Respiratory Medicine (2011) 105, 195e203

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/rmed

Dyspnea perception in asthma: Role of airways

inflammation, age and emotional status
Maria P. Foschino Barbaro a, Donato Lacedonia a, Grazia P. Palladino a,
Laura Bergantino a, Cinzia Ruggeri a, Domenico Martinelli b,
Giovanna E. Carpagnano a,*

a
Institute of Respiratory Disease, Department of Medical and Occupational Sciences, University of Foggia,
Ospedale Colonnello D’Avanzo, Via degli Aviatori 1, 71100 Foggia, Italy
b
Department of Medical Sciences, Section of Hygiene, University of Foggia, Apulia Regional Epidemiological Observatory,
Italy

Received 5 July 2010; accepted 11 September 2010

Available online 20 October 2010

KEYWORDS Summary
Asthma; Objectives: Dyspnea perception in asthmatics differs between subjects. Poor perception is usually
Airways inflammation; associated with increased risk of asthma attack/exacerbation. The advanced stage of the disease
Dyspnea; and the presence of eosinophilic airways inflammation have been recently recognized as being
Perception; responsible for poor dyspnea perception. However, few studies are available on this topic.
Breath condensate Design: The aim of this study was to analyse the influence of inflammatory pattern, age and affec-
tive status on dyspnea perception in asthmatic subjects.
Subjects and interventions: Seventy-one consecutive asthmatic patients were recruited and
underwent induced sputum, exhaled NO measurement and breath condensate collection. Percep-
tion of dyspnea was evaluated as a BORGeVAS/FEV1 slope before and after the broncho-reversibility
test and correlated with the stage of asthma, inflammatory markers, age and depression scale.
Results: Dyspnea perception decreases with the worsening of asthma, with the advance of age and
of depression status. Furthermore, airways inflammation plays a key role in the decline of dyspnea
perception as proved by the negative correlation observed between inflammatory cells in sputum,
exhaled pH and NO and BORGeVAS/FEV1 slope.
Conclusions: The results of our study suggested that airways inflammation, depression status,
advance age and severity of asthma influence dyspnea perception and suggest a straight control
to identify and better manage poor preceptor asthmatics.
ª 2010 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: þ39 0881733143; fax: þ39 0881733158.

E-mail address: ge.carpagnano@unifg.it (G.E. Carpagnano).

