A comparative and descriptive study of asthma in chronic

rhinosinusitis with nasal polyps

Kre Hkansson, M.D.,1 Simon Francis Thomsen, M.D., Ph.D.,2, Lars Konge, M.D., Ph.D.,3
Jann Mortensen, M.D., D.M.Sci.,4 Vibeke Backer, M.D., D.M.Sci.,3
and Christian von Buchwald, M.D., D.M.Sci.1

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ABSTRACT

Background: Chronic rhinosinusitis (CRS) is a common health problem that is subclassified as CRS with nasal polyps (CRSwNPs) or CRS without NPs
(CRSsNP). In accordance with the united airways concept, CRSwNPs frequently coexists with asthma but to date, this association remains unexplained and
its strength is uncertain. Here, we aimed to examine the association between CRSwNPs and asthma in collaboration between the neighboring specialities:
otorhinolaryngology and respiratory medicine.
Methods: A prospective clinical study was performed comprising 40 CRS patients scheduled for functional endoscopic sinus surgery and 21 control
persons. We performed nasal endoscopy, peak expiratory flow, spirometry, and bronchodilation tests. In selected cases, additional pulmonary tests were
performed. Atopy was assessed by skin-prick test or by measuring specific IgE in serum.
Results: Asthma was diagnosed in 26 patients with CRSwNPs (65%; odds ratio 5.9 [1.79, 19.65]; p 0.003), and 5 control persons (24%). Twenty-five
percent of the CRSwNP patients had undiagnosed asthma. Atopy was not significantly associated with CRSwNPs (p 0.39) or with coexisting asthma within
the CRSwNP group (p 0.50).
Conclusion: Compared with previous studies, we found a very high prevalence of asthma and, frequently, asthma was undiagnosed. Furthermore,
CRSwNPs was associated with chronic bronchitis and, in those with asthma, lower airway obstruction. These results call for a closer collaboration between
otorhinolaryngology and respiratory medicine in relation to patients with CRSwNPs, in research as well as in clinical practice.
(Am J Rhinol Allergy 28, 383387, 2014; doi: 10.2500/ajra.2014.28.4076)

hronic rhinosinusitis with nasal polyps (CRSwNPs) is a prevalent chronic disease that affects 24% of the population.1,2 It is
associated with significant medical costs and has an impact on general health.3 It has been linked with asthma repeatedly; however, the
cause of the association is unexplained and its strength remains
uncertain. Studies have reported that 2060% of CRSwNP patients
have coexisting asthma.421 However, some of these studies did not
meet international guidelines for the diagnosis of asthma and most
did not include controls. Additionally, some were based on highly
selected populations (e.g., in allergy clinics), whereas others did not
discriminate between CRSwNPs and CRS without NPs (CRSsNPs).
The pathogenetic mechanism behind coexisting asthma and CRS is
currently unknown. Clearly, the united airways concept applies, not
only to allergic respiratory diseases, but to a broad spectrum of
respiratory conditions including CRS.22,23 Inflammation of the upper
and lower airways may arise from the simultaneous exposure to the
same pathogens such as Staphylococcus aureus enterotoxins,6 biofilms,24 and other environmental factors (e.g., smoking).23 Alternatively, lower airway inflammation may be triggered through a systemic response or as a result of changes in the composition of the
inspired air (dry, cold, and nitric oxide depleted) caused by nasal
obstruction and, subsequently, mouth breathing.2528

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From the 1Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark, 2Department of Respiratory Medicine L, Bispebjerg Hospital and University of Copenhagen,
Copenhagen, Denmark, 3Center for Clinical Education, University of Copenhagen and
the Capital Region of Denmark, Copenhagen, Denmark, and 4Department of Clinical
Physiology, Nuclear Medicine and PET, Rigshospitalet and University of Copenhagen,
Copenhagen, Denmark
Funded by Candys Foundation and relge Hans Skovbys og Hustru Emma Skovbys
Foundation
The authors have no conflicts of interest to declare pertaining to this article
Address correspondence to Kre Hkansson, M.D., Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet and Faculty of Health and
Medical Sciences, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark
E-mail address: kaare.haakansson@regionh.dk
Copyright 2014, OceanSide Publications, Inc., U.S.A.

