- Email: [email protected]
Perception of dyspnea during exacerbation and histamine-related bronchoconstriction in patients with asthma
Perception of dyspnea during exacerbation and histamine-related bronchoconstriction in patients with asthma Mehmet Ekici, MD*; Aydanur Ekici, MD*; Turkan Kara, MD*; Hatice Keles, MD†; Ali Karlidag, MD*; Volkan Altunkaya, MD*; and Emel Bulcun, MD*
Background: Numerous studies have been performed concerning the perception of dyspnea during changes in airway caliber provoked in the laboratory setting, but studies of asthma exacerbation are scarce. Objective: To investigate whether the perception of dyspnea during histamine-induced bronchoconstriction might be used to identify patients with asthma who sense dyspnea poorly during exacerbation. Methods: The perception of dyspnea in 50 patients (45 female, 5 male) with asthma was evaluated at admission with exacerbation and during a stable period. Perceived intensity of dyspnea was estimated using a modified Borg scale. The perception of dyspnea in the stable period 4 to 6 weeks after exacerbation was measured with the histamine challenge test. Perception parameters were defined as the change in Borg score divided by the change in forced expiratory volume in 1 second (FEV1) as a percentage of the baseline FEV1 (⌬Borg/⌬FEV1) and as the Borg score at 20% decrease (PS20Histamine) or increase (PS20Exacerbation) in FEV1. Results: The perception of dyspnea during asthma exacerbation was unrelated to the perception of dyspnea during histamineinduced bronchoconstriction (for ⌬Borg/⌬FEV1,  ⫽ .08, P ⫽ .50; for PS20,  ⫽ ⫺.11, P ⫽ .40). The value for the agreement of poor perceivers at exacerbation and during the stable period was – 0.21 (P ⫽ .10). However, the intensity of dyspnea caused by histamine-induced bronchoconstriction was lower than that caused by asthma exacerbation (PS20: 1.6 ⫾ 1.1 vs 2.8 ⫾ 2.5, respectively, P ⫽ .004; ⌬Borg/⌬FEV1: 0.08 ⫾ 0.05 vs 0.21 ⫾ 0.28, respectively, P ⫽ .001). Conclusion: The perception of dyspnea during asthma exacerbation is not correlated with the perception of dyspnea during histamine-induced bronchoconstriction. Therefore, the perception of dyspnea during histamine-induced bronchoconstriction cannot be used to identify the asthmatic patients who perceive dyspnea poorly. Ann Allergy Asthma Immunol. 2006;96:707–712.
INTRODUCTION The perception of breathlessness during bronchoconstriction substantially varies among patients.1,2 By definition, symptom perception is a subjective measure. What is rated as slight to one person may be perceived as severe by another.3 The severity of bronchoconstriction is the major contributor to asthma symptoms but has substantial residual variability, perhaps owing to fear of impending harm, sensory adaptation, and intrinsic perceptual impairment.4 The perception of airway narrowing is likely to be an important determinant of symptoms of asthma.5 Subjective perception of airflow during acute obstruction has been shown to often be inaccurate.6 Accurate recognition of asthma symptoms is essential for prompting individuals with acute asthma to increase medication use or seek medical assistance.7,8 In 1976, Rubinfeld and Pain9,10 reported that asthmatic patients with “just noticeable” dyspnea had highly variable pulmonary impairment during
* Kirikkale University Faculty of Medicine, Department of Pulmonary Medicine, Kirikkale, Turkey. † Department of Internal Medicine, Kirikkale University Faculty of Medicine, Kirikkale, Turkey. Received for publication July 15, 2005. Accepted for publication in revised form September 5, 2005.
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naturally occurring asthma and chemically induced bronchoconstriction. However, this practice could lead to inadequate treatment if fluctuations in airways’ caliber are not always readily perceived by the patient.11 Reduced perception of dyspnea may predispose patients to a life-threatening attack.12,13 Numerous studies have been performed concerning the perception of dyspnea during changes in airway caliber provoked in the laboratory setting, but studies of asthma exacerbation are scarce. The aim of this study was to investigate whether the perception of dyspnea during histamineinduced bronchoconstriction might be used to identify asthmatic patients who sense dyspnea poorly during exacerbation. METHODS This study was part of a larger project that examined the course and consequences of diseases in asthmatic patients who had been followed up regularly for 7 years in the Respiratory Disease Clinics of Kirikkale University Hospital in Kirikkale, Turkey. A total of 50 asthmatic patients admitted to the hospital from September to December 2004 for exacerbation of asthma were entered into the study. Asthma diagnosis was made according to the American Thoracic Society criteria with symptoms of episodic wheezing, cough
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and shortness of breath responding to bronchodilators, and reversible airflow obstruction documented in at least one previous pulmonary function study.14 All patients were lifelong nonsmokers, and none of them reported a present or previous history of exposure to hazardous airborne substances. Asthma severity score was defined according to the National Asthma Education Program guidelines (ie, frequency of symptoms, degree of airflow obstruction, and frequency of use of oral glucocorticoids).15 Asthma exacerbation severity was defined as moderate and severe according to the 2002 Global Initiative for Asthma guidelines. Patients were evaluated at admission to the hospital and during a stable period after 4 to 6 weeks. Short-term treatment was initiated immediately after hospitalization. All patients were using inhaled steroids on discharge and were instructed to continue using this medication until their next visit. Ethical approval was obtained from the local ethics committee. Signed, informed consent was obtained from all patients. Perception of Bronchoconstriction During Exacerbation All asthmatic patients included in the study were evaluated on repeated occasions once admitted to the hospital: soon after admission (0 hour) and then at the 5th, 10th, 24th, 48th, and 72nd hours. Perceived intensity of dyspnea was estimated using a modified Borg scale (Table 1) labeled from 0 (no symptom) to 10 (maximum bearable).16,17 On each occasion the patients were first asked to score how dyspneic they felt using the Borg scale. At the same time, spirometry, including forced expiratory volume in 1 second (FEV1) and maximal midexpiratory flow, was performed using a portable spirometer (MicroLab, Kent, England). The change in Borg score (⌬Borg) was defined as the difference between the first evaluation (0 hour) and each of the assessments at 5, 10, 24, 48, and 72 hours after admission. The change in FEV1 as a percentage of the baseline FEV1 (⌬FEV1) was calculated by the following formula: (highest FEV1 L ⫺ lowest FEV1 L) ⫻ 00/lowest FEV1 L. The ratios of change in Borg score to the change in FEV1 (⌬Borg/ ⌬FEV1Exacerbation) at each occasion were then calculated to evaluate the individual patient’s ability to perceive changes in airway obstruction. In addition, the mean of these ratios was Table 1. Modified Borg Scale for the Intensity of Dyspnea Score 0 0.5 1 2 3 4 5 6 7 8 9 10
