Asthma in ear, nose, and throat primary care patients with

chronic rhinosinusitis with nasal polyps

Martin Frendø, M.D.,1 Kåre Håkansson, M.D., Ph.D.,1 Susanne Schwer, M.D.,2 Iben Rix, M.D.,1
Andreas T. Ravn, M.D.,3 Vibeke Backer, M.D., D.M.Sci.,4 and Christian von Buchwald, M.D., D.M.Sci.1

ABSTRACT

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Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory disorder associated with asthma. This association is well

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described in patients with CRSwNP undergoing endoscopic sinus surgery (ESS); however, some patients are never referred for surgery, and the frequency of
asthma in this group is largely unknown.
Objective: To determine the frequency of asthma in patients with CRSwNP treated in a primary care (PC) setting who have never been referred for surgery
and to compare this with ESS patients.
Methods: Fifty-seven patients with CRSwNP who had never undergone ESS were prospectively recruited from nine PC ear, nose, and throat clinics in

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the Copenhagen area. CRSwNP was diagnosed according to the European Position Paper on Chronic Rhinosinusitis and Nasal Polyps; severity was assessed
by using a visual analog scale. Allergy, lung function, and asthma tests (reversibility to ␤2-agonist, peak expiratory flow variability, and mannitol challenge)
were performed. Findings were compared with our previously published data from patients with CRSwNP referred for surgery.
Results: Asthma was diagnosed in 25 patients (44%) based on respiratory symptoms and a positive asthma test; of these, 12 (48%) had undiagnosed asthma

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prior to study onset. Furthermore, when using the same methods, we found a lower frequency of asthma in PC patients compared with ESS patients (44%
versus 65%, p ⫽ 0.04).
Conclusion: A high prevalence of asthma in PC patients with CRSwNP was found. Frequently, asthma was undiagnosed. However, asthma was
significantly less prevalent in PC patients compared with patients referred for ESS. The frequent concomitance of asthma, i.e., united airways disease, in PC
patients calls for closer collaboration between ear, nose, and throat specialists, and asthma specialists.

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(Am J Rhinol Allergy 30, e67–e71, 2016; doi: 10.2500/ajra.2016.30.4304)

C hronic rhinosinusitis with nasal polyps (CRSwNP) is a common

chronic disorder among adults, with a prevalence of 2–4%.1 It is
defined as an inflammatory disease of the nasal and sinus mucosa
CRSwNP referred for ESS and report a very high prevalence of
asthma (65%) in this group.26 However, an association between the
severity of nasal disease and the prevalence of asthma has been

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that causes varying degrees of nasal obstruction, secretion, loss of
smell, and headache for ⬎12 weeks.2 It is generally accepted that
upper and lower airway disease frequently coexists in both allergic
and nonallergic airway disease, a concept known as “the united
shown.6 Therefore, higher frequency of asthma could be hypothe-
sized in patients in SC, and this could have resulted in selection bias
in the majority of previous studies that concern asthma frequency in
CRSwNP, including our own previous study.26

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airways.”3,4 Results of a number of studies show a high prevalence of
asthma (20–90%) in patients with CRSwNP.5–28 However, most stud-
ies are from secondary care (SC) settings, i.e., hospitals, and included
mainly patients referred for endoscopic sinus surgery (ESS). In addi-
tion, few studies are based on comprehensive and standardized
asthma evaluation in accordance with international criteria; some
In Denmark, the majority of patients with CRSwNP are managed in
primary care (PC) ear, nose, and throat (ENT) clinics run by ENT
specialists; there are ⬃150 ENT clinics in Denmark, which has a
population of 5.6 million. These clinics serve as PC clinics and provide
direct and free access; however, ESS with the patient under general
anesthesia is not normally offered. Instead, recalcitrant patients with

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studies included highly selected patient groups (e.g., from an allergy
clinic), whereas other studies did not discriminate between CRSwNP
and chronic rhinosinusitis without nasal polyps. Consequently, the
prevalence of asthma in patients with CRSwNP never referred for ESS
remains largely unknown.16,20 The asthma prevalence in Denmark is
CRSwNP are referred for ESS to an SC ENT unit. In this study, we
examined patients from the PC sector who were never referred for
ESS and compared the resulting data with previously published data
on patients in SC from the same geographic area by using similar
criteria and methods.26 To our knowledge, this is the first study to use

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7–10% in the general population, thus similar to that of other indus- standardized clinical evaluation to assess the association between
trialized countries.29,30 We recently studied patients in SC with upper and lower airway disease in patients with CRSwNP in PC
never referred for ESS.