American Journal of Rhinology & Allergy

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In collaboration between the Departments of Otorhinolaryngology

and Respiratory Medicine in Copenhagen, we aimed to investigate
the prevalence of asthma in CRSwNPs. This is the first prospective
study of CRSwNPs and associated lower airway disease that includes
both standardized methods for upper and lower airway evaluation as
well as a control group.

MATERIALS AND METHODS

CRSwNP patients were consecutively included during June 2011
January 2013 at the Department of Otorhinolaryngology, Head and
Neck Surgery and Audiology, Copenhagen University Hospital. In
relation to CRSwNPs, our department serves as a secondary care
center. All CRSwNP patients lived in or around Copenhagen and
were referred for functional endoscopic sinus surgery; patients were
included irrespective of former surgery. All patients had been treated
according to guidelines with nasal steroids and saline irrigations for
3 months without recovery.
The control group comprised consecutively included patients undergoing nasal septal surgery and/or turbinate reduction.
We aimed to match the control and CRSwNP groups by age.
Exclusion criteria were age 18 years or 80 years; systemic steroids
3 months before inclusion; severe psychiatric disorders; need for
interpreter; pregnancy or nursing; immunodeficiencies; sarcoidosis,
cystic fibrosis, or primary ciliary dyskinesia; systemic vasculitis; unstable cardiovascular disease; dysregulated diabetes; forced expiratory volume in the 1st second (FEV1) 0.5 L; and thrombocytopenia
or International Normalized Ratio of 1.5.
The study was conducted in accordance with the Declaration of
Helsinki and was approved by the Ethics Committee of Copenhagen
County (H-B-2008-106).

Questionnaire
Participants completed a general questionnaire about nasal and
pulmonary symptoms, smoking, and nonsteroidal anti-inflammatory
drug sensitivity (see Appendix). Nasal symptoms were assessed using a visual analog scale (VAS); lower airway symptoms were assessed by the miniAsthma Quality-Of-Life Questionnaire (miniAQLQ).29

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Objective Measurements

Table 1 Lung disease in CRSwNP patients and controls

Upper Airway Disease. Nasal endoscopy was performed by a specialist in otorhinolaryngology and CRS was diagnosed and graded
according to the European Position Paper on Rhinosinusitis and
Nasal Polyps criteria.3 Biopsy specimens from all CRSwNP patients
underwent histological examination to exclude other pathologies.
Our protocol did not include an assessment of eosinophilic inflammationa defining feature in most European CRSwNP patients.30
Computed tomography scans were performed systematically before
surgery.
Lower Airway Disease. Peak expiratory flow (PEF) was recorded at
home before spirometry (Pocketpeak; nSpire Health, Longmont, CO)
and a 2-week day-to-day FEV1 variation of 20% was considered
abnormal.
Spirometry before and after inhalation of 4 puffs of 100 g of
salbutamol (Airomir; Teva, Petah Tiqwa, Israel) pressurized metereddose inhaler with spacer (NES-spacer; AstraZeneca, London, U.K.)
was performed using maximum flow volume curves according to the
standards specified by the European Respiratory Society and American Thoracic Society.31,32 Positive reversibility was defined as a 200
mL and 12% increase in FEV1 after 2-agonist. Participants were
asked not to take their 2-agonist in the morning before spirometry.
In four cases, a course of prednisolone was given for 10 days with
subsequent repetition of spirometry and reversibility to differentiate
chronic obstructive pulmonary disease (COPD) from asthma.

CRSwNPs
Controls

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Lower
Airway Disease

11
(27.5%)
14
(66.7%)

29*
(72.5%)
7#
(33.3%)

p 0.006

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The p value was calculated for the distribution of lung disease (asthma and
COPD) between groups.
*Twenty-six cases of asthma and three cases of COPD.
#Five cases of asthma and two cases of COPD.
CRSwNPs chronic rhinosinusitis with nasal polyps; COPD chronic
obstructive pulmonary disease.