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Intensity of dyspnea Nothing at all Very, very slight (just noticeable) Very slight Slight Moderate Somewhat severe Severe Very severe Very, very severe (almost maximal) Maximal
determined to derive a summary value reflecting all 5 values. The perception score corresponding to an increase in FEV1 by 20% (PS20Exacerbation) was calculated by linear interpolation of the last 2 points on the curve of change in Borg score and increase in the FEV1 during exacerbation. Histamine Challenge Test A histamine challenge test was performed in the stable period 4 to 6 weeks after exacerbation. Patients were asked to stop using bronchodilating agents for at least 12 hours before the histamine challenge test was performed during the stable period. Pulmonary functions were measured by a flow-sensing spirometer connected to a computer for data analysis (Jaeger, Wuerzburg, Germany). Each patient inhaled doubling concentrations of histamine up to 16 mg/mL or until a 20% decrease in FEV1 via a dosimeter with an output of 0.9 ⫾ 0.3 mL per puff occurred (Dosimeter APS Pro; Jaeger).18 Bronchial response to histamine was expressed as the provocative dose that caused a 20% decrease in FEV1 (PD20) and was calculated by the same computer program (LAB, version 4.3; Jaeger). PD20 was expressed as the geometric mean ⫾ SD. Perception of Histamine-Induced Bronchoconstriction Perceived intensity of dyspnea was estimated with a modified Borg scale used in exacerbation. Patients were asked to select an appropriate definition to determine dyspnea at the time of histamine challenge test. They were completely free to decide their own self-scores but warned to determine only dyspnea and to disregard any irritation of the nose or throat during the scoring. Borg scores were recorded immediately before each percentage of the predicted value for FEV1 (FEV1%) measurement during the challenge test and at the maximum decrease in FEV1%. The perception score corresponding to a decrease in FEV1 by 20% (PS20Histamine) was calculated by linear interpolation of the last 2 points on the perception and decrease in the FEV1% curve of the histamine challenge test.19 The change in dyspnea during bronchoconstriction was expressed as the Borg score change divided by the change in FEV1 as a percentage of the baseline FEV1 (⌬Borg/ ⌬FEV1Histamine).20 Statistical Analysis Clinical data are expressed as mean ⫾ SD. Regression analysis (bivariate model) was used to examine the possible relation of ⌬Borg/⌬FEV1Histamine with ⌬Borg/⌬FEV1Exacerbation at baseline and 5, 10, 24, 48, and 72 hours after admission, as well as with the mean ⌬Borg/⌬FEV1Exacerbation. The ⌬Borg/ ⌬FEV1Exacerbation values at each occasion were separately entered into the model as covariates to prevent colinearity and to test their effect. The relationship between PS20Histamine and PS20Exacerbation was evaluated in a bivariate model. Two approaches were followed to examine the relationships among variables at the within-person level of change over time in exacerbation. The first examined within-person relationships expressed across the entire pooled data set of 300 person assessments (50
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patients 6 times a day). In this approach, after pooling observations in exacerbation (300 Borg scores and 300 FEV1% values), the concurrent relationship between Borg score and FEV1% was analyzed using a bivariate model. The second approach examined within-person relationships between Borg score and FEV1% value for each patient (n ⫽ 50) separately using a bivariate model to identify and account for individual differences in dyspnea perception accuracy. P ⬎ .05 for linear relationship between Borg and FEV1 defined poor perceivers. Differences and agreement of poor perceivers between the 2 groups (exacerbation and stable period) were analyzed using and 2 tests. Furthermore, multiple linear regression analysis was performed with the perception of bronchoconstriction (⌬Borg/⌬FEV1or PS20) as the dependent variable and asthma severity, PD20, sex, age, and disease duration as predictor variables. Predictor variables were entered in the multivariate model using a stepwise procedure. All tests were performed 2-sided, and P ⬍ .05 was considered statistically significant. RESULTS The study group consisted of 5 male and 45 female patients with a mean age of 54 years (age range, 34 –78 years). Asthma exacerbation severity was moderate in 24 patients and severe in 26 patients. The characteristics of the patients with asthma are given in Table 2. The mean value of FEV1% at the time of admission, being the nadir FEV1 relative to predicted FEV1, was 57.2 ⫾ 18.6, and the mean FEV1% during the stable period was 90.0 ⫾ 21.7. The mean value of nadir FEV1% occurred by histamine-induced bronchoconstriction was 59.7 ⫾ 22.2, which was comparable with that obtained at admission with asthma exacerbation (P ⫽ .54). The Borg score at nadir FEV1 during histamine-induced bronchoconstriction was lower than that at admission (2.0 ⫾ 1.5 vs 4.7 ⫾ 2.3, respectively, P ⬍ .001). There was no relation among the Borg score at the time of admission, the Borg score at the nadir FEV1%, and the Borg score at the nadir FEV1% during histamine challenge ( ⫽ .13, P ⫽ .30). The magnitude of dyspnea perceived during exacerbation (⌬Borg/⌬FEV1Exacerbation) at the 5th, 10th, 24th, 48th, and 72nd hours after admission did not relate to the magnitude of dyspnea perceived during histamine challenge (⌬Borg/ Table 2. Characteristics of the Patients With Asthma* Characteristics
Mean ⴞ SD (N ⴝ 50)
Age, y Female/male, No. Asthma duration, y FEV1% Reversibility, %
53.2 ⫾ 13.7 45/5 12.4 ⫾ 9.2 57.2 ⫾ 18.6 16.1 ⫾ 7.1
Abbreviation: FEV1%, percentage of the predicted value for forced expiratory volume in 1 second. * Data are given in mean ⫾ SD unless otherwise indicated.
