Impaired Perception of Dyspnea in Patients with Severe Relation to Sputum Eosinophils

JOHANNES C. C. M. in ’t VEEN, HERMELIJN H. SMITS, ANTONIA J. J. RAVENSBERG, PIETER S. HIEMSTRA, PETER J. STERK, and ELISABETH H. BEL

Lung Function and Biochemistry Laboratory, Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands

Poor dyspnea perception might be a risk factor for developing asthma exacerbations. We investi- gated whether severe asthmatics with recurrent exacerbations (brittle asthma) have different dys- pnea perception and sputum cells compared with equally severe, but stable asthmatics, or patients with mild steroid-naive asthma. Fifteen brittle asthmatics (13 female, median age 28 yr [range, 20 to 47 yr]), 15 matched severe-stable asthmatics (14 female, median age 26 yr [range, 17 to 52 yr]), and 11 mild asthmatics (8 female, median age 25 yr [range, 19 to 43 yr]) underwent inhalation tests with methacholine (MCh), and hypertonic saline combined with sputum induction. Dyspnea was assessed

by Borg and Visual Analogue Scale (VAS), plotted against the percent fall in FEV1, and expressed as the slope of the regression line (Slope-Borg and Slope-VAS). The brittle and stable asthmatics had poorer perception than patients with mild asthma (Slope-Borg [p ϭ 0.036], Slope-VAS [p Ͻ 0.001] for MCh). In patients with brittle asthma the perception was less as compared with severe-stable asthma (Slope-Borg for MCh: p ϭ 0.05). In the severe asthmatics there was an inverse correlation between sputum eosinophilia and Slope-Borg and Slope-VAS (R ϭ Ϫ0.55, p ϭ 0.002 and R ϭ Ϫ0.37, p ϭ 0.049), whereas this correlation was a positive one in the mild asthmatics (R ϭ 0.79, p ϭ 0.012 and R ϭ 0.67, p ϭ 0.05). In conclusion, patients with severe asthma, particularly those with recurrent ex- acerbations, have blunted perception of dyspnea, which is related to the degree of sputum eosino- philia. This suggests that increased sputum eosinophilia is an indicator of clinical instabililty, and that eosinophilic airways inflammation might affect dyspnea perception in severe asthma. in ’t Veen JCCM, Smits HH, Ravensberg AJJ, Hiemstra PS, Sterk PJ, Bel EH. Impaired perception of dys- pnea in patients with severe asthma: relation to sputum eosinophils. AM J RESPIR CRIT CARE MED 1998;158:1134–1141.

Asthma is a chronic inflammatory disease of the airways, char- ing may help to detect patients who are at risk of not perceiv- acterized by episodic symptoms of chest tightness and wheez- ing a worsening of their asthma (7). Previously, it has been ing, associated with variable airways obstruction (1). In most shown that the severity of dyspnea appears to be greater in re- patients symptoms are well controlled by current anti-inflam- sponse to indirect stimuli (hypertonic saline) as compared matory therapy. However, severe exacerbations do still occur with direct stimuli (methacholine) at the same reduction of in a minority of patients, potentially leading to near-death or FEV1 (8, 9), which might be explained by differences in per- even death (2–4). An important endogenous factor that could ception due to inflammatory activity within the airways (8, 10, contribute to the development of frequent exacerbations in 11). In addition, it has been confirmed recently that there is asthma is a diminished perception of breathlessness (5). Be- an association between perception of breathlessness and air- cause of blunted perception, patients with severe asthma might way inflammation, as measured by eosinophilic infiltration not sense a forthcoming exacerbation, thereby not avoiding and epithelial shedding in bronchial biopsies from asthmatic bronchoconstrictive stimuli nor seeking medical care (5, 6). patients (12). The scoring of perception during bronchoprovocation test- In the present study we hypothesized that asthmatic pa- tients with recurrent exacerbations have a diminished percep- tion of dyspnea as compared with asthmatic patients without exacerbations. The aim of our study was to compare the per- (Received in original form October 27, 1997 and in revised form June 10, 1998) ception of dyspnea between patients with severe steroid- Sponsored by a grant from Glaxo Wellcome BV, The Netherlands. dependent asthma, with a recent history of recurrent exacer- Correspondence and requests for reprints should be addressed to Johannes C. C. M. bations (brittle asthma) with equally severe, but stable matched in ’t Veen, Lung Function and Biochemistry Laboratory, Department of Pul- monology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC Leiden, asthmatic control subjects (stable asthma) by using the Borg The Netherlands. score (13) and Visual Analogue Scale (VAS) score (14), dur- Am J Respir Crit Care Med Vol 158. pp 1134–1141, 1998 ing inhalation challenge tests with either methacholine or hy- Internet address: www.atsjournals.org pertonic saline. In addition, the perception of dyspnea in this