Allergy

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A skin-prick test (SPT) was performed with a panel of 10 allergen

extracts including birch, grass, mugwort, horse, cat, dog, Dermatophagoides pteronyssinus, and Dermatophagoides farinae, Alternaria, and Cladosporium herbarum (ALK Abello, Hrsholm, Denmark). A mean
wheal diameter of 3 mm was considered positive. In cases of dermographism or continued antihistamine intake (n 3), specific immunoglobulin E (IgE) to the SPT panel was measured on the ImmunoCAP 250 system (Thermo Fisher/former Phadia, Freiburg,
Germany). Atopy was defined as a positive SPT or positive specific
IgE to 1 or more of the 10 allergens.
Aspirin-exacerbated respiratory disease (e.g., Samters triad) was
defined as a positive answer to question 1 in combination with
CRSwNPs and asthma (see Appendix).36

Bronchial Challenge
Dry-powder mannitol (Aridol; Pharmaxis, Sydney, Australia) was
administered according to the manufacturers recommendations. A
positive challenge response was defined as a decrease in FEV1 of at
least 15% after inhalation of 635 mg of mannitol or less.33 For methacholine, a Morgan nebulizer generated the aerosols of the test solution. The response was measured by determining FEV1 2 minutes
after each inhalation. A positive challenge response was defined as a
decrease in FEV 1 of at least 20% after inhalation of 7.8 mol of
methacholine or less.
In accordance with the Global Initiative for Asthma guidelines,
bronchodilator tests and day-to-day variation in PEF were recorded
systematically along with respiratory symptoms suggestive of asthma
(i.e., cough, shortness of breath, wheezing, and chest tightness).34 We
performed additional tests if PEF variation was the only objective sign
of asthma or if lower airway disease was persistently suspected for
other reasons despite reversibility of 12% (marked symptoms and
airway obstruction). In this way, we based the diagnosis of asthma on
current respiratory symptoms and at least one positive objective
diagnostic test suggestive of asthma: reversibility to 2-agonist or
prednisolone or a positive bronchial challenge. In patients who were
taking asthma medication but in whom the spirometry was normal,
the medical file including similar testing was studied to confirm the
initial diagnosis. Tobacco consumption was recorded, and patients
were classified as never smokers, exsmokers, or smokers; the average
number of pack years was calculated for both smokers and exsmokers
([average number of cigarettes per day years]/20).
Based on the questionnaire, lung function tests, and smoking history, a specialist diagnosed lower airway disease. Asthma was categorized as (1) intermittent, (2) mild persistent, (3) moderate persistent,
or (4) severe persistent according to Global Initiative for Asthma
guidelines.35 COPD was defined according to the Global Initiative for
Chronic Obstructive Lung Disease criteria (postbronchodilator FEV1/
forced vital capacity, 70%). Chronic bronchitis was diagnosed from
question 5b (see Appendix). The evaluator was not blinded throughout the study; however, intraobserver variation was assessed by a
blinded reevaluation of 19 CRS cases mixed with 21 first-time evaluations of controls.

Lower
Airway Disease

Statistics

The statistical package SPSS Version 19.0 (IBM, Chicago, IL) was
used for the analysis. Pearsons chi-square or Fishers exact test was
applied for categorical variables according to expected cell counts in
contingency tables. Students t-test was used for normally distributed
continuous variables; Mann Whitney U test was used for nonparametric data. Finally, intraobserver agreement was assessed by Cohens -coefficient. We considered a value of p 0.05 statistically
significant. PEF variability data were log transformed before analysis.
Data were missing on asthma severity (n 1), pack years (n 1),
miniAQLQ (n 1), VAS (n 5), and spirometry (n 1).

RESULTS
We included 21 controls and 40 CRS patients. In CRSwNP patients,
the asthma diagnosis was based on reversibility and PEF (n 10),
patient history (n 8), bronchial challenge (n 6), and course of
prednisolone (n 2). In controls, the asthma diagnosis was based
on reversibility and PEF (n 4) and bronchial challenge (n 1).
Tables 1 and 2 show patient characteristics.