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⌬FEV1Histamine) (Table 3). In addition, linear regression analysis indicated that the mean magnitude of dyspnea perception during asthma exacerbation (mean ⌬Borg/⌬FEV1Exacerbation) was not related to the perception of dyspnea during histamine-induced bronchoconstriction (⌬Borg/⌬FEV1Histamine) ( ⫽ .08, P ⫽ .50, Fig 1). In addition, no significant relationship between PS20Histamine and PS20Exacerbation was found ( ⫽ ⫺.11, P ⫽ .40). After pooling 300 (50 ⫻ 6) observations in exacerbation, a significant concurrent relationship was apparent between Borg score and FEV1 (r2 ⫽ 0.11,  ⫽ ⫺.33, P ⬍ .001) (Fig 2). Eighteen patients (36.0%) were poor perceivers, defined by lack of a significant linear relation between Borg scores and FEV1 across time at exacerbation in each individual patient. In addition, 18 patients (36%) were poor perceivers, defined by a PS20Histamine value of less than 1 according to histamine challenge. However, only 22% of the poor perceivers of exacerbation did not sense histamine-induced bronchoconstriction (Table 4). The value of the agreement of poor perceivers between the 2 groups was ⫺0.21 (P ⫽ .10). Furthermore, perception of histamine-induced bronchoconstriction was lower than that of asthma exacerbation (PS20: 1.6 ⫾ 1.1 vs 2.8 ⫾ 2.5, respectively, P ⫽ .004; ⌬Borg/ ⌬FEV1: 0.08 ⫾ 0.05 vs 0.21 ⫾ 0.28, respectively, P ⫽ .001). Multiple linear regression analysis clarified that age ( ⫽ ⫺.37, P ⫽ .01) was a significant predictor for ⌬Borg/ ⌬FEV1Histamine, after adjusting for baseline FEV1 ( ⫽ ⫺.06, P ⫽ .74), asthma duration ( ⫽ .02, P ⫽ .87), PD20 ( ⫽ ⫺.03, P ⫽ .80), and sex ( ⫽ .17, P ⫽ .27) in histamineinduced bronchoconstriction. Multiple linear regression analysis also clarified that initial FEV1 ( ⫽ .35, P ⫽ .01) was a significant predictor for ⌬Borg/⌬FEV1Exacerbation after adjusting for age ( ⫽ ⫺.18, P ⫽ .10), asthma duration ( ⫽ ⫺.03, P ⫽ .80), PD20 ( ⫽ .07, P ⫽ .61), and sex ( ⫽ ⫺.13, P ⫽ .36) in asthma exacerbation.
Table 3. Bivariate Models With the ⌬Borg/⌬FEV1Histamine Value as the Dependent Variable and the ⌬Borg/⌬FEV1Exacerbation Values at Each Time Point as the Independent Variables ⌬Borg/⌬FEV1Exacerbation Intercept At admission 5 hours after admission 10 hours after admission 24 hours after admission 48 hours after admission 72 hours after admission
⌬Borg/⌬FEV1Histamine
*
P value
⫺.003 .23 .21 ⫺.007 ⫺.19 ⫺.13
⬍.001 .80 .10 .10 .60 .20 .30
Abbreviations: ⌬Borg/⌬FEV1Exacerbation, ratio of change in Borg score to the change in forced expiratory volume in 1 second (FEV1); ⌬Borg/ ⌬FEV1Histamine, Borg score change divided by the change in FEV1 as a percentage of the baseline FEV1. *  is the standardized regression coefficient.
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Table 4. Perception Categories According to Exacerbation and Histamine–Induced Bronchoconstriction
Category
Poor perceivers of histamineinduced bronchoconstriction Accurate perceivers of histamine-induced bronchoconstriction
Figure 1. The relationship between the Borg score change divided by the change in forced expiratory volume in 1 second (FEV1) as a percentage of the baseline FEV1 (⌬Borg/⌬FEV1Histamine) and mean ratio of change in Borg score to the change in FEV1 (⌬Borg/⌬FEV1Exacerbation).
Figure 2. The relation between changes in Borg score and forced expiratory volume in 1 second (FEV1) during exacerbation.
DISCUSSION The present study indicated that the perception of dyspnea during asthma exacerbation was unrelated to the perception of dyspnea during histamine-induced bronchoconstriction. Only 22% of the poor perceivers of exacerbation did not sense histamine-induced bronchoconstriction. In addition, baseline FEV1 was a significant predictor for poor perception of exacerbation-induced bronchoconstriction, whereas older age affected the perception of induced bronchoconstriction. Furthermore, the intensity of the dyspnea that occurred because of histamine-induced bronchoconstriction was lower than the intensity that occurred because of asthma exacerbation. Studies concerning the perception of exacerbation in asthmatic patients are scarce. The effect of changes in airway inflammation on perception is unclear. The difference in the
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Accurate Poor perceivers perceivers of of exacerbation, exacerbation, No. (%) (n ⴝ 18) No. (%) (n ⴝ 32) 4 (22)
14 (44)
14 (78)
18 (56)
perception of exacerbation and induced bronchoconstriction may be related to the type of airways constricted, the rapidity with which the constriction develops, or perhaps the presence or absence of an inflammatory component.21 Similarly, Boudreau et al22 investigated the relationship between intensity of dyspnea sensed during histamine-induced bronchoconstriction and the magnitude of breathlessness during spontaneously occurring bronchoconstriction and evaluated the relationship between breathlessness and flow rates during a 7-day observation period in 17 patients. They concluded that there was no correlation between the perception of breathlessness during changes in airway caliber provoked in the laboratory setting and breathlessness experienced during spontaneously occurring bronchoconstriction. On the other hand, the study by Weiner et al23 showed that the perception of dyspnea during methacholine-induced bronchoconstriction was similar to that during -agonist–induced bronchodilation, a result that is not consistent with the results of the present study in which the perception of histamine-induced bronchoconstriction was compared with that of exacerbation-related bronchoconstriction in asthmatic patients. Although bronchial smooth muscle dilation plays an important role in the perception of dyspnea during -agonist–induced bronchodilation, mainly the changes in airway inflammation beside the changes in airway smooth muscle predict the perception of dyspnea during recovery from exacerbation. Turcotte et al21 indicated that late asthmatic response following antigen challenge in 2 patients and exercise in 1 patient was not perceived as well as early asthmatic response. They concluded that the reduced perception of breathlessness after the late response could be due to differences in the type of airways constricted. Furthermore, in a study designed to characterize the late response in exercise-induced asthma, Bierman et al24 attempted to identify the airways affected in the immediate and the late responses. Their data suggest that large and small airways appear to be constricted in the early response, whereas small airways appear to be constricted primarily in the late response. These studies were performed during a stable period. In the present study, the perception of asthma exacerbation was compared with that of histamineinduced bronchoconstriction during a stable period. Exacerbation and induced bronchoconstriction may yield different