From the 1Department of Otorhinolaryngology, Head and Neck Surgery and Audiol-
ogy, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark, 2Susanne
Schwer Øre-Næse-Halsklinik, Valby, Copenhagen, Denmark, 3Frederiksberg Øre-
Næse-Halsklinik, Frederiksberg, Copenhagen, Denmark, and 4Department of Respira-
tory Medicine L, Bispebjerg Hospital and University of Copenhagen, Copenhagen,
Denmark
Support was received from Pharmaxis Ltd., Sydney, Australia. This study was funded
by the nonprofit foundations Danish Regional Collaboration of Specialists Foundation
(“Fonden for Faglig Udvikling af Speciallægepraksis”) and Lundbeck Foundation
(“Lundbeckfonden”). None of these entities was involved in the conception, execution,
interpretation, or publication strategy of this study
Preliminary results were presented at the 25th Congress of the European Rhinologic
Society, Amsterdam, Netherlands, June 22–26, 2014
Address correspondence to Martin Frendø, M.D., 2072, Blegdamsvej 9, 2100, Copen-
hagen, Denmark
E-mail address: martin.frendoe-soerensen.01@regionh.dk
Copyright © 2016, OceanSide Publications, Inc., U.S.A.
METHODS
This was a prospective observational study. Qualifying patients were
consecutively recruited from nine PC ENT clinics in the Capital Region
of Denmark from December 2013 to December 2014. All the participants
lived in the Copenhagen area and were treated with topical nasal steroid
according to the European Position Paper on Chronic Rhinosinusitis and
Nasal Polyps.2 Patients were offered participation in the study based on
clinical history and objective findings. Before inclusion, nasal endoscopy
was performed by an ENT specialist.
Inclusion criteria were patients, ages 18–80 years old, who met the
European Position Paper on Chronic Rhinosinusitis and Nasal Polyps
criteria for CRSwNP.2 Exclusion criteria were previous or planned ESS,
immunodeficiency, cystic fibrosis or primary ciliary dyskinesia, the need
for linguistic interpreter, systemic steroid treatment within the preceding