in ’t Veen, Smits, Ravensberg, et al.: Perception of Dyspnea and Asthmatic Airway Inflammation 1135 group of severe asthmatics was compared with the perception (Rotadisk) for at least 4 wk. Hereafter, the subjects underwent two in- of a group of patients with mild, -naive asthma. halation challenge tests within one week on two different occasions at In order to study the relation between dyspnea and noninva- the same time of day: on the first day a methacholine challenge was sive markers of asthmatic airway inflammation, we also as- performed, and on the second day a hypertonic saline challenge test sessed the relation between the perception of breathlessness, followed by sputum induction. During the challenge tests, dyspnea was measured after each dose of agonist using Borg and VAS scales. and markers of inflammation in induced sputum. Compliance with the inhaled corticosteroid medication was checked before each challenge by counting the used Rotadisk blisters. METHODS Methacholine Inhalation Challenge Test Subjects Methacholine challenge tests were performed according to a stan- Three groups of patients with bronchial asthma participated in the dardized tidal breathing method (15). Methacholine in isotonic saline study. All subjects had a history of episodic dyspnea and wheezing. was aerosolized at room temperature in doubling concentrations Classification of asthma severity was based on history, symptoms, clin- (0.015 to 32 mg/ml) by a DeVilbiss 646 nebulizer (DeVilbiss Co., Som- ical features, and medication requirement according to international erset, PA; output 0.13 ml/min), with the straw in fixed position, con- guidelines (1). The forced expiratory volume in one second (FEV1) nected to a three-way valve with an expiratory filter (Pall Ultipor was within the normal range (Ͻ 70% predicted) at baseline, or after BB 50T; Pall Biomedical, Portsmouth, England). The aerosols were inhalation of 400 ␮g salbutamol per metered dose inhaler connected inhaled by tidal breathing during 2 min at 5-min intervals through the to an aerosol chamber. All subjects were hyperresponsive to inhaled mouth with the nose clipped. Measurements of FEV1 were made in methacholine (MCh) as shown by a provocative concentration to triplicate before the test (baseline), and in duplicate (30 and 90 s) after cause a 20% fall in FEV1 (PC20) of less than 8 mg/ml (15). Atopic sta- each increasing dose. The challenge test was discontinued if FEV1 tus was assessed or excluded by specific IgE to a panel of common dropped 20% or more from baseline. The provocative concentration aeroallergens (Phadiatop; Pharmacia, Uppsala, Sweden). Group I of MCh resulting in a 20% fall in FEV1 (PC20 MCh) was calculated by (brittle asthma) consisted of 15 patients (13 female, 2 male, age 20 to linear interpolation of the log-dose response curves (15). 47 yr) with severe asthma, who had had two or more exacerbations during the preceding year requiring treatment with oral corticoste- Hypertonic Saline Inhalation Challenge Test roids, despite high dose inhaled corticosteroid therapy (beclometha- Hypertonic saline challenge tests were performed according to a rec- sone dipropionate/budesonide 800 ␮g twice daily or fluticasone propi- ommended protocol (15). Sodium chloride aerosols (Hyp) 4.5% (wt/ onate 500 ␮g twice daily). Group II (stable asthma) consisted of 15 vol) were generated at room temperature by an ultrasonic nebulizer matched control subjects (14 female, 1 male, age 17 to 52 yr) with (Ultraneb 2000; DeVilbiss, Somerset, PA) with