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sensations, activating different sensory mechanisms. The basic concept underlying this law is simple: a discrete symptom is associated with a specific neural process; different symptoms have different neural processes.4 Pulmonary afferents, chest wall afferents, and motor command give rise to perceptual experiences during breathing, and the magnitude and interrelationship between these neural stimuli change in the presence of asthma. Both mechanoreceptor afferent information and motor discharge may individually give rise to perceived symptoms, or the altered balance between motor drive and mechanical displacement may be perceived as “inappropriate.”25 Another important finding of the present study was that there was a significant concurrent relationship between the changes in Borg score and FEV1 during exacerbation. Previously, it was reported that short-term change in FEV1 predicted short-term changes in breathlessness of 12 patients, aged 27 to 62 years, with exacerbation of asthma.26 Furthermore, another study indicated that the relationship between changes in peak expiratory flow rate and symptoms over time was poor in 21 adults with moderate to severe asthma ( ⫽ ⫺.17, P ⬍ .001).27 In contrast, Boulet et al28 showed that there was no significant correlation between the improvement of airflow obstruction and asthma symptoms in 18 (69%) of 26 asthmatic patients who recorded their respiratory symptoms and twice-daily peak expiratory flow rates during 4 weeks after the acute exacerbation. Kendrick et al29 also reported that 152 (60%) of 255 asthmatic patients aged 17 to 76 years showed no significant correlation between visual analog asthma scores and simultaneous peak flow measurements (P ⬎ .05) for 14 consecutive days and were termed poor discriminators. Lastly, the present study clarified that older age was a significant predictor of poor perception of histamine-induced bronchoconstriction after adjusting for disease severity, asthma duration, and sex. Similarly, reduced perception of bronchoconstriction due to chemical agents has been reported in elderly asthmatic patients.30,31 In conclusion, the present study suggests that exacerbation may cause more dyspnea for a given change in FEV1 than chemical agents such as histamine. Perception of dyspnea during asthma exacerbation is not correlated with the perception of dyspnea during histamine-induced bronchoconstriction. Therefore, the perception of dyspnea during histamineinduced bronchoconstriction cannot be used to identify the asthmatic patients who poorly perceive dyspnea. Studies concerning the perception of chemically induced bronchoconstriction should be interpreted with caution in clinical practice. REFERENCES 1. Burdon JG, Juniper EF, Killian KJ, Hargreave FE, Campbell EJ. The perception of breathlessness in asthma. Am Rev Respir Dis. 1982;126:825– 828. 2. Bijl-Hofland ID, Cloosterman SG, Folgering HT, Akkermans RP, van Schayck CP. Relation of the perception of airway
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obstruction to the severity of asthma. Thorax. 1999;54:15–19. 3. Wamboldt MZ, Bihun JT, Szefler S, Hewitt J. Perception of induced bronchoconstriction in a community sample of adolescents. J Allergy Clin Immunol. 2000;106:1102–1107. 4. Killian KJ, Watson R, Otis J, St Amand TA, O’Byrne PM. Symptom perception during acute bronchoconstriction. Am J Respir Crit Care Med. 2000;162:490 – 496. 5. Salome CM, Leuppi JD, Freed R, Marks GB. Perception of airway narrowing during reduction of inhaled corticosteroids and asthma exacerbation. Thorax. 2003;58:1042–1047. 6. Silverman B, James C, Misra S, Schneider AT, Chiaramonte LT. Training perception of acute airflow obstruction. Ann Allergy Asthma Immunol. 1990;64:373–375. 7. Eckert DJ, Catcheside PG, McEvoy RD. Blunted sensation of dyspnoea and near fatal asthma. Eur Respir J. 2004;24: 197–199. 8. Cade JF, and Pain MCF. Pulmonary function during clinical remission of asthma. How reversible is asthma? Aust N Z J Med. 1973;3:545–551. 9. Rubinfeld AR, Pain MCF. Perception of asthma. Lancet. 1976; 24:882– 884. 10. Rubinfeld AR, Pain MCF. How mild is mild asthma? Thorax. 1977;32:177–181. 11. Rubinfeld AR, Pain MCF. Conscious perception of bronchospasm as a protective phenomenon in asthma. Chest. 1977;72: 154 –158. 12. Kikuchi Y, Okabe S, Tamura G, et al. Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med. 1994;12,330:1329 –1334. 13. Magadle R, Berar-Yanay N, Weiner P. The risk of hospitalization and near-fatal and fatal asthma in relation to the perception of dyspnea. Chest. 2002;121:329 –333. 14. American Thoracic Society. Standards for diagnosis and care of patients with chronic obstructive pulmonary diseases (COPD) and asthma. Am Rev Respir Dis. 1987;136:225–244. 15. National Asthma Education Program. Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Institutes of Health; 1991. Publication 91–3042. 16. Borg G. A category scale with ratio properties for intermodal and interindividual comparisons. In: Geissler HG, Petzold P, eds. Psychophysical Judgement and the Process of Perception. Berlin, Germany: VEB Deutscher Verlag der Wissenschaften; 1982:25–34. 17. Wilson RC, Jones PWA. comparison of the visual analogue scale and modified Borg scale for the measurement of dyspnoea during exercise. Clin Sci. 1989;76:277–282. 18. Foresi A, Mattoli S, Corbo GM, et al. Comparison of bronchial response to ultrasonically nebulized distilled water, exercise and methacholine in asthma. Chest. 1986;90:822– 826. 19. Boulet LP, Leblanc P, Turcotte H. Perception scoring of induced bronchoconstriction as an index of awareness of asthma symptoms. Chest. 1994;105:1430 –1433. 20. Rutgers SR, ten Hacken NH, Koeter GH, Postma DS. Borg scores before and after challenge with adenosine 5-monophosphate and methacholine in subjects with COPD and asthma. Eur Respir J. 2000;16:486 – 490. 21. Turcotte H, Corbeil F, Boulet LP. Perception of breathlessness during bronchoconstriction induced by antigen, exercise, and histamine challenges. Thorax. 1990;45:914 –918. 22. Boudreau D, Styhler A, Gray-Donald K, Martin JG. A comparison of breathlessness during spontaneous asthma and hista-
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23.
24. 25. 26. 27.
28.
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mine-induced bronchoconstriction. Clin Invest Med. 1995;18: 25–32. Weiner P, Beckerman M, Berar-Yanay N, Magadle R. The perception of dyspnea after bronchoconstriction and bronchodilation in patients with asthma. Respir Med. 2003;97: 1120 –1125. Bierman CW, Spiro SG, Petheram I. Characterization of the late response in exercise-induced asthma. J Allergy Clin Immunol. 1984;74:701–706. Banzett RB, Dempsey JA, O’Donnell DE, Wamboldt MZ. Symptom perception and respiratory sensation in asthma. Am J Respir Crit Care Med. 2000;162:1178 –1182. Rosi E, Lanini B, Ronchi MC, et al. Dyspnea, respiratory function and sputum profile in asthmatic patients during exacerbations. Respir Med. 2002;96:745–750. Apter AJ, Affleck G, Reisine ST, et al. Perception of airway obstruction in asthma: sequential daily analyses of symptoms, peak expiratory flow rate, and mood. J Allergy Clin Immunol. 1997;99:605– 612. Boulet LP, Milot J, Turcotte H. Relationship between changes in diurnal variation of expiratory flows, lung volumes and
respiratory symptoms after acute asthma. Respir Med. 1991;85: 487– 493. 29. Kendrick AH, Higgs CM, Whitfield MJ, Laszlo G. Accuracy of perception of severity of asthma: patients treated in general practice. BMJ. 1993;14:422– 424. 30. Connolly MJ, Crowley JJ, Charan NB, Nielson CP, Vestal RE. Reduced subjective awareness of bronchoconstriction provoked by methacholine in elderly asthmatic and normal subjects as measured on a simple awareness scale. Thorax. 1992;47: 410 – 413. 31. Ekici M, Apan A, Ekici A, Erdemoglu AK. Perception of bronchoconstriction in elderly asthmatics. J Asthma. 2001;38: 691– 696.
