Clinical and Experimental Allergy, 1992, Volume 22, pages
Bronchial responsiveness to exercise in a random sample of 494 children and adolescents from Copenhagen V. BACKER and C. S. ULRIK Laboratory of Respiratory Physiology. Department of Medicine B. University Hospital, Rigshospitalet. Copenhagen, Denmark Summary To investigate the bronchial response to exercise, we studied a random sample of 494 children and adolescents, aged 7-16 years, from Copenhagen. Exercise challenge consisted olstcady running on a lO'Vn sloping treadmill for 6 min in a climate chamber. Furthermore, in 464 subjects a hislamine challenge test was also performed. Of the 494 subjects studied, 81 (16"..) had at least 10% and 30 (6%) at least 15% reduction in FEV, within 15 min after exercise. Twenty-nine (6'/.,) subjects had bronchial hy[>erresponsiveness to both histamine and exercise, 48 (10%) subjects had bronchial hyper responsiveness to exercise, but histamine responsiveness within the normal range, whereas 340 (73%) subjects had neither bronchial hyperresponsiveness to exercise nor inhaled histamine. With regard to the presence of asthma defined as substantial exercise induced bronchoconstriction (A-FEV, ^ lO^.i), exercise testing may not be appropriate for identifying clinical asthma in a random sample, becausethehighest predictive value of a positive lest was 25%. On the other hand, a history of clinical asthma was frequently associated with increased bronchial responsiveness to exercise (77'^,)- In conclusion. 16% of a random sample o^ children and adolescents had abnormal bronchial responsiveness to exercise {AFEV|^10%), 6% of the subjects had a A F E V I 5 J 1 5 % . Furthermore, because of a low predictive value of a positive test, the exercise challenge test has only a supplementary role in the detection of clinical asthma in population samples. Clinical and Experimental Allergy, Vol. 22, pp. 741-747. Submitted 30 October 1991; revised 24 January 1992; 3 February 1992. Introduction
The prevalence o^ asthma among children and adolescents seems to be increasing in most countries. However, the prevalence of asthma differs substantially between countries [1 4], which may be caused by true differences or the fact that there is no generally accepted criteria for the diagnosis of asthma. Bronchial hyperresponsiveness (BH R) is one of the cardinal features ofasthma, and it has earlier been shown that the bronchial response to different stimuli are closely related in asthmatics [5 7]. BHRto inhaled stimuli such as histamine and methacholine can, however, also be demonstrated in some non-asthmatic subjects [1,3.8]. whereas a substantial bronchial response to exercise is seldom found in non-asthmatic subjects [9]. Thus. BHR toinhaled histamine or methacholine alone is Correspondence: Dr V. Backer, Jagtvcj 200. DK-2!00 Copenhagen. Denmark.
not sufficiently sensitive or specific to provide a definite diagnosis of clinical asthma [I .3], whereas exercise challenge test might be a more suitable method for differentiating subjects with symptoms of asthma from non-asthmatic subjects in population studies. Viral respiratory infections (VRI) are known to increase the severity of the asthmatic symptoms [10] and possibly the bronchial response to exercise, as the bronchial response to exercise correlates with the severity symptoms [9]. Furthermore, in non-asthmatic subjects, acute symptomatic viral respiratory infection is found to induce temporary increase in bronchial responsiveness to inhaled histamine [I I]. Non-asthmatic subjects with no evidence of recent VRI who have asymptomatic increased bronchial response to exercise may have bronchial lability to endogenous substances, which might be a stronger marker for future development ofasthma than bronchial hyperresponsiveness to inhaled agents. 741
742
V. Backer and C. S. Ulrik
The purpose of the present study was to investigate the prevalence of increased bronchial responsiveness to exercise in a random sample of Danish children and adolescents. Material Subject.s A random sample of 983 children and adolescents living in the area surrounding the University Hospital in Copenhagen was drawn from the civil registration list and invited to participate in the study in 1986. All invited subjects were born in the first week of each month, aged between 7 and 16 years (median 12 yr). and all were Caucasian. Five-hundred and twenty-seven (54'^) accepted the invitation and were examined, of whom 262 were boys and 265 were girls. A sample of 100 families, who did not respond when contacted by letter, was contacted by telelphone; the description of the nonresponders has been presented