American Journal of Rhinology & Allergy e67

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Table 1 Group means of PC patients*#
Asthma (n ⴝ 25)
Age (min-max), y 51.8 (27–72)
FEV1 predicted (min-max), % 92.4 (56–120)
FVC predicted (min-max), % 109.0 (72–137)
FEV1:FVC predicted (min-max) 88.2 (68–104)
Reversibility (min-max), % 7.8 (⫺6.7 to 28.6)
Reversibility (min-max), mL 217 (⫺210 to 620)
PEF variation (min-max), % 28.7 (8–82)
PEF variation (min-max), L/min 103 (30–180)
VAS, median (min-max) 5.4 (0.2–9.5)
BMI, median (min-max) 24.8 (19.1–33.1)
PC ⫽ primary care; COPD ⫽ chronic obstructive pulmonary disease; min ⫽ minimum; max ⫽ maximum; FEV1 ⫽ forced expiratory volume in 1 second;
FVC ⫽ forced vital capacity; PEF ⫽ peak expiratory flow; VAS ⫽ visual analog scale (higher scores indicate worse nasal symptoms); BMI ⫽ body mass index.
*Data on patients in secondary care were previously reported.
#Four patients with COPD were not included in this table.
3 months, upper respiratory tract infection within the preceding 2 weeks,
nonwhite descent, pregnancy, or nursing.
Asthma and allergy testing was performed over two visits. Skin-
prick test, spirometry, and ␤2-agonist reversibility test were per-
formed at the first visit. At the second visit, 2 weeks later, a mannitol
challenge test was performed and peak expiratory flow measure-
ments were collected. This study was conducted in accordance with
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the Declaration of Helsinki and was approved by the ethics commit-
tee of the Copenhagen Capital Region (H-2-2013–015).
Diagnosis of Asthma
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Pulmonary testing was carried out at the Research Department of
Respiratory Medicine, Bispebjerg University Hospital, Copenhagen,
by the first author (M.F.); respiratory disease was diagnosed by a
senior respiratory physician (V.B.) with extensive experience in clin-
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ical diagnosis of asthma and chronic obstructive pulmonary disease
(COPD) as well as research. After testing, the participants filled out a
questionnaire. Asthma was diagnosed in accordance with the Global
Initiative for Asthma guidelines as the presence of respiratory symp-
toms and a positive asthma test, i.e., reversibility toward ␤2-agonist,
day-to-day variation in peak expiratory flow, or airway hyperrespon-
siveness to inhaled mannitol.27
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Questionnaire
The participants completed a questionnaire on medical history,
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general health, nasal and pulmonary symptoms, height, weight, non-
steroidal anti-inflammatory drug sensitivity, and medication use. Na-
sal symptoms were evaluated by using a visual analog scale (VAS).
Objective Measurements for Asthma and Allergy
The patients were instructed not to use ␤2-agonists or antihista-
mines on the days of the examination, whereas inhaled corticoste-
roids were allowed.
Peak Flow and Spirometry. Lung function was assessed by spirometry
(EasyOne Spirometer; ndd Medical Technologies, Zurich, Switzer-
land) before and after inhalation of four puffs of 0.5 mg terbutalin
sulfate (Bricanyl Turbuhaler; AstraZeneca, London, U.K.). A positive
reversibility test was defined as a 200-mL and ⬎12% increase in
forced expiratory volume in 1 second (FEV1) after ␤2-agonist. Peak
expiratory flow was measured at home by using a mechanical peak
flow meter (Pocketpeak; nSpire Health, Longmont, CO) twice daily
for 14 consecutive days; significant day-to-day variation was defined
as at least 100 L/min.
Bronchial Challenge. A bronchial challenge test with dry-powder
mannitol (Aridol; Pharmaxis, Sydney, Australia) was performed.
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No asthma or COPD (n ⴝ 28) p Value
45.0 (23–71) 0.07
96.2 (52–116) 0.36
106.6 (74–130) 0.57
92.7 (63–107) 0.10
4.1 (⫺1.7 to 8.6) 0.14
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139 (⫺80 to 350) 0.27
17.5 (0–48) 0.01
85 (0–210) 0.17
4.3 (0–7.9) 0.17
P
24.2 (18.7–34.2) 0.40
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FEV1 was measured 60 seconds after each dose; a decrease in FEV1 of
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at least 15% after inhalation of 635 mg of mannitol or less was
considered a positive challenge response.28
Allergy. A skin-prick test was performed with a panel of 10 aller-
gens as well as a positive and negative control according to interna-
tional recommendations.29 The allergens were as follows: birch, grass,
mugwort, horse, cat, dog, Dermatophagoides pteronyssinus and Der-
matophagoides farinae, Alternaria, and Cladosporium herbarum (ALK
Abello, Hørsholm, Denmark). All skin-prick tests were conducted
and interpreted by the first author (M.F.). A wheal diameter of ⬎3
mm was considered positive. Atopy was defined as a positive skin-
prick test response to any of the 10 allergens with a positive skin
reaction to histamine. A diagnosis of aspirin-exacerbated respiratory
disease was based on a history of symptoms from nose, lungs, or skin
when exposed to nonsteroidal anti-inflammatory drugs.
Statistics
The statistical package IBM SPSS Version 22 (IBM, Chicago, IL) was
used. For categorical variables, we used the Pearson ␹2 test or the
Fisher exact test, depending on the minimum cell counts in contin-
gency tables. We used the Student’s t-test for normally distributed
data, the Mann Whitney U test for nonparametric data, and Shapiro-
Wilk test to assess normal distribution of data. Data were missing on
pack-years (n ⫽ 3), reversibility test (n ⫽ 3), VAS (n ⫽ 9), and peak
expiratory flow variation (n ⫽ 9). A p value of ⬍0.05 was considered
statistically significant.
RESULTS
Fifty-seven patients participated; 25 (44%) had asthma and 4 (7%)
had COPD. Group characteristics and lung function parameters for
the PC patients are presented in Table 1. In Tables 2 and 3, group
characteristics and the prevalence of lower airway disease are com-
pared with previously published data from patients in SC.
Lower Airway Disease
Twenty-nine PC patients reported asthma or had symptoms sug-
gestive of asthma. Asthma was confirmed in 25 of these (44% of the
included patients), and 12 of these (48%) had undiagnosed asthma
before the study (Table 2). Apart from peak flow variation and
prevalence of hyperresponsiveness to mannitol, no significant differ-
ences in lung function were found between patients with asthma and
patients without asthma (Table 1). COPD was diagnosed in four
patients (7%), whereas aspirin-exacerbated respiratory disease (i.e.,
Samter triad) was found in three (5%).
May–June 2016, Vol. 30, No. 3
Table 2 Group characteristics, patients in the PC and patients in the SC groups
PC Group (n ⴝ 57) SC Group (n ⴝ 40) p Value
Sex, % men 70.2 70.0 0.99
Age, mean (min-max), y 49.3 (23–72) 51.1 (25–78) 0.53
Previous asthma diagnosis, % 29.8 47.5 0.08
COPD, % 7.0 7.5 1.0
Pack-years, median (min-max) 0.0 (0–60) 5.0 (0–51) 0.59