Requests for reprints should be addressed to: Mehmet Ekici, MD Ataturk Bulvari 9. sok. Haci Mustafa Bey Ap. No. 2/2 Kirikkale, 07100 Turkey E-mail: [email protected]
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Background: Numerous studies have been performed concerning the perception of dyspnea during changes in airway caliber provoked in the laboratory setting, but studies of asthma exacerbation are scarce. Objective: To investigate whether the perception of dyspnea during histamine-induced bronchoconstriction might be used to identify patients with asthma who sense dyspnea poorly during exacerbation. Methods: The perception of dyspnea in 50 patients (45 female, 5 male) with asthma was evaluated at admission with exacerbation and during a stable period. Perceived intensity of dyspnea was estimated using a modified Borg scale. The perception of dyspnea in the stable period 4 to 6 weeks after exacerbation was measured with the histamine challenge test. Perception parameters were defined as the change in Borg score divided by the change in forced expiratory volume in 1 second (FEV1) as a percentage of the baseline FEV1 (⌬Borg/⌬FEV1) and as the Borg score at 20% decrease (PS20Histamine) or increase (PS20Exacerbation) in FEV1. Results: The perception of dyspnea during asthma exacerbation was unrelated to the perception of dyspnea during histamineinduced bronchoconstriction (for ⌬Borg/⌬FEV1,  ⫽ .08, P ⫽ .50; for PS20,  ⫽ ⫺.11, P ⫽ .40). The value for the agreement of poor perceivers at exacerbation and during the stable period was – 0.21 (P ⫽ .10). However, the intensity of dyspnea caused by histamine-induced bronchoconstriction was lower than that caused by asthma exacerbation (PS20: 1.6 ⫾ 1.1 vs 2.8 ⫾ 2.5, respectively, P ⫽ .004; ⌬Borg/⌬FEV1: 0.08 ⫾ 0.05 vs 0.21 ⫾ 0.28, respectively, P ⫽ .001). Conclusion: The perception of dyspnea during asthma exacerbation is not correlated with the perception of dyspnea during histamine-induced bronchoconstriction. Therefore, the perception of dyspnea during histamine-induced bronchoconstriction cannot be used to identify the asthmatic patients who perceive dyspnea poorly. Ann Allergy Asthma Immunol. 2006;96:707–712.
INTRODUCTION The perception of breathlessness during bronchoconstriction substantially varies among patients.1,2 By definition, symptom perception is a subjective measure. What is rated as slight to one person may be perceived as severe by another.3 The severity of bronchoconstriction is the major contributor to asthma symptoms but has substantial residual variability, perhaps owing to fear of impending harm, sensory adaptation, and intrinsic perceptual impairment.4 The perception of airway narrowing is likely to be an important determinant of symptoms of asthma.5 Subjective perception of airflow during acute obstruction has been shown to often be inaccurate.6 Accurate recognition of asthma symptoms is essential for prompting individuals with acute asthma to increase medication use or seek medical assistance.7,8 In 1976, Rubinfeld and Pain9,10 reported that asthmatic patients with “just noticeable” dyspnea had highly variable pulmonary impairment during
* Kirikkale University Faculty of Medicine, Department of Pulmonary Medicine, Kirikkale, Turkey. † Department of Internal Medicine, Kirikkale University Faculty of Medicine, Kirikkale, Turkey. Received for publication July 15, 2005. Accepted for publication in revised form September 5, 2005.
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naturally occurring asthma and chemically induced bronchoconstriction. However, this practice could lead to inadequate treatment if fluctuations in airways’ caliber are not always readily perceived by the patient.11 Reduced perception of dyspnea may predispose patients to a life-threatening attack.12,13 Numerous studies have been performed concerning the perception of dyspnea during changes in airway caliber provoked in the laboratory setting, but studies of asthma exacerbation are scarce. The aim of this study was to investigate whether the perception of dyspnea during histamineinduced bronchoconstriction might be used to identify asthmatic patients who sense dyspnea poorly during exacerbation. METHODS This study was part of a larger project that examined the course and consequences of diseases in asthmatic patients who had been followed up regularly for 7 years in the Respiratory Disease Clinics of Kirikkale University Hospital in Kirikkale, Turkey. A total of 50 asthmatic patients admitted to the hospital from September to December 2004 for exacerbation of asthma were entered into the study. Asthma diagnosis was made according to the American Thoracic Society criteria with symptoms of episodic wheezing, cough
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and shortness of breath responding to bronchodilators, and reversible airflow obstruction documented in at least one previous pulmonary function study.14 All patients were lifelong nonsmokers, and none of them reported a present or previous history of exposure to hazardous airborne substances. Asthma severity score was defined according to the National Asthma Education Program guidelines (ie, frequency of symptoms, degree of airflow obstruction, and frequency of use of oral glucocorticoids).15 Asthma exacerbation severity was defined as moderate and severe according to the 2002 Global Initiative for Asthma guidelines. Patients were evaluated at admission to the hospital and during a stable period after 4 to 6 weeks. Short-term treatment was initiated immediately after hospitalization. All patients were using inhaled steroids on discharge and were instructed to continue using this medication until their next visit. Ethical approval was obtained from the local ethics committee. Signed, informed consent was obtained from all patients. Perception of Bronchoconstriction During Exacerbation All asthmatic patients included in the study were evaluated on repeated occasions once admitted to the hospital: soon after admission (0 hour) and then at the 5th, 10th, 24th, 48th, and 72nd hours. Perceived intensity of dyspnea was estimated using a modified Borg scale (Table 1) labeled from 0 (no symptom) to 10 (maximum bearable).16,17 On each occasion the patients were first asked to score how dyspneic they felt using the Borg scale. At the same time, spirometry, including forced expiratory volume in 1 second (FEV1) and maximal midexpiratory flow, was performed using a portable spirometer (MicroLab, Kent, England). The change in Borg score (⌬Borg) was defined as the difference between the first evaluation (0 hour) and each of the assessments at 5, 10, 24, 48, and 72 hours after admission. The change in FEV1 as a percentage of the baseline FEV1 (⌬FEV1) was calculated by the following formula: (highest FEV1 L ⫺ lowest FEV1 L) ⫻ 00/lowest FEV1 L. The ratios of change in Borg score to the change in FEV1 (⌬Borg/ ⌬FEV1Exacerbation) at each occasion were then calculated to evaluate the individual patient’s ability to perceive changes in airway obstruction. In addition, the mean of these ratios was Table 1. Modified Borg Scale for the Intensity of Dyspnea Score 0 0.5 1 2 3 4 5 6 7 8 9 10
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Intensity of dyspnea Nothing at all Very, very slight (just noticeable) Very slight Slight Moderate Somewhat severe Severe Very severe Very, very severe (almost maximal) Maximal