0954-6111/$ - see front matter ª 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.rmed.2010.09.013
196
Introduction
Dyspnea is a multidimensional, subjective perception of
breathing difficulty commonly seen in patients affected by
respiratory diseases.1 In recent years several studies have
explored the correlation between dyspnea and the degree
of airways obstruction in asthmatics using measurement
tools including both one-dimensional and multidimen-
sional scales that measure changes in the perception of
dyspnea.1
The perception of airway narrowing seems to be reduced
in subjects with severe asthma and seems to be associated
with an increased risk of asthma attack/exacerbation.2e4
Also inflammatory activity within the airways of asth-
matic subjects could explain differences in dyspnea
perception.5e7 In particularly, the eosinophilia in sputum
and bronchial biopsies seems to affect dyspnea perception
in severe asthmatics and has been suggested as an indicator
of clinical instability.8
Consequently markers of inflammation more than hyper-
responsiveness testing to different agonists are needed to
give more insight into this issue9 and could be of clinical
importance to identify patients who are likely to have
a poor perception of symptoms3 and could help in advanced
practice roles to successfully manage these patients.1
Another possibility is that subjects become cortically
less sensitive to the peripheral signals of dyspnea with
increasing age.9 Familiarity with this symptom may lead to
desensitization.9 Age was previously associated with the
perception of bronchoconstriction in COPD and in asthma
but results are contrasting.10e12
The progression of chronic diseases (such as asthma) is
often associated with a progression of depression status13
and could increase perceived dyspnea.14,15 Affective
states can profoundly impact upon the perception of
dyspnea, but little is known about this relationship in
patients with airways obstruction.16
Study design
In the present study we carried out an in-depth study of the
influence of inflammatory pattern, age and affective state
on dyspnea perception.
With this aim in mind we analysed the perception of
dyspnea evaluated as BORGeVAS/FEV1 slope in asthmatic
subjects before and after the broncho-reversibility test and
correlated them with some markers of airways inflamma-
tion (sputum inflammatory cell count, exhaled nitric oxide
(NO) and pH), age and depression status.
Material and method
Subjects
Seventy-one consecutive asthmatic patients
(49.4  0.23.2 yr) were recruited to the study from the
outpatient facility of the Institute of Respiratory Disease of
the University of Foggia, Italy. Written informed consent
was obtained from all subjects, and the study was approved
by the institutional ethics committee.
M.P. Foschino Barbaro et al.
All the subjects enrolled in the study were non-smokers and
had no bronchial or respiratory tract infection, clinically
significant psychiatric disease, other cardio-respiratory
diseases or any severe exacerbation of asthma that had
resulted in hospitalization in the month before the entrance
test. All asthmatics were assessed at a period of stability of at
least 4 weeks. 20 subjects exhibited mild intermittent asthma,
20 exhibited mild persistent asthma, 20 moderate asthma and
finally 11 severe asthma. Asthmatic patients were treated
according to GINA guidelines.17 Severity of asthma was
assessed on the basis of clinical (diurnal/nocturnal symptoms)
and functional parameters (FEV1 and PEF variability). Mild
intermittent asthmatics were not receiving any medication on
a regular basis, but they did use an inhaled b2-agonist, as
needed, for symptom relief. Mild persistent asthmatics were
given therapy with low inhaled corticosteroids (equivalent to
<500 mg BDP) regularly. Persistent moderate asthmatics were
treated as baseline medications with medium doses of inhaled
corticosteroids (equivalent to 200e500 mg BDP) and LABA,
while severe asthmatics with high doses of inhaled cortico-
steroids (equivalent 500e1000 mg BDP) and LABA. At the first
visit (visit 1) a physical examination, including body mass index
(BMI) measurement, atopy assessment, BORG and VAS, beck
depression scale, exhaled NO measurement and spirometry
with bronchial obstruction reversibility test. After 3 days from
first visit (visit 2) subjects underwent breath condensate
collection followed by sputum induction.
Perception of airway dilatation
The perception of airway dilatation was measured before and
after the reversibility challenge. After 20 min from salbutamol
inhalation (400 mg) but before the measurement of spiro-
metric function each subject was asked “how does your
dyspnea feel right now?” and used a modified BORG scale18,19
and a VAS scale. The slope and intercept of the regression of
BORG score and VAS score and the percent increase in FEV1
were calculated for each subject. Individual BORG/FEV1, VAS/
FEV1 slopes and intercept values were used to calculate the
perception increase at 12% (or 200 ml) increase in FEV1.20
Subjects were asked to rate subjective quantification of
the sensation of breathlessness on a visual analogue scale
(VAS) and BORG scale. The relationship between changes in
VAS/BORG value and the increase in FEV1 as a percentage
of the baseline value was analysed by determining the
linear regression slope between the two parameters and
indicates the perception of airways obstruction.
Atopic status
A skin prick test (SPT) was performed for a panel of inhalant
allergens as previously described21 for common aero-
allergens (Lofarma, Italy).
Lung function
Forced expiratory volume in 1 s (FEV1) and forced vital
capacity (FVC) were measured using a spirometer (Sensor-
medics, USA). The best value of three maneuvers was
expressed as a percentage of the predicted normal value.
After baseline evaluation, spirometry was repeated 15 min
Dyspnea perception in asthma 197

Jaeger, Wurzburg, Germany). Subjects breathed through

a mouthpiece and a two-way non-rebreathing valve, which
also served as a saliva trap. They were asked to breathe at
a normal frequency and at tidal volume, wearing a nose clip,
for a period of 10 min. Subjects were instructed to swallow
any saliva they felt in their mouth. At least 1 ml of condensate
was collected as ice at 20  C, transferred to Eppendorf
tubes and stored at 80  C immediately. Samples were
stored for not more than 2 months before analysis. Amylase
concentration was measured in all samples to exclude any
salivary contamination.