a calibrated particle equally severe asthma, using equivalently high-dose inhaled cortico- size (mass median aerodynamic diameter 4.5 ␮m), with the output set steroid therapy, without a history of exacerbations during the previ- at maximal (2.5 ml/min at the mouthpiece). The aerosols were admin- ous year. The patients were recruited from our outpatient pulmonary istered to the subjects through a 100-cm-long tube with an internal di- department. Most of them visited our hospital for many years, mostly ameter of 22 mm, and were inhaled by mouth through a two-way on a 3 to 6 mo basis, and during exacerbations. Inhaled valve (No. 2700; Hans-Rudolph, Kansas City, MO), while the nose were routinely tapered to the lowest possible doses. The 15 pairs of was clipped. The exposure time was doubled as follows: 15, 30 s, patients were individually matched for age (two groups: 16 to 39 yr or 1 min, 2, 4, and 8 min. Measurements of forced expiratory volume in 40 to 55 yr), FEV postbronchodilator (70 to 85% or у 85% pre- 1 one second (FEV1) were made in triplicate before (baseline) and at 60 dicted), and PC20 MCh (Ϯ 2 doubling doses), and for at least one of and 90 s after each exposure to the aerosol. The output delivered to the following two criteria: sex and atopic status (two groups: atopy or the two-way valve was determined by weighing the nebulization no atopy). Group III (mild asthma) consisted of 11 patients (8 female, chamber before and after nebulization. The challenge test was discon- 3 male, age 19 to 43 yr) with mild steroid-naive asthma. All subjects tinued when FEV1 had dropped more than 20% from baseline value, had inhaled short acting ␤2-agonists on demand as rescue medication. or when the maximal dose had been given. The provocative cumula- None of the subjects had a history of other than tive dose of Hyp resulting in a 15% decrease (the cutoff point [11, 15] asthma, and did not use any other medication for their asthma during that should be regarded as abnormal) in FEV1 (PD15 Hyp) was calcu- the study. All subjects were nonsmokers or ex-smokers (for more than lated by linear interpolation of the log-dose response curves (15). 12 mo, with less than 5 pack-yr). The subjects were studied during a clinically stable period, without symptoms of an upper respiratory Assessment of Perception of Dyspnea tract infection for 4 wk prior to the study. The subject characteristics The severity of dyspnea during the challenge tests was assessed by a are summarized in Table 1. The study was approved by the Hospital Borg scale and VAS scale, at 20 s after inhalation of each dose, just Medical Ethics Committee, and informed consent was given by all before the measurement of the FEV curves. Each subject was asked subjects. 1 by oral question to rate their asthma sensation (Borg) and breathless- ness (VAS) in a standardized way. The Borg scale is a vertical list with Design labeled categories (0–10) describing increasing intensities of asthma On a screening day inclusion criteria were checked, and the subjects sensations (0 ϭ “nothing at all,” and 10 ϭ “maximal”) (13). The sub- were made familiar with bronchial provocation testing. The inhaled jects were asked directly after inhaling each dose the same standard- corticosteroid medication of all patients of Groups I and II was ized question: “How severe is your asthma during and directly after matched by changing it to fluticasone propionate 500 ␮g twice daily the inhalation? 0 is nothing, 10 is maximal.” The VAS scale is a hori-