determined to derive a summary value reflecting all 5 values. The perception score corresponding to an increase in FEV1 by 20% (PS20Exacerbation) was calculated by linear interpolation of the last 2 points on the curve of change in Borg score and increase in the FEV1 during exacerbation. Histamine Challenge Test A histamine challenge test was performed in the stable period 4 to 6 weeks after exacerbation. Patients were asked to stop using bronchodilating agents for at least 12 hours before the histamine challenge test was performed during the stable period. Pulmonary functions were measured by a flow-sensing spirometer connected to a computer for data analysis (Jaeger, Wuerzburg, Germany). Each patient inhaled doubling concentrations of histamine up to 16 mg/mL or until a 20% decrease in FEV1 via a dosimeter with an output of 0.9 ⫾ 0.3 mL per puff occurred (Dosimeter APS Pro; Jaeger).18 Bronchial response to histamine was expressed as the provocative dose that caused a 20% decrease in FEV1 (PD20) and was calculated by the same computer program (LAB, version 4.3; Jaeger). PD20 was expressed as the geometric mean ⫾ SD. Perception of Histamine-Induced Bronchoconstriction Perceived intensity of dyspnea was estimated with a modified Borg scale used in exacerbation. Patients were asked to select an appropriate definition to determine dyspnea at the time of histamine challenge test. They were completely free to decide their own self-scores but warned to determine only dyspnea and to disregard any irritation of the nose or throat during the scoring. Borg scores were recorded immediately before each percentage of the predicted value for FEV1 (FEV1%) measurement during the challenge test and at the maximum decrease in FEV1%. The perception score corresponding to a decrease in FEV1 by 20% (PS20Histamine) was calculated by linear interpolation of the last 2 points on the perception and decrease in the FEV1% curve of the histamine challenge test.19 The change in dyspnea during bronchoconstriction was expressed as the Borg score change divided by the change in FEV1 as a percentage of the baseline FEV1 (⌬Borg/ ⌬FEV1Histamine).20 Statistical Analysis Clinical data are expressed as mean ⫾ SD. Regression analysis (bivariate model) was used to examine the possible relation of ⌬Borg/⌬FEV1Histamine with ⌬Borg/⌬FEV1Exacerbation at baseline and 5, 10, 24, 48, and 72 hours after admission, as well as with the mean ⌬Borg/⌬FEV1Exacerbation. The ⌬Borg/ ⌬FEV1Exacerbation values at each occasion were separately entered into the model as covariates to prevent colinearity and to test their effect. The relationship between PS20Histamine and PS20Exacerbation was evaluated in a bivariate model. Two approaches were followed to examine the relationships among variables at the within-person level of change over time in exacerbation. The first examined within-person relationships expressed across the entire pooled data set of 300 person assessments (50
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patients 6 times a day). In this approach, after pooling observations in exacerbation (300 Borg scores and 300 FEV1% values), the concurrent relationship between Borg score and FEV1% was analyzed using a bivariate model. The second approach examined within-person relationships between Borg score and FEV1% value for each patient (n ⫽ 50) separately using a bivariate model to identify and account for individual differences in dyspnea perception accuracy. P ⬎ .05 for linear relationship between Borg and FEV1 defined poor perceivers. Differences and agreement of poor perceivers between the 2 groups (exacerbation and stable period) were analyzed using and 2 tests. Furthermore, multiple linear regression analysis was performed with the perception of bronchoconstriction (⌬Borg/⌬FEV1or PS20) as the dependent variable and asthma severity, PD20, sex, age, and disease duration as predictor variables. Predictor variables were entered in the multivariate model using a stepwise procedure. All tests were performed 2-sided, and P ⬍ .05 was considered statistically significant. RESULTS The study group consisted of 5 male and 45 female patients with a mean age of 54 years (age range, 34 –78 years). Asthma exacerbation severity was moderate in 24 patients and severe in 26 patients. The characteristics of the patients with asthma are given in Table 2. The mean value of FEV1% at the time of admission, being the nadir FEV1 relative to predicted FEV1, was 57.2 ⫾ 18.6, and the mean FEV1% during the stable period was 90.0 ⫾ 21.7. The mean value of nadir FEV1% occurred by histamine-induced bronchoconstriction was 59.7 ⫾ 22.2, which was comparable with that obtained at admission with asthma exacerbation (P ⫽ .54). The Borg score at nadir FEV1 during histamine-induced bronchoconstriction was lower than that at admission (2.0 ⫾ 1.5 vs 4.7 ⫾ 2.3, respectively, P ⬍ .001). There was no relation among the Borg score at the time of admission, the Borg score at the nadir FEV1%, and the Borg score at the nadir FEV1% during histamine challenge ( ⫽ .13, P ⫽ .30). The magnitude of dyspnea perceived during exacerbation (⌬Borg/⌬FEV1Exacerbation) at the 5th, 10th, 24th, 48th, and 72nd hours after admission did not relate to the magnitude of dyspnea perceived during histamine challenge (⌬Borg/ Table 2. Characteristics of the Patients With Asthma* Characteristics
Mean ⴞ SD (N ⴝ 50)
Age, y Female/male, No. Asthma duration, y FEV1% Reversibility, %
53.2 ⫾ 13.7 45/5 12.4 ⫾ 9.2 57.2 ⫾ 18.6 16.1 ⫾ 7.1
Abbreviation: FEV1%, percentage of the predicted value for forced expiratory volume in 1 second. * Data are given in mean ⫾ SD unless otherwise indicated.
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⌬FEV1Histamine) (Table 3). In addition, linear regression analysis indicated that the mean magnitude of dyspnea perception during asthma exacerbation (mean ⌬Borg/⌬FEV1Exacerbation) was not related to the perception of dyspnea during histamine-induced bronchoconstriction (⌬Borg/⌬FEV1Histamine) ( ⫽ .08, P ⫽ .50, Fig 1). In addition, no significant relationship between PS20Histamine and PS20Exacerbation was found ( ⫽ ⫺.11, P ⫽ .40). After pooling 300 (50 ⫻ 6) observations in exacerbation, a significant concurrent relationship was apparent between Borg score and FEV1 (r2 ⫽ 0.11,  ⫽ ⫺.33, P ⬍ .001) (Fig 2). Eighteen patients (36.0%) were poor perceivers, defined by lack of a significant linear relation between Borg scores and FEV1 across time at exacerbation in each individual patient. In addition, 18 patients (36%) were poor perceivers, defined by a PS20Histamine value of less than 1 according to histamine challenge. However, only 22% of the poor perceivers of exacerbation did not sense histamine-induced bronchoconstriction (Table 4). The value of the agreement of poor perceivers between the 2 groups was ⫺0.21 (P ⫽ .10). Furthermore, perception of histamine-induced bronchoconstriction was lower than that of asthma exacerbation (PS20: 1.6 ⫾ 1.1 vs 2.8 ⫾ 2.5, respectively, P ⫽ .004; ⌬Borg/ ⌬FEV1: 0.08 ⫾ 0.05 vs 0.21 ⫾ 0.28, respectively, P ⫽ .001). Multiple linear regression analysis clarified that age ( ⫽ ⫺.37, P ⫽ .01) was a significant predictor for ⌬Borg/ ⌬FEV1Histamine, after adjusting for baseline FEV1 ( ⫽ ⫺.06, P ⫽ .74), asthma duration ( ⫽ .02, P ⫽ .87), PD20 ( ⫽ ⫺.03, P ⫽ .80), and sex ( ⫽ .17, P ⫽ .27) in histamineinduced bronchoconstriction. Multiple linear regression analysis also clarified that initial FEV1 ( ⫽ .35, P ⫽ .01) was a significant predictor for ⌬Borg/⌬FEV1Exacerbation after adjusting for age ( ⫽ ⫺.18, P ⫽ .10), asthma duration ( ⫽ ⫺.03, P ⫽ .80), PD20 ( ⫽ .07, P ⫽ .61), and sex ( ⫽ ⫺.13, P ⫽ .36) in asthma exacerbation.