in a previous paper [2], All participants and their parents were interviewed by one person (V.B.) and completed a questionnaire about respiratory and allergic symptoms, i.e. symptoms of asthma (doctors diagnosis of asthma, wheezing, cough, dyspnoea, use and effeet of anti-asthmatic medication, and respiratory problems caused by provocative factors such as allergens and exercise) [12]. rhinitis (sneezing, running or blocked nose, not associated with colds), atopic dermatitis (an itchy dry rash on the face, arms or legs) and urticaria (itchy, generalized irregular weal-like lesions) in themselves, their siblings and their parents [2]. Of the 527 participants, 494 (94%) subjects had a technically satisfactory exercise challenge test, whereas 28 adolescents, mostly female teenagers, were unable to complete the exercise test after a few minutes' running because of poor physical fitness. None of these subjects experienced a reduction in FEVi after having stopped the test. The protocol was evaluated and approved by the local ethical committee and informed consent was obtained from all participants. The Helsinki II declaration was adhered to throughout the study. Methods In subjects with recent or present symptoms of chest infection, i.e. cough, dyspnoea or malaise with fever (>38 C), the examination was postponed for 6 weeks from the day of debut. Lung function and bronchial challenge tests All subjects were asked not to smoke for 2 hr before the tests and the subjects were asked to avoid anti-asthmatic
medication in accordance with the recommendations by Eiser et al. [13]. The forced expiratory volume in 1 sec (FEVi) (Vitalograph®), was measured in all participants. Predicted values (%pred) based on the sex and height of the subjects were calculated according to Zapletal [ 14]. A bronchial challenge test with inhaled histamine was performed in accordance with Cockcroft et al. [15]. The exercise test consisted of steady running on a iO'Mi sloping treadmill for 6 min in a climate chamber. The speed was adjusted to maintain the heart rate between 160 and 180 beats per minute. The ambient air temperature and relative humidity were kept constant at 21 C and 4050%, respectively. The FEVi was measured before the test, immediately after (time 0) and after I. 3. 5, tOand 15 min. If needed, inhalation of salbutamol {5 mg) was given to aid recovery. The highest of three FEV| readings was used for analysis. The maximum bronchial response to exercise (BRE), i.e. the maximal A~ FEVi within 15 min after exercise, was recorded and the response was calculated as the '^)A—FEV| from the maximum pre-exercise value [9]. Serum immunoglobulin class-specific antibodies Blood samples were kept at — 20 C, and later analysed for IgM antibodies towards parainfluenza virus 1 and 2. Influenza virus A and B, adenovirus; and IgM and IgG antibodies towards respiratory syncytial virus (RSV), using the enzyme linked immunosorbent assay (ELISA) technique. All subjects had viral antibodies measured when entering the study, whereas no convalescents serum was taken. Serum immunoglobulin E The total serum IgE was determined by paper radioimmunosorbent test (PRIST. Pharmacia Copenhagen. Denmark). Statistical analysis Association between the bronchial response to exercise and inhaled histamine was analysed by chi-square test and the association between BRF and frequency of viral antibodies was analysed by Fischers exact test. A Spearman rank correlation (rs) analysis was performed between the bronchial response to exercise and the serum values of log IgH. The sensitivity, specificity and the predictive value of a positive and a negative test (PV + and PV —, respectively) in regard to (i) respiratory symptoms and (ii) the exercise test were calculaled as follows: (i) sensitivity (positive test and respiratory symptoms/all with positive test), speci-
Bronchial rc.spon.sivene.Ks to exerci.'ie
743
Table 1. Relationship between bronchial response to inhaled histatnine and exercise among 464 unselected children and adolescents. Subjects with a PC20 < 8 0 mg/ ml were classified as having bronchial hyperresponsiveness (BHR).
BHR—All
Non-BHR—All (n = 388)
18
9 39 340
Exercise (A%FEV,)
10
20
30
40
50
60
70
80
90
100
10-14% < 10%
1]
47
Rjise positive rate (l-specificity)
Hg. I. ROC curves for 494 children and adolescents tested with exercise challenge test using increasing fall in FEV'i as cut-off. The diagnostit: value of bronchial responsiveness at lO'i'o (•), 12"/.. (*), 15% (A) iind 20% (•) are illustrated on the curve. The heavily drawn line (45 ) indicates the state where the diagnostic test provides no more than chance inrormaiion.