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Atopy, % 31.6 37.5 0.56
VAS, median (min-max) 4.9 (0–9.5) 7.6 (0.7–9.7) ⬍0.01
BMI, median (min-max), kg/m2 24.3 (18.7–34.2) 24.4 (20.2–32.3) 0.91
Asthma, % 43.9 65.0 0.04

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PC ⫽ primary care; SC ⫽ secondary care; min ⫽ minimum; max ⫽ maximum; COPD ⫽ chronic obstructive pulmonary disease; VAS ⫽ visual analog scale
(representing severity of nasal symptoms; higher scores indicate worse quality of life); BMI ⫽ body mass index.

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Table 3 Lower airway disease in patients with CRSwNP in PC almost half of these were undiagnosed, which indicated that asthma
and in SC is often overlooked. Second, asthma was significantly less prevalent
in PC compared with patients in SC, which indicated that those with
Patients – Lower Airway ⴙ Lower Airway more severe upper airway disease more frequently have lower airway
Disease, no. (%) Disease, no. (%) disease. However, nasal symptoms (i.e., VAS score) were not signif-

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In PC 28 (49.1) 29 (50.9)* p ⫽ 0.03# icantly associated with asthma in PC patients. Our results showed
In SC 11 (27.5) 29 (72.5)§ that, even in PC patients never referred for ESS, asthma was common
CRSwNP ⫽ chronic rhinosinusitis with nasal polyps; PC ⫽ primary care; and that the need for ESS may be a predictor for asthma. Furthermore,
SC ⫽ secondary care; COPD ⫽ chronic obstructive pulmonary disease. self-reported asthma was not reliable when assessing airway disease
*Twenty-five cases of asthma and four cases of COPD. in patients with CRSwNP because asthma is often underdiagnosed.30

#Calculated for the prevalence of lower airway disease between the groups.
*§Twenty-six cases of asthma and three cases of COPD.
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Most studies in this area included only patients in SC referred for
ESS. Consequently, little is known about the prevalence of asthma in
the large group of patients with CRSwNP in PC who have never
undergone ESS. Few studies investigated the frequency of asthma in

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In comparison with previously reported data on patients in SC, no
significant difference was found for age, sex, COPD, atopy (Table 2),
or frequency of self-reported asthma. The prevalence of lower airway
disease in the PC group was 51% and thus significantly lower than in
patients outside hospitals. In a Scottish study by Williamson et al.16
from a rhinology clinic that comprised 57 patients who were non-
smokers, asthma was found in 39% of these patients, which is in
agreement with our findings. However, no standardized asthma cri-
teria were used. Furthermore, 27% of the enrolled patients had pre-

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the SC group (73%, p ⫽ 0.03) (Table 3). Also, asthma was found to be
significantly less prevalent in the PC group (44% versus 65%; p ⫽
0.04) (Table 2).
Atopy
Atopy was found in 18 PC patients (32%) and was neither signifi-
viously undergone ESS.31
A questionnaire-based study by Johansson et al.1,20 examined the
frequency of self-reported asthma symptoms in patients with
CRSwNP recruited either outside hospitals (32% [n ⫽ 38]) or in an SC
unit (36% [n ⫽ 44]); no significant difference was reported. In contrast,
we found a significant difference in asthma prevalence between the