Exhaled pH measurement

A stable pH was achieved in all cases after deaeration/

decarbonation of breath condensate specimens by bubbling
with argon (350 ml/min) for 10 min, as previously repor-
ted.22 pH was then measured within 15 min of condensate
collection by means of a pH meter (Jenway-350, Ltd
Gransmore Green, England) with a 0.00e14.00 pH range
and a resolution/accuracy on the order of 0.01  0.02 pH.
The reproducibility of the repeated measurements of pH
was confirmed by the Bland and Altman test and by the
variation coefficient.23,24

Measurement of exhaled NO

A rapid-response chemiluminescence NO analyzer (NIOX) was

Figure 1 Dyspnea perception (BORG/FEV1) slope in severe
compared to mild-moderate asthma patients (panel A); dysp-
nea perception (VAS/FEV1) slope in severe compared to mild-
moderate asthma patients (panel B).
after the subjects had inhaled 400 mg of salbutamol.
Reversibility of airways obstruction was expressed in terms
of the percent changes from baseline of the forced expi-
ratory volume in 1 s (FEV1).
Exhaled breath condensate
The exhaled breath condensate was collected using
a condenser which allowed for the non-invasive collection of
the non-gaseous components of the expired air (EcoScreen,
used to quantify oxides of nitrogen (NOs). Two-point cali-
brations were performed daily using 5.2-parts per million
calibration gas. Exhaled NO (FENO) was measured using
a previously described restricted breath technique, which
employed expiratory resistance and positive mouth pressure
to close the velum and exclude nasal NO, and a constant
expiratory flow of 45 mL/s. Subjects inhaled to total lung
capacity, and exhaled while targeting a constant pressure of
20 mm Hg. Exhalations proceeded until a clear NO plateau of
at least 3 s duration was achieved. Repeated exhalations were
performed until the three plateaus agreed within 5%.25,26
Sputum induction and analysis
According to the method described by Spanevello et al.
sputum was induced through inhalation of hypertonic saline

Table 1 Anthropometric and functional data of asthmatic patients.

Mild intermittent asthma Mild persistent asthma Moderate asthma Severe asthma
Subjets (F) 11/20 12/20 11/20 8/11
AGE (yr) 47.3  3.2 48.2  3.5 51.1  3.9 53.2  3.4
Atopy 16/20 15/20 13/20 0/11
FEV1 (%) 92.4  4.6*,^^ 88.3  4.5*,^^ 71.7  3.5 44.7  4.5
FVC (%) 102.6  4.9*,^ 97.5  3.2*,^ 88.5  4.6 60.5  4.6
FEV1/FVC (%) 89.2  3.3*,^ 75.2  3.5*,^ 68.3  2.7 63.8  4.7
BMI (Kg/m2) 27.5  1.3 27.3  0.9 26.9  0.6 28.2  1.6
*p < 0.05 Mild intermittent asthma and Mild persistent asthma vs Moderate asthma.
^p < 0.05 Mild intermittent asthma vs severe asthma.

p < 0.05 Moderate asthma vs Severe asthma.

p < 0.01 Moderate asthma vs Severe asthma.
^^p < 0.01.
198 M.P. Foschino Barbaro et al.

Table 2 Comparison between BORGeVAS/FEV1 slope and asthma stage.

Mean DS 95% CI
Slope BORG
Stable-moderate 0.15 0.1403527 0.19 0.11 p Z 0.0002
Severe 0.25 0.1110409 0.30 0.21
Slope VAS
Stable-moderate 1.29 1.07 1.6 0.98 p < 0.0001
Severe 2.76 1.30 3.29 2.23

Figure 2 Correlation between dyspnea perception (BORG/FEV1) slope and variables analysed.
Dyspnea perception in asthma 199

Figure 3 Correlation between dyspnea perception (VAS/FEV1) slope and variables analysed.