Lower Airway Disease

Twenty-six patients with CRSwNPs (65%, odds ratio [OR] 5.9
[1.79, 19.65]; p 0.003) had asthma compared with five controls (24%;
Table 2). Undiagnosed asthma was found in 10 CRSwNP patients
(25%) and 3 controls (14%). Thus the relative risk of undiagnosed
asthma in the CRSwNP group was not significantly increased (relative risk 1.75 [0.54, 5.68]). In the CRSwNPs with asthma group, 12%
(n 3) had intermittent asthma; 19% (n 5) had mild persistent
asthma; 39% (n 10) had moderate persistent asthma, and 27% (n
7) had severe persistent asthma. In the CRSwNPs with asthma group,
46% (12/26) showed positive reversibility compared with 80% (4/5)
of the controls with asthma. Only CRSwNP patients with asthma
showed significantly lower FEV1/forced vital capacity ratios (percent

SeptemberOctober 2014, Vol. 28, No. 5

Table 2 Group characteristics

Sex (male, %)
Age (yr), mean (minmax)
Asthma (%)
Previous asthma diagnosis (%)
Current asthma medication (%)
COPD (%)
Chronic bronchitis (%)
Pack years, median (minmax)
Atopy (%)
VAS, median (minmax)
Total miniAQLQ, median (min-max)
Endoscopy score, median (minmax)

CRSwNPs (n 40)

Controls (n 21)

p Value

70
51.1 (2578)
65
47.5
47.5
7.5
42.5
5 (051)
37.5
7.6 (0.79.7)
6.5 (2.37.0)
6 (210)

71.4
43.5 (2071)
23.8
14.3
0
9.5
9.5
2 (030)
23.8
2.1 (08.3)
6.8 (3.07.0)
0

1.0
0.21
0.01
0.01
0.001
1.0
0.01
0.93
0.39
0.001
0.001
0.001

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CRSwNPs chronic rhinosinusitis with nasal polyps; COPD chronic obstructive pulmonary disease; VAS visual analogue scale (higher scores indicate
worse QoL); miniAQLQ miniasthma quality-of-life questionnaire (score from 1 to 7, lower scores indicate worse QoL); QoL quality of life; mun
minimum; max maximum.

Table 3 Group means and between-group analyses

CRSwNPs

Age
(minmax)
FEV1 predicted
(minmax)
FVC predicted
(minmax)
FEV1/FVC predicted
(minmax)
Reversibility (%)
(minmax)
Reversibility (mL)
(minmax)
PEF variation (%)
(minmax)
PEF variation (L/min)
(minmax)
VAS (median)
(minmax)
Total miniAQLQ (median)
(minmax)

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Controls

Asthma
n 26

No asthma
n 11

52.2
(2578)
92.3*
(62130)
104.9
(79143)
90.4#
(67108)
10.4#
(1228)
282
(320570)
24.5
(666)
93
(25240)
7.4
(0.79.5)
6.4
(3.76.9)

49.6
(2768)
108.2
(84123)
110.8
(83136)
101.3
(89112)
4.6
(510)
179
(150360)
19.9
(1033)
84
(40200)
7.6
(3.59.7)
6.7
(5.57.0)

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Asthma
n5

No asthma
n 14

43
(2067)
98.8
(81113)
108.7
(93121)
94.0
(88104)
11.5*
(416)
396*
(120580)
40.3#
(2167)
121
(90220)
1.6
(0.56.6)
6.8
(3.06.8)

42.6
(2271)
108.6
(88126)
107.1
(85123)
103.7
(98112)
3.7
(38)
173
(70370)
19.6
(942)
90
(30180)
3.2
(08.3)
6.9
(6.67.0)

All tests against nonasthmatic controls. Patients with COPD were excluded.
*Students t-test shows significant difference (p 0.05).
#Students - test with p 0.01.
MannWhitney U test with p 0.05.
Mann-Whitney U test with p 0.01.
FEV1 forced expiratory volume in the 1st s; FVC forced vital capacity; PEF peak expiratory flow; min minumum; max maximum; CRSwNPs
chronic rhinosinusitis with nasal polyps; miniAQLQ miniasthma quality-of-life questionnaire; COPD chronic obstructive pulmonary disease; VAS
visual analog scale.

predicted) compared with controls (p 0.001); spirometric data are

listed in Table 3. All asthmatic patients had late-onset asthma (after
the age of 16 years), except one, (mean age, 45 years; range, 1470
years).9 Four CRSwNP patients had Samters triad (10%).
Sex and smoking habits were matched between groups, whereas
age was not (mean, 52 and 44 years, respectively). Thus, the median
number of pack years (Table 2) as well as the percentage of former/
active smokers (data not shown) was similar in the two groups.
Accordingly, no difference in the prevalence of COPD was found.
Chronic bronchitis, on the other hand, was significantly associated

American Journal of Rhinology & Allergy

with CRSwNPs (p 0.007) but not with asthma (p 0.16) or smoking

(p 0.17) within the CRSwNP group.
Intraobserver agreement between the first and second lower airway
evaluation was achieved in 15 of 19 patients ( 0.65; p 0.001).