Table 3. Bivariate Models With the ⌬Borg/⌬FEV1Histamine Value as the Dependent Variable and the ⌬Borg/⌬FEV1Exacerbation Values at Each Time Point as the Independent Variables ⌬Borg/⌬FEV1Exacerbation Intercept At admission 5 hours after admission 10 hours after admission 24 hours after admission 48 hours after admission 72 hours after admission
⌬Borg/⌬FEV1Histamine
*
P value
⫺.003 .23 .21 ⫺.007 ⫺.19 ⫺.13
⬍.001 .80 .10 .10 .60 .20 .30
Abbreviations: ⌬Borg/⌬FEV1Exacerbation, ratio of change in Borg score to the change in forced expiratory volume in 1 second (FEV1); ⌬Borg/ ⌬FEV1Histamine, Borg score change divided by the change in FEV1 as a percentage of the baseline FEV1. *  is the standardized regression coefficient.
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Table 4. Perception Categories According to Exacerbation and Histamine–Induced Bronchoconstriction
Category
Poor perceivers of histamineinduced bronchoconstriction Accurate perceivers of histamine-induced bronchoconstriction
Figure 1. The relationship between the Borg score change divided by the change in forced expiratory volume in 1 second (FEV1) as a percentage of the baseline FEV1 (⌬Borg/⌬FEV1Histamine) and mean ratio of change in Borg score to the change in FEV1 (⌬Borg/⌬FEV1Exacerbation).
Figure 2. The relation between changes in Borg score and forced expiratory volume in 1 second (FEV1) during exacerbation.
DISCUSSION The present study indicated that the perception of dyspnea during asthma exacerbation was unrelated to the perception of dyspnea during histamine-induced bronchoconstriction. Only 22% of the poor perceivers of exacerbation did not sense histamine-induced bronchoconstriction. In addition, baseline FEV1 was a significant predictor for poor perception of exacerbation-induced bronchoconstriction, whereas older age affected the perception of induced bronchoconstriction. Furthermore, the intensity of the dyspnea that occurred because of histamine-induced bronchoconstriction was lower than the intensity that occurred because of asthma exacerbation. Studies concerning the perception of exacerbation in asthmatic patients are scarce. The effect of changes in airway inflammation on perception is unclear. The difference in the
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Accurate Poor perceivers perceivers of of exacerbation, exacerbation, No. (%) (n ⴝ 18) No. (%) (n ⴝ 32) 4 (22)
14 (44)
14 (78)
18 (56)
perception of exacerbation and induced bronchoconstriction may be related to the type of airways constricted, the rapidity with which the constriction develops, or perhaps the presence or absence of an inflammatory component.21 Similarly, Boudreau et al22 investigated the relationship between intensity of dyspnea sensed during histamine-induced bronchoconstriction and the magnitude of breathlessness during spontaneously occurring bronchoconstriction and evaluated the relationship between breathlessness and flow rates during a 7-day observation period in 17 patients. They concluded that there was no correlation between the perception of breathlessness during changes in airway caliber provoked in the laboratory setting and breathlessness experienced during spontaneously occurring bronchoconstriction. On the other hand, the study by Weiner et al23 showed that the perception of dyspnea during methacholine-induced bronchoconstriction was similar to that during -agonist–induced bronchodilation, a result that is not consistent with the results of the present study in which the perception of histamine-induced bronchoconstriction was compared with that of exacerbation-related bronchoconstriction in asthmatic patients. Although bronchial smooth muscle dilation plays an important role in the perception of dyspnea during -agonist–induced bronchodilation, mainly the changes in airway inflammation beside the changes in airway smooth muscle predict the perception of dyspnea during recovery from exacerbation. Turcotte et al21 indicated that late asthmatic response following antigen challenge in 2 patients and exercise in 1 patient was not perceived as well as early asthmatic response. They concluded that the reduced perception of breathlessness after the late response could be due to differences in the type of airways constricted. Furthermore, in a study designed to characterize the late response in exercise-induced asthma, Bierman et al24 attempted to identify the airways affected in the immediate and the late responses. Their data suggest that large and small airways appear to be constricted in the early response, whereas small airways appear to be constricted primarily in the late response. These studies were performed during a stable period. In the present study, the perception of asthma exacerbation was compared with that of histamineinduced bronchoconstriction during a stable period. Exacerbation and induced bronchoconstriction may yield different
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sensations, activating different sensory mechanisms. The basic concept underlying this law is simple: a discrete symptom is associated with a specific neural process; different symptoms have different neural processes.4 Pulmonary afferents, chest wall afferents, and motor command give rise to perceptual experiences during breathing, and the magnitude and interrelationship between these neural stimuli change in the presence of asthma. Both mechanoreceptor afferent information and motor discharge may individually give rise to perceived symptoms, or the altered balance between motor drive and mechanical displacement may be perceived as “inappropriate.”25 Another important finding of the present study was that there was a significant concurrent relationship between the changes in Borg score and FEV1 during exacerbation. Previously, it was reported that short-term change in FEV1 predicted short-term changes in breathlessness of 12 patients, aged 27 to 62 years, with exacerbation of asthma.26 Furthermore, another study indicated that the relationship between changes in peak expiratory flow rate and symptoms over time was poor in 21 adults with moderate to severe asthma ( ⫽ ⫺.17, P ⬍ .001).27 In contrast, Boulet et al28 showed that there was no significant correlation between the improvement of airflow obstruction and asthma symptoms in 18 (69%) of 26 asthmatic patients who recorded their respiratory symptoms and twice-daily peak expiratory flow rates during 4 weeks after the acute exacerbation. Kendrick et al29 also reported that 