Table 3 Correlation between BORG/FEV1 slope and solution (4.5%) with an ultrasonic nebulizer (DeVilbiss 65;
variables. DeVilbiss Corporation, Somerset, PA) and analysed after
selection of plug.27 Nine asthmatics were not able to
BORG/FEV1 Rho p
produce adequate sputum samples (defined as containing
Asthma stage 0.4452 0.0001 at least 500 non-squamous cells and their expectorates
Sputum neutrophils 0.3887 0.0008 were discharged).
Sputum eosinophils 0.2692 0.0232
Exhaled pH 0.4547 0.0001
Exhaled NO 0.4311 0.0002 Statistical analysis
Beck 0.2639 0.0261
Age 0.4004 0.0006 BORG and VAS scores of all subjects were plotted against
FEV1. The slope, representing an index of dyspnea8 was
200 M.P. Foschino Barbaro et al.

In patient affected by mild-moderate asthma, a negative

Table 4 Correlation between VAS/FEV1 slope and
correlation was observed between the increased percep-
variables.
tion of dyspnea (measured as slope VAS/FEV1 and slope
VAS/FEV1 Rho p BORG/FEV1) and percentage of eosinophils in sputum
Asthma stage 0.5012 <0.0001 (r Z 0.51; p < 0.005 and r Z 0.61; p < 0.001), BECK
Sputum neutrophils 0.5555 <0.0001 (r Z 0.5; p < 0.001 and r Z 0.3; p < 0.05), NO
Sputum eosinophils 0.2875 0.0151 (r Z 0.4; p < 0.05 and r Z 0.6; p < 0.001) and age
Exhaled pH 0.5773 <0.0001 (r Z 0.3; p < 0.05 and r Z 0.3; p < 0.05) while was
Exhaled NO 0.3313 0.0048 positive with exhaled pH (r Z 0.45; p < 0.05 and r Z 0.36;
Beck 0.2737 0.0209 p < 0.05) (Tables 5 and 6).
Age 0.4076 0.0005 In patient affected by severe asthma, a negative
correlation was observed between the increased percep-
tion of dyspnea (measured as slope BORG/FEV1), and
calculated by linear regression analysis. Differences of percentage of neutrophils in sputum (r Z 0.585;
Borg/FEV1 (mm-% increase FEV1) and VAS/FEV1 (mm-% p < 0.001 and r Z 0.49; p < 0.005) (Tables 5 and 6).
increase FEV1) slopes between the groups were analysed by The regression model showed that BORG/FEV1 is asso-
ManneWhitney test. Correlation between data was ciated with sputum neutrophils, VAS/FEV1 with sputum
assessed by Spearman correlations test. Data were neutrophils.
expressed as the mean SD. Differences were considered
statistically significant if p value <0.05. Discussion
In order to evaluate the effect of variables (sputum
neutrophils, sputum eosinophils, exhaled pH, exhaled NO, In this study we observed that dyspnea perception
BECK, asthma stage, age) on Borg/FEV1 or VAS/FEV1 decreases with the increase of stage of asthma, with age
a stepwise linear regression model was implemented. and depression status. Furthermore, we proved that the
airways inflammation plays a key role in the worsening of
Results dyspnea perception as demonstrated by the correlation
observed between inflammatory cells in sputum, exhaled
A significant decrease of dyspnea perception measured as pH and NO and BORGeVAS/FEV1 slope.
BORGeVAS/FEV1 slope was observed in severe compared to As expected, we confirmed that the severity of asthma
mild-moderate asthma patients (p Z 0.0002, p < 0.0001) importantly influences dyspnea perception reporting a nega-
(Fig. 1 AeB). A significant decrease of dyspnea perception tive correlation between BORGeVAS/FEV1 slope and stage.
was observed with the increase of the stage of asthma Previous studies showed that the perception of airway
(p < 0.0001) (Tables 1 and 2). A negative correlation was in narrowing is reduced in subjects with severe asthma,28,29
fact observed between slope VAS/FEV1 and slope BORG/ notwithstanding the fact that the dyspnea is clinically
FEV1 and stage (r Z 0.4, p < 0.0001; r Z 0.5, considered as a marker of asthma severity.30 In this regard
p < 0.001). inflammatory activity within the airways seems to explain
A negative correlation was observed between the differences in dyspnea perception in different stages of
increased perception of dyspnea (measured as slope VAS/ asthma. The responsibility of poor perception of dyspnea in
FEV1 and slope BORG/FEV1) and percentage of neutrophils severe asthmatics has been attributed to the main inflam-
in sputum (r Z 0.4; p < 0.001 and r Z 0.5; p < 0.0001), matory cells, the eosinophils, whose increase in percent-
percentage of eosinophils in sputum (r Z 0.3; p < 0.05 ages is related to the progression of asthma severity.31e33
and r Z 0.3; p < 0.05), exhaled NO (r Z 04; p < 0.0005 An increase of sputum eosinophilia has been reported to
and r Z 0.3; p < 0.005), depression status (r Z 0.3; reduce BORGeVAS/FEV1 slope29 as well as the eosinophil
p < 0.05 and r Z 0.3; p < 0.05) and age (r Z 0.4; infiltration and epithelial shedding in bronchial biopsies
p < 0.001 and r Z 0.4; p < 0.001) while was positive with from asthmatic subjects to blunt perception of dyspnea.8
exhaled pH (r Z 0.4; p < 0.0005 and r Z 0.6; p < 0.0001) A new biological phenotype of severe asthma mainly
(Figs. 2 and 3, Tables 3 and 4). characterized by a neutrophilic airway inflammation has