TABLE 1 SUBJECT CHARACTERISTICS*

Variable Brittle Asthma Stable Asthma Mild Asthma

Sex 13 F, 2 M 14 F, 1 M 8 F, 3 M Age 28 (20–47) 26 (17–52) 25 (19–43) Atopy 12/15 14/15 9/11

FEV1% pred, postbronchodilator 91.6 (72–124) 100.5 (72–118) 98.3 (81–114) PC20 MCh, mg/ml 0.69 (0.03–8.65) 0.71 (0.10–5.82) 0.65 (0.07–5.80) PD15 Hyp, ml 5.0 (1.1–15.8) (n ϭ 10) 10.2 (3.8–12.2) (n ϭ 5) 4.1 (3.2–14.65) (n ϭ 6)

* Values are median (range). No significant differences were observed between the groups.

1136 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 158 1998

37Њ C for 15 min to ensure complete homogenization. The homoge- nized sputum was centrifuged at 350 ϫ g for 10 min. The cell pellet was resuspended in 10 ml phosphate-buffered saline, filtered through a nylon gauze (pore size approximately 1 mm), cytocentrifuged for 3 min at 1,500 rpm (Shandon cytocentrifuge 3; Shandon Southern Instruments, Sewickley, PA), and stained with Diff-Quik (Baxter, Düdingen, Swit- zerland). The total cell count was measured by using a standard hema- cytometer. Differential cell counts were performed by counting at least 500 nonsquamous cells in a blind way, and are expressed as per- centage of nonsquamous cells. Sputum samples containing more than 80% squamous cells were excluded from the analysis because of poor cytospin quality (17).

Analysis of Perception of Dyspnea Borg and VAS scores of all subjects were plotted against percentage of fall in FEV1 from baseline, and individual Borg/FEV1 and VAS/ MCh MCh Hyp FEV1 slopes (Slope-Borg , Slope-VAS , Slope-Borg , and Slope-VASHyp, respectively), representing an index of dyspnea (12), and their corresponding intercepts, representing baseline Borg and VAS, were calculated by linear regression analysis for both MCh and Hyp challenges (Figure 1). Figure 1. Representative example of relation between Borg and decrease in FEV1. The closed line represents the linear regression of Statistical Analysis a patient with stable asthma (triangle) with adequate perception, Data are expressed as median (range). Nonparametric tests were used and the dashed line represents a patient with brittle asthma (in- because the data of Borg/FEV and VAS/FEV slopes were skewed. verted triangle) with poor perception. The figure includes the cor- 1 1 Differences between the groups were analyzed by Mann-Whitney relation coefficient (R), the slope, and the intercept (X0) for both U-test. Correlation (R) between data was assessed by Spearman cor- patients. relations test. At a p value of 0.05 or less, differences were considered to be statistically significant. Sample size estimations using data ob- tained in a pilot study showed that 15 patients in the brittle and stable zontal straight line (100 mm) labeled “no breathlessness at all” (0 asthma group would allow a detection of at least a 50% reduction in mm) at one end and “most extreme breathlessness ever experienced” Slope-BorgMCh and Slope-VASMCh (2-sided ␣ ϭ 0.05, 1-sided ␤ ϭ (100 mm) at the other, whereby equal distances are meant to repre- 0.80). In order to evaluate whether differences in perception were as- sent equal increments in the severity of breathlessness (8, 14). The sociated with differences in sputum cell counts, an analysis of covari- subjects were asked: “How severe is your breathlessness during and ance was performed after ranking the data, with perception as depen- directly after the inhalation? Left is no breathlessness at all, right is dent variable and percentage sputum cells as covariate (18). the most severe breathlessness ever experienced.” The scoring sys- tems were presented on a monitor in front of the subject, who re- corded the severity on the scales by means of the keyboard arrows of RESULTS a computer, while the value was stored online (8). During the tests the Subject Characteristics subjects were blinded to their lung function response. Subject characteristics are summarized in Table 1. There were Sputum Induction no significant differences in age, FEV1 postbronchodilator, Sputum induction was performed in association with the hypertonic and airway responsiveness to MCh between the patients with saline challenge test as described earlier (16) with some modifications brittle and stable asthma, as well as between the patients with (17). During the challenge, subjects were asked to rinse their mouth severe (brittle and stable) asthma versus the patients with with tap water after each inhalation period and were encouraged to mild asthma. Although a larger number of patients with brittle cough and expectorate sputum if present in a clean plastic container. asthma responded with a 15% or greater fall in FEV1 after hy- When FEV1 fell more than 20% from baseline or the maximal dose pertonic saline inhalation as compared with the patients with was given, all subjects received 400 ␮g salbutamol by spacer device. stable and mild asthma, the PD15 Hyp did not differ between Hereafter, sputum induction was continued by inhalation of hyper- the three groups. tonic saline with expectoration of sputum every 5 min to a maximum of 15 min. The volume of the whole, pooled sputum sample was deter- Perception of Breathlessness mined, and an equal volume of dithiotreitol 0.1% (wt/vol, Sputolysin; Calbiochem, La Jolla, CA) was added. The samples were gently mixed Baseline perception, as measured by the Borg/FEV1 and using a wide-bore plastic pipet, and placed in a shaking water bath at VAS/FEV1 intercepts for both challenges, did not differ signif-