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cantly associated with coexisting asthma (p ⫽ 0.15) nor with sensiti-
zation to a specific allergen. In comparison with the patients in SC,
there was no significant difference in the prevalence of atopy (p ⫽
0.56) (Table 2).
PC and SC groups. In comparison with the studies by Williamson et
al.16 and Johansson et al.,1,20 we found a slightly higher prevalence of
asthma in PC patients. However, methodologic differences among
these and other studies of asthma in patients with CRSwNP are

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VAS
The median VAS score was 4.9 in PC patients and thus significantly
lower than in the SC group (7.6; p ⬍ 0.01). VAS scores were neither
associated with asthma within the PC group (p ⫽ 0.17), nor when
pooling the patients for the PC and SC groups (p ⫽ 0.28).
Body Mass Index (BMI) and obesity
BMI (weight 关kg兴/height2 关m兴) was not correlated to asthma within
the PC group (p ⫽ 0.40; Table 1), nor was there a difference in BMI or
obesity (defined as BMI ⱖ 30) between PC and SC patients (p ⫽ 0.91;
Table 2; p ⫽ 1.0).35 Obesity was found in 10% of PC patients and was
not significantly associated with asthma (p ⫽ 0.29).
DISCUSSION
This, to our knowledge, is the first study of asthma frequency in
patients with CRSwNP in PC to use objective criteria for both upper
and lower airway disease and asthma evaluation by a respiratory
specialist. First, we found that 44% of PC patients had asthma and
substantial; in future research, standardized, international criteria for
asthma should be used.
Our findings indicated that, in both PC and SC units, lower airway
inflammation is much more prevalent in patients with CRSwNP than
in the background population. However, despite the frequent coex-
istence of CRSwNP and asthma, neither the European Position Paper
on Chronic Rhinosinusitis and Nasal Polyps2 nor the American Acad-
emy of Otolaryngology—Head and Neck Surgery provide specific
treatment guidelines for patients with coexisting CRSwNP and
asthma.32,33
Numerous hypotheses concerning the pathophysiologic link be-
tween upper and lower airway inflammation have been proposed. A
recent study from our own research group found significantly higher
levels of inflammation in the nasal polyps compared with the bronchi
of the same patients. These findings indicated that the nasal polyps
could be a driver of airway inflammation rather than a secondary
phenomenon in CRSwNP.34 If so, this may explain why patients in
SC, who, in this study, showed higher levels of nasal symptoms,
indicative of more severe upper airway inflammation, also have
higher levels of lower airway inflammation, i.e., asthma.

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 Our results are important for a number of reasons. The high fre-
quency of undiagnosed asthma in PC patients calls for closer collab-
oration between ENTs and respiratory specialists because unrecog-
nized asthma reduces quality of life in these patients.35 In addition,
recent research indicates that patients with chronic rhinosinusitis and
concomitant asthma are more likely to experience delayed surgical
intervention, which may worsen long-term clinical outcomes.36–38
Therefore, early multidisciplinary diagnosis and treatment of the
united airways are needed. Furthermore, future studies should take
into account the difference in lower airway disease between PC
patients and patients in SC because results from one sector may have
limited validity in the other sector.
Our study was limited by the number of participants and observa-
tions. A larger number of patients and objective data on nasal disease
severity (e.g. endoscopy scores) could elucidate potential differences
within and between groups.44,45 Also, selection bias may affect our
results: patients with CRSwNP and with symptoms of asthma may
have been more likely to participate in the study, which led to
possible overestimation of asthma frequency. Conversely, patients
who had already undergone asthma evaluation may have been less
inclined to participate, which caused the opposite effect. Also, a
control group would have further validated our findings.
CONCLUSION
Results of the present study indicated that asthma was common
and frequently undiagnosed in patients with CRSwNP, regardless of
health care sector; however, asthma was more prevalent in patients
selected and referred for ESS compared with PC patients.
ACKNOWLEDGMENTS
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We thank PC ENT specialists Anders Schermacker, Anne-Louise
Reventlow-Mourier, Bo Huniche, Jeanne Rungby, Jesper Micheelsen,
Leif Hahn, Samih Charabi, and Torben Boesen for patient referrals.
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