licity (negative test and no respiratory symptoms/all negative test). PV + (positive test and respiratory symptoms/all with respiratory symptoms) and PV— (negative test and no respiratory symptoms/all subjects without respiratory symptoms); (ii) sensilivily (asthmatic subjects with positive test/all asthmatic subjects), specificity (nonasthmatic with negative tesl/all non-asthmatic subjects). PV-i- (asthmatic subjects with positive test/all subjects with positive test) and PV — (non asthmatic subjects with negative test/all subjects with negative test). The receiver operating characteristic (ROC) curve (Fig. I) was constructed as the relationship between true positive rate (sensitivity) and false positive-rate (I-specificity) and was calculated for asthmatic/non-asthmatic and for each percentage change in FEVj after exercise. Furthermore, differences in bronchial response to exercise (BRE). FEV|, age and height between grotips of respiratory symptoms were analysed using Kruskal-Wallis lest and when appropriate, the Mann-Whitney test was used. Results The median reduction in FEVi after exercise in this random sample of children and adolescents was 4 0 % (95% percentile - 7 i o 15). Of the 494 subjects studied, 81 (16%) subjects had bronchial hyperresponsiveness to exercise (BHR-exercise) with at least 10% reduction in FEV| (AFEVi^lO%) within 15 min after exercise, of whom 30 (6^'Ai) had exercise-induced bronchoconstruction of AFEV|>15%. Four-hundred and sixty-four (94%) of the 494 subjects had a bronchial challenge with histamine and exercise performed (Table 1). A significant relationship between the bronchial response to exercise
* P. which is in keeping with fmdings from another Scandinavian country [4]. Furthermore, 13 subjects had monosymptomatic respiratory symptoms and BHR-exercise, which suggest that they may have clinical asthma as well, as a history of respiratory symptoms and signs of airway variability are suggestive for asthma [26]. One explanation, for the differences between 5 3% and 16%, might be that a separation between asthma and non-asthma is not possible as both bronchial responsiveness and respiratory symptoms appear to be a continuum instead of an on-off phenomenon; the point at which children claim that they have respiratory symptoms might be different, and slight exercise induced dyspnoea may never be recorded. Furthermore, poor health education in the community may also lead to an underreporting of respiratory symptoms. Anyhow, the present findings suggest that \6% of the population have airways which respond abnormally, similar to findings in asthmatic
746
V. Backer and C. S. Vlrik
airways. Although these findings are not suggestive for clinical asthma they may be suggestive for increased degree of pulmonary lability. We found that the subjects with a history of clinical asthma frequently had abnomial airway variability, suggesting that a clinical diagnosis of asthma is indicative for airway variability, as a high PV+ (77%,) was found. These findings support the presumption that bronchial asthma may be associated with perception of variability of airway obstruction both at rest and after exercise. The clinical diagnosis of asthma may therefore be used as screening for airway variability, whereas lack of symptoms are highly suggestive for lack of airway variability as the P V - was high (87%). On the other hand, the predictive value of a positive exercise test in this random sample of children and adolescents was disappointingly low (25%), supporting the suggestion that not only children with current clinical asthma have substantial exercise-induced bronchoconstriction. The present findings, however, are in keeping with studies of bronchial hyperresponsiveness to inhaled histaminc in random samples [27]. Cockcroft et al. [28] concluded on behalf of the literature that BHR to inhaled histamine is insufficient to discriminate between asthma and non-asthma in population samples. With regard to the presence of clinical asthma in unselected samples, exercise testing might also be inappropriate, whereas a history of asthma seems to be suggestive for airway variability. These findings suggest that exercise testing may be suitable in the clinical situation, especially in children with a higher degree of bronchial responsiveness [29]. Furthermore, exercise tests might be helpful for identifying a subject with increased risk for subsequent development of asthma in the future, but inappropriate to distinguish clinical asthma from non-asthma in population samples. In conclusion, significantly increased bronchial responsiveness to exercise was found in 16% of a random sample of children and adolescents aged 7 16 years. Furthermore, increased airway variability was of little value in regard to the clinical diagnosis of asthma, whereas the clinical diagnosis of asthma was diagnostic for increased airway variability. On the other hand, increased bronchial responsiveness to exercise indicates abnormal airway variability irrespective of the presence or absence of respiratory symptoms. Aeknowledgments