Atopy
Atopy was not significantly associated with CRSwNPs. However,
we found more atopy among CRSwNP patients (38%) compared with
controls (23%; p 0.28). Atopy was not associated with coexisting

385

asthma within the CRSwNP group (OR 1.83 [0.45, 7.41]; p 0.50).
Furthermore, no association was found between CRSwNPs and sensitization to any specific aeroallergen.

Quality of Life and VAS

In comparison with nonasthmatic controls, CRSwNP patients
scored significantly lower in the miniAQLQ questionnaire irrespective of asthma. Within the control group, we found significantly lower
miniAQLQ scores in asthmatic patients (p 0.01); a similar tendency
was seen within the CRSwNP group (p 0.12). CRSwNP patients
showed higher VAS and endoscopy scores, but neither of these were
associated with asthma (p 0.66 and p 0.14, respectively).

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DISCUSSION
Asthma was diagnosed in 65% of the CRSwNP patients; 25% had
undiagnosed asthma. Furthermore, CRSwNPs was associated with
chronic bronchitis and, in those with asthma, lower airway obstruction. Atopy was not significantly associated with CRSwNPs or coexisting asthma.
Previous studies of the prevalence of lower airway disease in
CRSwNPs have shown conflicting results and have been characterized by varying degrees of clinical evidence. In contrast to many of
these previous studies, we evaluated the lower airways according to
international guidelines; a respiratory physician evaluated lower airway disease, and controls were included.
Asthma often stays unrecognized; nevertheless, it was surprising
that 25% of the CRSwNP patients had undiagnosed and untreated
asthma.37 This calls for a closer collaboration between otorhinolaryngology and respiratory medicine, in research as well as in clinical
practice.
Our findings are important for a number of reasons. CRSwNPs is
associated with a significant reduction in general quality of life (QoL),
and this reduction is attributed to nasal obstruction, nasal secretion,
loss of smell, and facial pressure.38 However, QoL may be further
decreased by unrecognized asthma.39 In this study we showed that
CRSwNPs, irrespective of asthma status, was associated with a significant reduction in miniAQLQ scores, and more so in asthmatic
patients compared with nonasthmatic patients. Moreover, we found
that 66% of the asthmatic CRSwNP patients had moderate-to-severe
persistent asthma, which, in fact, is less than previously reported.40
These findings suggest that asthma independently affects the QoL in
CRSwNP patients; however, upper and lower airway symptoms and
their relative impacts on the QoL are difficult to distinguish, even in
disease-specific QoL schemes such as the miniAQLQ. Second, sufficient and systematic treatment of the bronchial tree could ameliorate
QoL in these patientsas a result of reduced pulmonary symptoms,
but potentially also through a reduction in systemic inflammation
that, in turn, could improve nasal disease control.41 Finally, our
findings suggest that many patients with CRSwNPs undergo surgery
and general anesthesia with unrecognized and untreated asthma.
Twenty-four percent of our control persons had asthma and 19%
showed positive reversibility; thus, our control group did not represent the background population. In comparison, a study of the Swedish background population (n 3088; age, 4773 years) showed that
24% had positive reversibility.42 The high asthma prevalence among
controls in our study probably was caused by selection biasit is
known that asthma patients often experience nasal symptoms and in
some, such symptoms could have led to surgery.9 As a consequence,
we might have underestimated ORs and risk estimates, and in future
studies we recommend using controls without upper airway symptoms.
Similarly, selection bias might have exaggerated the prevalence of
asthma in the CRSwNP group and if so, our results only apply to
other secondary centers. The asthma prevalence in CRSwNPs outside
hospitals is largely unknown.14,18 Williamson et al.14 found that 70% of
a primary care CRSwNP population had either asthma or asymptom-