TABLE 2 BASELINE PERCEPTION OF DYSPNEA*

Variable Intercept-BorgMCh Intercept-VASMCh Intercept-BorgHyp Intercept-VASHyp

Brittle 0.58 (Ϫ0.17 to 2.0) 6.25 (Ϫ1.6 to 24.0) 0.68 (Ϫ2.5 to 3.0) 5.1 (Ϫ1.1 to 20.8) Stable 0.57 (Ϫ0.1 to 3.0) 10.3 (Ϫ1.2 to 25.9) 0.47 (Ϫ0.8 to 1.8) 4.3 (Ϫ3.4 to 25.7) p Value† 0.82 0.33 0.27 0.163 Mild 0.71 (Ϫ0.6 to 2.1) 9.4 (Ϫ3 to 25.3) 0.31 (Ϫ0.3 to 2.5) 7.5 (Ϫ2.8 to 21.4) p Value‡ 0.75 0.52 0.76 0.83

Ϫ1 Ϫ1 * Intercepts of Borg/FEV1 (%fall FEV1 ) and VAS/FEV1 (mm и %fall FEV1 ) for MCh and Hyp challenge, respectively. Data are expressed as median (range). † Patients with brittle asthma compared with stable asthmatic control subjects. ‡ Patients with mild asthma compared with the patients with severe (brittle and stable) asthma.

in ’t Veen, Smits, Ravensberg, et al.: Perception of Dyspnea and Asthmatic Airway Inflammation 1137

Ϫ1 Figure 2. The slopes of Borg/FEV1 and VAS/FEV1 (mm · %fall FEV1 ) induced by MCh (A and B) and Hyp (C and D) for the patients with brittle (inverted triangles), stable (triangles), and mild (open circles) asthma. Data are expressed as median and individual scores.