We are indebted to the laboratory of respiratory physiology for the use of equipment and to the laboratory technician, K. Bottger, who has helped with the tests. This study was supported by Department of Virology (Statens Serum Institute), The Danish Asthma and Allergy Foun-
dation, The Health Foundation, Pharmacia Copenhagen, Bayer Denmark, Christian X's Foundation and the Foundation of Engineer C. O. Hansen and wife H. E. born Kruse. References 1 Pattemore PK, Asher MI, Harrison AC, Mitchell EA, Rea HH, Stewart AW. Ethnic differences in prevalenee of asthma symptoms and bronchial hyperresponsiveness in New Zealand schoolchildren. Thorax 1989; 44:168-76. 2 Backer V, Bach-Mortensen N, Dirksen A. Prevalence atid predictors of bronchial hypcrresponsiveness in children aged 7-16 years. Allergy 1989; 44:214-19. 3 SalomeCM,PeatJK, Britton WJ. WoolcockAJ. Bronchiiil hyperresponsiveness in two populations of Australian schoolchildren. I. Relation to respiratory symptoms and diagnosed asthma. Clin Allergy 1987; 17:271-81. 4 Aberg N, Engstrom I, Lindberg U. Allergic diseases in Swedish school children. Aeta Psdiatr Scand 1989; 78:24652. 5 FouricPR. Joubert JR. Determination of airway hyperreactivity in asthmatic children: a comparison among exercise, nebulized water, and histamine challenge. Pediatr Fulmonol 1988; 4:2-7. 6 Mellis CM. Kattan M, Keens TG, Levison H. Comparative study of histamine and exercise challenges in asthmatic children. Am Rev Respir Dis 1978; 117:911-15. 7 Foresi A, Mattoli S, Corbo GM, Polidori G, Ciappi G. Comparison of bronchial responses to ultrasonically nebulized distilled water, exercise, and methacholine in asthma. Chest 1986; 90:822-826. 8 Sears MR. Jones DT. Holdaway MD, Hewitt CJ. Flannery FM. HerbisonGP ('?«/. Prevalence of bronchial reactivity to inhaled methacholine in New Zealand children. Thorax 1986; 41:283-9. 9 Anderson SD, Silverman M. Konig P, Godfrey S. Exerciseinduced asthma. Br J Dis Chest 1975; 69:1-39. 10 Wclliver RC, Wong DT. Middleton E. Sun M, McCarthy N, Ogra PL. Role of parainlluenza virus-specific IgE in pathogenesis of croup and wheezing subsequent to infection. J Pediatr 1982; 101:889-96, 11 Empey DW, Laitinen LA, Jacobs L, Gold WM, Nadcl JA, Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection. Am Rev Respir Dis 1976; 113:131-9. 12 Hopp RJ, Bewtra AK, Nair NM. Townley RG. Specificity and sensitivity of methacholine inhalation challenge in normal and asthmatic children. J Allergy Clin Immunol 1984; 74:154-8, 13 Eiser NM. Kerrebijn KF. Quanjer PH. Guidelines for standardization of bronchia! challenges with (nonspecific) bronchoconstricting agents. Bull Europ Physiopath Resp 1983; 19:495-514. 14 Zapletal A, Samanek M. Paul T. Lung function in children and adolescents. In: Herzog H, ed. Methods, reference values. Basel: Karger, 1987; I-220.
Bronchial responsiveness to exercise
15 Cockcroft DW, Killian DN, Mellon JJA. Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977; 7:235-43. 16 Bardagi S. Agudo A, Gonzalez CA. Romero P. Prevalence of exercise-induced bronchial hyperreactivity in children. Eur Respir J 1991; 4 (Suppl) 274s. 17 Keeley DJ, Neill P. Gallivan S. Comparison of the prevalence of reversible airways obstruction in rural and urban Zimbabwean children. Thorax 1991; 46:549- 53. 18 Barry DMJ, Burr ML, Limb ES. Prevalence of asthma among 12 years old children in New Zealand and South Wales: a comparative survey. Thorax 1991; 46:405 9. 19 Nierkerk van CH, Weinberg EG, Shore SC, De v Heese H, van Schalkwyk DJ. Prevalence of asthma: a comparative study of urban and rural Xhosa children. Clin Allergy 1979; 9.319-24. 20 Peat JK, Salome CM., Woolcock AJ. Longitudinal changes in atopy during a 4-year period: relation to bronchial hyperresponsiveness and respiratory symptoms in a population sample of Australian schoolchildren. J Allergy Clin Immunol 1990; 85:65-74. 21 Konig P, Godfrey S. Exercise-induced bronchial lability in monozygotic (identical) and dizygotic (nonidentical) twins. J Allergy Clin Immunol 1974; 54:280-7. 22 Mclntosh K, Ellis EF, Hoffman LS, Lybass TG. Eller JJ, Fulginiti VA. The association of viral and bacterial respira-