Table 5 Correlation between VAS/FEV1 slope and variables in mild-moderate and severe asthmatics.
VAS/FEV1 Asthma stage
Mild-Moderate Severe
Rho p Rho p
Sputum neutrophils 0.245 0.120 0.585 0.0009
Sputum eosinophils 0.512 0.0047 0.2060 0.3343
Exhaled pH 0.4557 0.0013 0.0048 0.9823
Exhaled NO 0.4301 0.0297 0.1651 0.4408
Beck 0.4658 0.0010 0.0375 0.8620
Age 0.3141 0.0335 0.1544 0.4714
Dyspnea perception in asthma
Table 6 Correlation between VAS/FEV1 slope and variables in mild-moderate and severe asthmatics.
BORG/FEV1 Asthma stage
Mild-Moderate
Rho
Sputum neutrophils 0.3209
Sputum eosinophils 0.6145
Exhaled pH 0.3684
Exhaled NO 0.5811
Beck 0.3339
Age 0.3218
been recently identified by the ENFUMOSA study group.34
However, no one, to our knowledge, investigated the
dyspnea perception in this different biological type of
severe asthma notwithstanding the fact that it could better
clarify the responsibility of eosinophils per se or of all
inflammatory cells including neutrophils in influencing
dyspnea perception. Also in this group we described a poor
perception of dyspnea and a negative correlation of the
BORGeVAS/FEV1 slope with the increase of neutrophils
percentages that led us to suggest that neutrophils also
participate in reducing dyspnea perception.
To better investigate the responsibility of airways
inflammation at all we correlated the VASeBORG/FEV1
slope with other inflammatory markers such as the exhaled
NO and pH, that are known to be influenced both from
eosinophils and neutrophils.
In particularly, exhaled NO and exhaled pH are
commonly used for diagnosing asthma, assessing control
and severity, titrating inhaled corticosteroids and detecting
ongoing airways inflammation.34e38
The correlation of dyspnea perception observed with
exhaled NO and exhaled pH further confirms that the
airways inflammation is involved independently of the cell
type mainly present and that decreased dyspnea percep-
tion is associated with increased inflammatory activity in
the peripheral airways.39
In this study for the first time we compared the efficacy
of two direct scales commonly used to measure and monitor
dyspnea, the VAS and the BORG. We observed that the VAS/
FEV1 slope was found to better represent the dyspnea
perception than BORG/FEV1 slope. This was comprehen-
sible considering that the VAS is more immediate and easy,
being a visual analogic scale compared to BORG that
required questions related to every-day activities that
subjects don’t test after the 20 min required for the
broncho-dilatation test.
Previous studies underlined substantial differences in
dyspnea perception between chronic obstructive pulmo-
nary disease (COPD) and asthma, partly because the former
experiences bronchoconstriction chronically while the
latter does so episodically. As asthma is a chronic disease
just as COPD is, we hypothesized that asthmatics with
chronic obstruction may lead to desensitization of dyspnea
perception for familiarity with this symptom as well as
COPD.9
Our suggestion is further in line with previous studies
showing that, with the increase of age, subjects become
201
Severe
p Rho p
0.0278 0.4912 0.00215
0.0009 0.1848 0.3873
0.0108 0.0275 0.8986
0.004 0.2422 0.1015
0.0218 0.2888 0.1711
0.0292 0.1351 0.5291
less sensitive to dyspnea. One possible explanation for this
hypothesis is that the number and activity of those lung
receptors transmitting sensory information to the central