152 (60%) of 255 asthmatic patients aged 17 to 76 years showed no significant correlation between visual analog asthma scores and simultaneous peak flow measurements (P ⬎ .05) for 14 consecutive days and were termed poor discriminators. Lastly, the present study clarified that older age was a significant predictor of poor perception of histamine-induced bronchoconstriction after adjusting for disease severity, asthma duration, and sex. Similarly, reduced perception of bronchoconstriction due to chemical agents has been reported in elderly asthmatic patients.30,31 In conclusion, the present study suggests that exacerbation may cause more dyspnea for a given change in FEV1 than chemical agents such as histamine. Perception of dyspnea during asthma exacerbation is not correlated with the perception of dyspnea during histamine-induced bronchoconstriction. Therefore, the perception of dyspnea during histamineinduced bronchoconstriction cannot be used to identify the asthmatic patients who poorly perceive dyspnea. Studies concerning the perception of chemically induced bronchoconstriction should be interpreted with caution in clinical practice. REFERENCES 1. Burdon JG, Juniper EF, Killian KJ, Hargreave FE, Campbell EJ. The perception of breathlessness in asthma. Am Rev Respir Dis. 1982;126:825– 828. 2. Bijl-Hofland ID, Cloosterman SG, Folgering HT, Akkermans RP, van Schayck CP. Relation of the perception of airway
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obstruction to the severity of asthma. Thorax. 1999;54:15–19. 3. Wamboldt MZ, Bihun JT, Szefler S, Hewitt J. Perception of induced bronchoconstriction in a community sample of adolescents. J Allergy Clin Immunol. 2000;106:1102–1107. 4. Killian KJ, Watson R, Otis J, St Amand TA, O’Byrne PM. Symptom perception during acute bronchoconstriction. Am J Respir Crit Care Med. 2000;162:490 – 496. 5. Salome CM, Leuppi JD, Freed R, Marks GB. Perception of airway narrowing during reduction of inhaled corticosteroids and asthma exacerbation. Thorax. 2003;58:1042–1047. 6. Silverman B, James C, Misra S, Schneider AT, Chiaramonte LT. Training perception of acute airflow obstruction. Ann Allergy Asthma Immunol. 1990;64:373–375. 7. Eckert DJ, Catcheside PG, McEvoy RD. Blunted sensation of dyspnoea and near fatal asthma. Eur Respir J. 2004;24: 197–199. 8. Cade JF, and Pain MCF. Pulmonary function during clinical remission of asthma. How reversible is asthma? Aust N Z J Med. 1973;3:545–551. 9. Rubinfeld AR, Pain MCF. Perception of asthma. Lancet. 1976; 24:882– 884. 10. Rubinfeld AR, Pain MCF. How mild is mild asthma? Thorax. 1977;32:177–181. 11. Rubinfeld AR, Pain MCF. Conscious perception of bronchospasm as a protective phenomenon in asthma. Chest. 1977;72: 154 –158. 12. Kikuchi Y, Okabe S, Tamura G, et al. Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med. 1994;12,330:1329 –1334. 13. Magadle R, Berar-Yanay N, Weiner P. The risk of hospitalization and near-fatal and fatal asthma in relation to the perception of dyspnea. Chest. 2002;121:329 –333. 14. American Thoracic Society. Standards for diagnosis and care of patients with chronic obstructive pulmonary diseases (COPD) and asthma. Am Rev Respir Dis. 1987;136:225–244. 15. National Asthma Education Program. Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Institutes of Health; 1991. Publication 91–3042. 16. Borg G. A category scale with ratio properties for intermodal and interindividual comparisons. In: Geissler HG, Petzold P, eds. Psychophysical Judgement and the Process of Perception. Berlin, Germany: VEB Deutscher Verlag der Wissenschaften; 1982:25–34. 17. Wilson RC, Jones PWA. comparison of the visual analogue scale and modified Borg scale for the measurement of dyspnoea during exercise. Clin Sci. 1989;76:277–282. 18. Foresi A, Mattoli S, Corbo GM, et al. Comparison of bronchial response to ultrasonically nebulized distilled water, exercise and methacholine in asthma. Chest. 1986;90:822– 826. 19. Boulet LP, Leblanc P, Turcotte H. Perception scoring of induced bronchoconstriction as an index of awareness of asthma symptoms. Chest. 1994;105:1430 –1433. 20. Rutgers SR, ten Hacken NH, Koeter GH, Postma DS. Borg scores before and after challenge with adenosine 5-monophosphate and methacholine in subjects with COPD and asthma. Eur Respir J. 2000;16:486 – 490. 21. Turcotte H, Corbeil F, Boulet LP. Perception of breathlessness during bronchoconstriction induced by antigen, exercise, and histamine challenges. Thorax. 1990;45:914 –918. 22. Boudreau D, Styhler A, Gray-Donald K, Martin JG. A comparison of breathlessness during spontaneous asthma and hista-
711
23.
24. 25. 26. 27.
28.
712
mine-induced bronchoconstriction. Clin Invest Med. 1995;18: 25–32. Weiner P, Beckerman M, Berar-Yanay N, Magadle R. The perception of dyspnea after bronchoconstriction and bronchodilation in patients with asthma. Respir Med. 2003;97: 1120 –1125. Bierman CW, Spiro SG, Petheram I. Characterization of the late response in exercise-induced asthma. J Allergy Clin Immunol. 1984;74:701–706. Banzett RB, Dempsey JA, O’Donnell DE, Wamboldt MZ. Symptom perception and respiratory sensation in asthma. Am J Respir Crit Care Med. 2000;162:1178 –1182. Rosi E, Lanini B, Ronchi MC, et al. Dyspnea, respiratory function and sputum profile in asthmatic patients during exacerbations. Respir Med. 2002;96:745–750. Apter AJ, Affleck G, Reisine ST, et al. Perception of airway obstruction in asthma: sequential daily analyses of symptoms, peak expiratory flow rate, and mood. J Allergy Clin Immunol. 1997;99:605– 612. Boulet LP, Milot J, Turcotte H. Relationship between changes in diurnal variation of expiratory flows, lung volumes and
respiratory symptoms after acute asthma. Respir Med. 1991;85: 487– 493. 29. Kendrick AH, Higgs CM, Whitfield MJ, Laszlo G. Accuracy of perception of severity of asthma: patients treated in general practice. BMJ. 1993;14:422– 424. 30. Connolly MJ, Crowley JJ, Charan NB, Nielson CP, Vestal RE. Reduced subjective awareness of bronchoconstriction provoked by methacholine in elderly asthmatic and normal subjects as measured on a simple awareness scale. Thorax. 1992;47: 410 – 413. 31. Ekici M, Apan A, Ekici A, Erdemoglu AK. Perception of bronchoconstriction in elderly asthmatics. J Asthma. 2001;38: 691– 696.
Requests for reprints should be addressed to: Mehmet Ekici, MD Ataturk Bulvari 9. sok. Haci Mustafa Bey Ap. No. 2/2 Kirikkale, 07100 Turkey E-mail: [email protected]
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