23
24
25
26
27
28
29
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tory infections with exacerbations of wheezing in young asthmatic children. J Pediatr 1973; 82:578-90. Busse WW. Respiratory infections; their role in airway responsiveness and the pathogenesis of asthma. J Allergy Clin Immunol 1990; 85:671-83. Laitinen LA, Elkin RB, Empye DW. Jacobs L, Mills J, NadelJ A. Bronchial hyperresponsiveness in normal subjects during attenuated influenza virus infection. Am Rev Respir Dis 1991: 143:358-61. Peal JK. Salome CM, Sedgwick CS, Kerrebijn J, Woolcock AJ. A prospective study of bronchial hyperresponsiveness and respiratory symptoms in a population of Australian schoolchildren. Clin Exp Allergy 1989; 19:299-306. Godfrey S, Springer C, Noviski N, Maayan CH. Avital A. Exercise but not methacholinc differentiates asthma from chronic lung disease in children. Thorax I99I; 46:488-92. Pattemore PK, Asher Ml, Harrison AC. Mitchell EA. Rea HH. Stewart AW. The interrelationship among bronchial hyperresponsiveness. the diagnosis of asthma, and asthma symptoms. Am Rev Respir Dis 1990; 142:549-54. Cockcroft DW, Hargreave FE. Airway hyperresponsiveness. Relevance of random population data to clinical usefulness. Am Rev Respir Dis 1990; 142:497 500. Clough JB. Hulchinson SA, Williams JD. Holgate ST. Airway response to exercise and methacholine in children with respiratory symptoms. Arch Dis Child 1991; 66:579-83.
Bronchial responsiveness to exercise in a random sample of 494 children and adolescents from Copenhagen V. BACKER and C. S. ULRIK Laboratory of Respiratory Physiology. Department of Medicine B. University Hospital, Rigshospitalet. Copenhagen, Denmark Summary To investigate the bronchial response to exercise, we studied a random sample of 494 children and adolescents, aged 7-16 years, from Copenhagen. Exercise challenge consisted olstcady running on a lO'Vn sloping treadmill for 6 min in a climate chamber. Furthermore, in 464 subjects a hislamine challenge test was also performed. Of the 494 subjects studied, 81 (16"..) had at least 10% and 30 (6%) at least 15% reduction in FEV, within 15 min after exercise. Twenty-nine (6'/.,) subjects had bronchial hy[>erresponsiveness to both histamine and exercise, 48 (10%) subjects had bronchial hyper responsiveness to exercise, but histamine responsiveness within the normal range, whereas 340 (73%) subjects had neither bronchial hyperresponsiveness to exercise nor inhaled histamine. With regard to the presence of asthma defined as substantial exercise induced bronchoconstriction (A-FEV, ^ lO^.i), exercise testing may not be appropriate for identifying clinical asthma in a random sample, becausethehighest predictive value of a positive lest was 25%. On the other hand, a history of clinical asthma was frequently associated with increased bronchial responsiveness to exercise (77'^,)- In conclusion. 16% of a random sample o^ children and adolescents had abnormal bronchial responsiveness to exercise {AFEV|^10%), 6% of the subjects had a A F E V I 5 J 1 5 % . Furthermore, because of a low predictive value of a positive test, the exercise challenge test has only a supplementary role in the detection of clinical asthma in population samples. Clinical and Experimental Allergy, Vol. 22, pp. 741-747. Submitted 30 October 1991; revised 24 January 1992; 3 February 1992. Introduction
The prevalence o^ asthma among children and adolescents seems to be increasing in most countries. However, the prevalence of asthma differs substantially between countries [1 4], which may be caused by true differences or the fact that there is no generally accepted criteria for the diagnosis of asthma. Bronchial hyperresponsiveness (BH R) is one of the cardinal features ofasthma, and it has earlier been shown that the bronchial response to different stimuli are closely related in asthmatics [5 7]. BHRto inhaled stimuli such as histamine and methacholine can, however, also be demonstrated in some non-asthmatic subjects [1,3.8]. whereas a substantial bronchial response to exercise is seldom found in non-asthmatic subjects [9]. Thus. BHR toinhaled histamine or methacholine alone is Correspondence: Dr V. Backer, Jagtvcj 200. DK-2!00 Copenhagen. Denmark.
