor the presence of peripheral opacities in both lungs
strength, sensation, and gait were normal. There on chest imaging. Eosinophilic granulomatosis
was no skin rash or erythema. with polyangiitis is a vasculitis of small and

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

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Clinical Problem-Solving



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

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sistent with the diagnosis. The patients clinical granulomatosis with polyangiitis. The American
presentation and biopsy results are most consis- College of Rheumatology has established that
tent with a diagnosis of eosinophilic granuloma- eosinophilic granulomatosis with polyangiitis is
tosis with polyangiitis, although she does not probable when four of the following six criteria
currently appear to have extrapulmonary mani- are present: asthma, peripheral eosinophilia great-
festations of the disease. Glucocorticoid therapy er than 10% on the differential white-cell count,
is indicated, and a test for latent tuberculosis in- mononeuropathy (including mononeuropathy mul-
fection would be recommended before the treat- tiplex) or polyneuropathy, migratory or transient
ment is started. radiographic pulmonary opacities, paranasal sinus
abnormality, and extravascular eosinophil infiltra-
The patient received a diagnosis of eosinophilic tion on biopsy.2 In a study involving 20 patients
granulomatosis with polyangiitis and was started with eosinophilic granulomatosis with polyangi-
on 60 mg of prednisone daily. The results of a itis and 787 control patients with other forms of
purified protein derivative skin test were negative. vasculitis, the presence of four or more of the six
She was discharged home and seen in clinic 3 days criteria yielded a sensitivity of 85% and a speci-
later, where she reported resolution of dyspnea ficity of 99.7% for the diagnosis of this condi-
and wheezing. Her absolute peripheral eosinophil tion.2 The initial presentation in patients with
count at this visit was 1630 per microliter (as com- eosinophilic granulomatosis with polyangiitis of-
pared with 10,990 per microliter at presentation) ten includes symptoms resembling those of asth-
and transiently decreased to a level within normal ma, allergic rhinitis, and atopic disease. Subse-
limits 2 weeks later. However, within a few weeks quent phases of the syndrome are characterized
her eosinophil count became elevated again. Aza- by peripheral-blood eosinophilia and eosinophilic
thioprine was started, initially at a dose of 100 mg infiltration of the organs, followed by necrotizing
daily. During the next month, the dose was in- vasculitis of small and medium-sized vessels with
creased to 150 mg daily as a slow tapering of pred- granuloma formation.
nisone was initiated. Prednisone treatment was In addition to pulmonary disease, the major
discontinued after 13 months. Eighteen months manifestations of eosinophilic granulomatosis
after receiving her diagnosis, the patient contin- with polyangiitis include peripheral neuropathy,
ued to do well while taking 150 mg of azathio- skin lesions, cardiomyopathy, and involvement
prine daily. of the ear, nose, and throat.3 Other manifestations
can include eosinophilic gastroenteritis, peritoni-
tis, or colitis, necrotizing glomerulonephritis, hy-
C om men ta r y
pertension, and venous thromboembolic disease.4
The patient presented with an atopic history and A long-term follow-up study of a cohort of
symptoms and signs of asthma, but her symptoms 101 patients with eosinophilic granulomatosis
progressed despite appropriate step-up therapy. with polyangiitis showed that 80% of patients
Her marked peripheral-blood eosinophilia and had a first remission but that 81% had relapse
pulmonary consolidations put allergic broncho- over a median follow-up of 6 years.5 Overall sur-
pulmonary aspergillosis high on the differential vival was 93% over the same median follow-up
diagnosis. The working group of the International period.5 The five-factor score which is based
Society for Human and Animal Mycology has pub- on an age greater than 65 years, cardiac symp-
lished diagnostic criteria in which either skin- toms, gastrointestinal involvement, renal insuf-
test positivity for aspergillus or detectable levels ficiency, and the absence of symptoms related to
of IgE against Aspergillus fumigatus must be pres- the ear, nose, and throat (one point for each
ent to make a diagnosis of allergic bronchopul- factor, for five points in total) has been used
monary aspergillosis.1 This patient had negative to predict prognosis at the time of diagnosis.6,7
test results on both counts. In a study involving 1108 consecutive patients,
Wedge biopsy of the lung showed airway scores of 0, 1, and 2 or higher were associated
changes related to asthma, eosinophilic pneu- with respective 5-year mortality rates of 9%, 21%,
monia, and eosinophilic vasculitis with areas of and 40%.7 ANCA positivity, present in approxi-
infarction that were consistent with eosinophilic mately 40% of patients with eosinophilic granu-

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Clinical Problem-Solving

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

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

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Clinical Problem-Solving

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

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