1138 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 158 1998 icantly between the patients with brittle and stable asthma, brittle and stable severe asthmatics was no longer significant neither between the patients with severe (brittle and stable) (p ϭ 0.17). asthma and mild asthma (Table 2). However, the slopes of Borg/FEV1 and VAS/FEV1 were different between the groups DISCUSSION (Figure 2): the Slope-BorgMCh was significantly lower in the The results of the present study show that bronchoconstriction patients with brittle asthma as compared with the patients is less well perceived by patients with severe inhaled steroid- with stable asthma (Figure 2A: p ϭ 0.05), whereas similar dependent asthma as compared with patients with mild ste- trends for Slope-VASMCh, Slope-BorgHyp, and Slope-VasHyp roid-naive asthma. In addition, in patients with severe asthma did not reach significance (Figures 2B–2D: p ϭ 0.085, p ϭ 0.061, suffering from recurrent exacerbations, the perception of bron- and p ϭ 0.10, respectively). In addition, the Slope-BorgMCh and choconstriction during well-controlled periods tends to be less Slope-VASMCh scores were significantly lower for the patients as compared with patients with equally severe, but stable dis- with severe (brittle and stable) asthma as compared with the ease. In patients with severe asthma, the perception of bron- patients with mild asthma (Figures 2A and 2B: p ϭ 0.036 and choconstriction is inversely correlated with the percentage of p Ͻ 0.001, respectively). However, perception during the inha- eosinophils in induced sputum, whereas there is a positive cor- lation of hypertonic saline was not perceived differently be- relation in patients with mild asthma. The results suggest that tween the groups. ongoing airway inflammation in severe asthma, despite treat- ment with inhaled corticosteroids, is associated with a reduced Induced Sputum perception of airflow obstruction, which might be a risk factor Two subjects, one with stable and one with mild asthma, were for recurrent exacerbations. not able to produce any sputum. In addition, sputum from one This study is the first to show a difference in perception of patient with mild asthma contained Ͼ 80% squamous cells induced bronchoconstriction between patients with severe and was therefore excluded from analysis. No significant dif- asthma with and without recurrent exacerbations during well ferences in cellular parameters were observed between the pa- controlled periods. Two earlier reports showed a poor percep- tients with brittle and stable severe asthma, except for a higher tion of breathlessness in patients with severe asthma during an percentage of sputum eosinophils in the brittle asthma group ongoing exacerbation (6, 19), but this normalized after recov- (Table 3: p ϭ 0.05). The sputum of patients with mild steroid- ery from the exacerbation. Boulet and coworkers were not naive asthma contained a lower number of nonsquamous cells able to identify a difference in perception of laboratory-induced per milliliter sputum, and a slightly higher percentage of epi- bronchospasm between a group of patients with near-fatal thelial cells as compared with the sputum of the group with se- asthma attacks and an asthmatic control group, which might vere asthma. be due to a smaller sample size in their study (20). Our results extend the findings of Kikuchi and colleagues who showed that Perception of Dyspnea versus Sputum Cell Counts patients with near-fatal asthma attacks have a reduced ventila- In the group with severe asthma treated with fluticasone propi- tory response to hypoxia as compared with patients without onate there was a correlation between the percentage of bron- near-fatal asthma attacks as well as normal subjects (21). In chial epithelial cells and the Slope-BorgMCh (Figure 3A: R ϭ 0.38, their study the perception of breathlessness did not differ be- p ϭ 0.04). In this group there also appeared to be an inverse tween patients with and without near-fatal attacks, which might correlation between percentage sputum eosinophils and the be explained by the method of provoking dyspnea by breathing Slope-BorgMCh (R ϭ Ϫ0.31, p ϭ 0.097), Slope-BorgHyp (Figure through inspiratory resistances (22). 3B: R ϭ Ϫ0.55, p ϭ 0.002), and Slope-VASHyp (R ϭ Ϫ0.37, One earlier study by Roisman and colleagues reports a re- p ϭ 0.049). In the patients with mild asthma the percentage lationship between perception of bronchoconstriction and air- sputum epithelial cells tended to be correlated with the Slope- way inflammation in patients with mild-to-moderate asthma BorgHyp (Figure 3C: R ϭ 0.59, p ϭ 0.09). Furthermore, the (12). They found that perception of bronchoconstriction in- percentage sputum eosinophils was positively correlated with duced by bradykinin was inversely related to the number of the Slope-BorgHyp (Figure 3D: R ϭ 0.79, p ϭ 0.012) and the eosinophils in bronchial biopsies, which is in line with our ob- Slope-VASHyp (R ϭ 0.67, p ϭ 0.05). No other significant served correlation between sputum eosinophils and percep- correlations were observed between percentage sputum cells tion of bronchoconstriction induced by hypertonic saline. An- and the slopes of Borg/FEV1 or VAS/FEV1. When using per- other finding by the group of Roisman was that perception centage of sputum eosinophils as covariate in the analysis of of dyspnea was positively correlated with the percentage of variance, the observed difference in Slope-BorgMCh between basement membrane covered with epithelial cells, whereas we

TABLE 3 SPUTUM CELL COUNTS*

Variable Total Cells % Squamous Cells % Eosinophils % Epithelial Cells % Neutrophils % Macrophages % Lymphocytes

Brittle 1.45 23.7 2.7 11.4 35.2 44.8 1.2 (0.26–2.32) (0.6–50.5) (0.1–14.3) (0.6–21.8) (12.3–84.3) (12.1–70.5) (0.6–2.9) Stable 1.72 14.6 0.53 10.1 29.0 49.1 1.2 (0.94–3.77) (1.9–65.4) (0.1–13.5) (1.3–34.4) (15.9–85.2) (12.1–69.8) (0.2–2.0) p Value† 0.93 0.97 0.05 0.73 0.88 0.93 0.38 Mild 0.62 19.4 2.4 17.8 25.3 48.5 1.2 (0.27–2.54) (4.7–50.3) (0.1–11.0) (8.4–32.0) (5.0–59.7) (25.8–76.8) (0.1–2.2) p Value‡ 0.006 0.73 0.84 0.04 0.11 0.45 0.81