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386

atic airway inflammation and Johansson et al.18 found no difference in

the prevalence of self-reported asthma inside or outside of hospitals.
Accordingly, we believe that the high asthma prevalence in our
CRSwNP group is less shaped by selection bias.
We found an association between CRSwNPs and chronic bronchitis
independent of asthma, which, to our knowledge, has not been reported before. This association could indicate that the nasal discharge
characteristic of CRSwNPs is mirrored by sputum production in the
lower airways or, alternatively, productive cough could be a result of
postnasal dripping.
A high prevalence of atopy has been reported in some CRSwNP
populations43,44 but not in others.45 In addition, anti-IgE treatment has
recently shown efficacy in CRSwNP patients.46 However, selection
bias might explain the high prevalence of atopy previously reported
and the effect of anti-IgE was independent of atopic status. We found
no association between atopy, CRSwNPs, and coexisting asthma.
Instead, we found asthma in CRSwNPs to be characterized by late
onset, which is in line with previous reports.44
Study limitations include, first, a larger sample size that would
have given a more accurate estimate of the asthma prevalence in this
patient population and for this reason, we have reported ORs with
confidence intervals to give transparency to the reader. Second, age
was not successfully matched between the CRSwNP group and controls. All pulmonary data, however, are reported in percent of predicted and thus are adjusted for age, height, and sex. Third, participants discontinued nasal steroids 34 weeks before spirometry,
whereas asthma medication was uninterrupted. This could have improved spirometric data in patients taking asthma medication (only
CRSwNP patients). Fourth, we report that 10% of the CRSwNP patients had Samters triad. This is in agreement with previous studies8,45,47; however, we did not perform a bronchial challenge test with
acetylsalicylic acid, which is considered the gold standard. Finally,
a single physician performed the evaluation of lower airway disease
but because the intraobserver agreement was substantial, we did not
include an additional rater.
To date, this is the most rigorous study of the association between
CRSwNPs and lower airway disease and we found a very high
prevalence of asthma. Therefore, in accordance with the united airways concept, asthma should always be suspected in CRSwNP patients undergoing functional endoscopic sinus surgery.

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APPENDIX
1. Did you ever experience symptoms from the nose, lungs, or skin
when exposed to nonsteroidal anti-inflammatory drug?
2a. Do you smoke? Yes (more than one cigarette, cheroot, cigar, or
pipe of tobacco a day); yes (less than one cigarette, cheroot, cigar,
or pipe of tobacco a day); or no.
2b. Are you a former smoker? Yes (more than one cigarette, cheroot,
cigar, or pipe of tobacco a day); yes (less than one cigarette,
cheroot, cigar, or pipe of tobacco a day); or no.
2c. How many years have you been smoking?
3b. Have you ever taken medicine for asthma? Yes or no.
3c. If yes, could you please list name and dose?
4a. During the day or night, during the last 4 weeks have you
experienced wheezing? No; less than once a week; more than
once a week but less than once a day; daily; or yes continuously.
4b. During the day or night, during the last 4 weeks have you
experienced chest tightness? No; less than once a week; more
than once a week but less than once a day; daily; or yes continuously.
4c. During the day or night, during the last 4 weeks have you
experienced breathlessness? No; less than once a week; more
than once a week but less than once a day; daily; or yes continuously.
4d. During the day or night, during the last 4 weeks have you
experienced coughing? No; less than once a week; more than
once a week but less than once a day; daily; or yes continuously.

SeptemberOctober 2014, Vol. 28, No. 5

20.

5a. Do you have asthma? Yes or no.

5b. Do you normally have a productive cough (in the morning
and/or during the day) on most days over a minimum of 3
mo/yr and occurring over the last 2 years? Yes or no.

ACKNOWLEDGMENTS

21.

22.

The authors acknowledge Candys Foundation and relge Hans

Skoubys og Hustru Emma Skoubys Foundation for supporting their
work. Both of these are nonprofit organization and neither have been
involved in the conception, execution, interpretation, or publication
strategy of this study. They would also like to acknowledge Carol
Bang-Christensen for linguistic correction.

23.
24.

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