nervous system may decrease with age.40 Another possi-
bility is that subjects become cortically less sensitive to the
peripheral signals of dyspnea with increasing age.9 This
hypothesis has been tested in COPD subjects where
a negative association has been observed between age and
perception of bronchoconstriction.9 For the first time we
tested this hypothesis in asthmatics confirming the pres-
ence of a negative correlation between dyspnea perception
and age.
We finally analysed the possible influence of the affec-
tive status on dyspnea perception starting from data that
showed that depression increases perceived dyspnea in
COPD.15 We described that when the progression of the
disease is associated with a progression of depression status
this could further decrease perceived dyspnea in asthma as
well as in other chronic diseases.15 Also in this case we
found a negative correlation with depression scale points
and VASeBORG/FEV1 slope. Our data provided an additional
support to Chetta’s suggestion40 that emotional status
might be always evaluated as well as lung function in
subjects with chronic respiratory diseases.
To better clarify the main cause of dyspnea perception
we used a linear regression model and observed that the
neutrophils are correlated with VAS and BORG slope, sug-
gesting that the inflammatory cells that characterize
severe asthma could be responsible for a good or poor
dyspnea perception more than the stage of disease, age or
emotional status.
An apparent limit of study is represented by the high
concentration of eosinophils in the induced sputum
notwithstanding the inhaled steroid therapy. However,
a persistent airway eosinophilia and T cell activation in the
presence of corticosteroids has been found in other studies
of chronic asthma and implies that corticosteroids are not
adequately suppressing the inflammatory process.34 The
increased excretions of NO in exhaled air observed in those
asthmatics taking regular oral corticosteroids is further
evidence of persistent airways inflammation and possible
relative resistance to steroids since, in mild-to moderate
disease, inducible NO synthase in bronchial epithelium is
highly sensitive to suppression with corticosteroids.34
In conclusion, the results of our study can be said to
point to the fact that dyspnea perception may be influ-
enced by several factors such as airways inflammation,
202
depression status, age and severity of the disease that
could usefully be taken into account when attempting to
achieve a better understanding of the mechanisms and
assessment of dyspnea and when helping in advanced
practice roles in order to successfully manage asthma. The
non-invasiveness of the methods used to assess the factors
recognized could certainly facilitate the task of identifying
the poor perceptors that when underestimating the
severity of their disease often undergo an inadequate
clinical and therapeutic follow-up and run the risk of
asthma attack/exacerbation and will help in the task of
following them during the progression of the chronic
disease.
Conflict of interest
All authors deny any financial conflicts of interest (such as
employment, consultancy, stock ownership, honoraria and
paid expert testimony) as well as other forms of conflict of
interest, including personal, academic and intellectual
issues.
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