* Total nonsquamous sputum cells (106 cells и mlϪ1) and sputum differential cell counts (%). Results are expressed as median (range). † Patients with brittle asthma compared with stable asthmatic control subjects. ‡ Patients with mild asthma compared with the brittle and stable asthmatic patients. in ’t Veen, Smits, Ravensberg, et al.: Perception of Dyspnea and Asthmatic Airway Inflammation 1139

Ϫ1 Figure 3. The correlation between the Slope-Borg (%fall FEV1 ) and sputum epithelial cells (%) (A and C) and sputum eosinophils (%) (B and D) in patients with severe asthma (A and B: brittle [inverted triangles], stable [triangles] asthma), all treated with inhaled steroids, and in patients with mild steroid-naive asthma (C and D: mild [open circles] asthma).

found that perception of dyspnea correlated positively with might be explained by the use of high doses of corticosteroids the number of bronchial epithelial cells in induced sputum. in the patients with severe asthma. Second, the measurement This discrepancy might be explained by the fact that the epi- of dyspnea perception was performed in a standardized way. thelial cells in induced sputum possibly do not reflect epithe- All patients were clinically stable for at least 4 wk before the lial denudation, but shedding of an abundance of epithelial study, and dyspnea was scored by using validated Borg and cells on an intact basement membrane. VAS assessment scales (7, 13) presented on a monitor with a It is unlikely that methodological errors influenced our re- uniform verbal instruction during standardized bronchial prov- sults. First, the two groups of patients with severe asthma were ocation tests (15). Third, the sample size of 15 subjects might individually matched for all factors known to influence per- have been too small to detect significant differences in all dys- ception of bronchoconstriction, including sex (23), age (23, pnea scores between the two groups of patients with severe 24), baseline lung function (25, 26), airway responsiveness (6, asthma. However, for all parameters there appeared to be a 25), recent exacerbations (6), and inhaled corticosteroid medi- consistent trend suggesting a blunted perception in the pa- cation (5, 12, 27). The female gender was slightly, but not sig- tients with recurrent exacerbations. nificantly overrepresented in the patients with severe asthma Our study shows that the perception of dyspnea in patients as compared with the patients with mild asthma. Theoreti- with severe asthma, in particular in those with recurrent exac- cally, this could have biased our data, because women are erbations, is impaired. Theoretically, poor perception of dys- known to have an improved perception of bronchoconstric- pnea in patients with severe asthma could be explained by ad- tion compared with men (23). However, this female domi- aptation to more severe airway narrowing resulting in a higher nance would have resulted in an improved perception in the threshold for experiencing dyspnea. Indeed, adaptation has severe asthmatics, whereas we observed the opposite. been shown to influence perception of dyspnea after a recent In addition, the patients with mild asthma did not differ sig- exacerbation, but these effects do not appear to be long lasting nificantly from the patients with severe asthma with respect to (6). Because the patients in our study had to be recovered age, baseline lung function, airway responsiveness to metha- from any exacerbation for at least 4 wk, we expected the per- choline nor percentage sputum eosinophils. The latter findings ception of dyspnea to be normalized. Therefore, it could be 1140 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 158 1998 postulated that the observed difference is not the consequence References of, but a risk factor for recurrent exacerbations. Perception of dyspnea is mediated by several mechanisms 1. National Heart, Lung, and Blood Institute. 1992. International consen- sus report on diagnosis and treatment of asthma. Eur. Respir. J. 5:601– (28) including hyperinflation (29), increase in the work of 641. breathing (28) possibly by activating proprioreceptors of re- 2. Kay, A. B. 1996. Pathology of mild, severe, and fatal asthma. Am. J. spiratory muscles (30), and by direct stimulation of airway Respir. Crit. Care Med. 154(Suppl.):S66–S69. mechanoreceptors (31). In addition to these mechanical path- 3. Lang, D. M., and M. Polansky. 1994. Patterns of asthma mortality in ways, eosinophilic airway inflammation has also been pro- Philadelphia from 1969 to 1991. N. Engl. J. 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