not sufficiently sensitive or specific to provide a definite diagnosis of clinical asthma [I .3], whereas exercise challenge test might be a more suitable method for differentiating subjects with symptoms of asthma from non-asthmatic subjects in population studies. Viral respiratory infections (VRI) are known to increase the severity of the asthmatic symptoms [10] and possibly the bronchial response to exercise, as the bronchial response to exercise correlates with the severity symptoms [9]. Furthermore, in non-asthmatic subjects, acute symptomatic viral respiratory infection is found to induce temporary increase in bronchial responsiveness to inhaled histamine [I I]. Non-asthmatic subjects with no evidence of recent VRI who have asymptomatic increased bronchial response to exercise may have bronchial lability to endogenous substances, which might be a stronger marker for future development ofasthma than bronchial hyperresponsiveness to inhaled agents. 741
742
V. Backer and C. S. Ulrik
The purpose of the present study was to investigate the prevalence of increased bronchial responsiveness to exercise in a random sample of Danish children and adolescents. Material Subject.s A random sample of 983 children and adolescents living in the area surrounding the University Hospital in Copenhagen was drawn from the civil registration list and invited to participate in the study in 1986. All invited subjects were born in the first week of each month, aged between 7 and 16 years (median 12 yr). and all were Caucasian. Five-hundred and twenty-seven (54'^) accepted the invitation and were examined, of whom 262 were boys and 265 were girls. A sample of 100 families, who did not respond when contacted by letter, was contacted by telelphone; the description of the nonresponders has been presented in a previous paper [2], All participants and their parents were interviewed by one person (V.B.) and completed a questionnaire about respiratory and allergic symptoms, i.e. symptoms of asthma (doctors diagnosis of asthma, wheezing, cough, dyspnoea, use and effeet of anti-asthmatic medication, and respiratory problems caused by provocative factors such as allergens and exercise) [12]. rhinitis (sneezing, running or blocked nose, not associated with colds), atopic dermatitis (an itchy dry rash on the face, arms or legs) and urticaria (itchy, generalized irregular weal-like lesions) in themselves, their siblings and their parents [2]. Of the 527 participants, 494 (94%) subjects had a technically satisfactory exercise challenge test, whereas 28 adolescents, mostly female teenagers, were unable to complete the exercise test after a few minutes' running because of poor physical fitness. None of these subjects experienced a reduction in FEVi after having stopped the test. The protocol was evaluated and approved by the local ethical committee and informed consent was obtained from all participants. The Helsinki II declaration was adhered to throughout the study. Methods In subjects with recent or present symptoms of chest infection, i.e. cough, dyspnoea or malaise with fever (>38 C), the examination was postponed for 6 weeks from the day of debut. Lung function and bronchial challenge tests All subjects were asked not to smoke for 2 hr before the tests and the subjects were asked to avoid anti-asthmatic
medication in accordance with the recommendations by Eiser et al. [13]. The forced expiratory volume in 1 sec (FEVi) (Vitalograph®), was measured in all participants. Predicted values (%pred) based on the sex and height of the subjects were calculated according to Zapletal [ 14]. A bronchial challenge test with inhaled histamine was performed in accordance with Cockcroft et al. [15]. The exercise test consisted of steady running on a iO'Mi sloping treadmill for 6 min in a climate chamber. The speed was adjusted to maintain the heart rate between 160 and 180 beats per minute. The ambient air temperature and relative humidity were kept constant at 21 C and 4050%, respectively. The FEVi was measured before the test, immediately after (time 0) and after I. 3. 5, tOand 15 min. If needed, inhalation of salbutamol {5 mg) was given to aid recovery. The highest of three FEV| readings was used for analysis. The maximum bronchial response to exercise (BRE), i.e. the maximal A~ FEVi within 15 min after exercise, was recorded and the response was calculated as the '^)A—FEV| from the maximum pre-exercise value [9]. Serum immunoglobulin class-specific antibodies Blood samples were kept at — 20 C, and later analysed for IgM antibodies towards parainfluenza virus 1 and 2. Influenza virus A and B, adenovirus; and IgM and IgG antibodies towards respiratory syncytial virus (RSV), using the enzyme linked immunosorbent assay (ELISA) technique. All subjects had viral antibodies measured when entering the study, whereas no convalescents serum was taken. Serum immunoglobulin E The total serum IgE was determined by paper radioimmunosorbent test (PRIST. Pharmacia Copenhagen. Denmark). Statistical analysis Association between the bronchial response to exercise and inhaled histamine was analysed by chi-square test and the association between BRF and frequency of viral antibodies was analysed by Fischers exact test. A Spearman rank correlation (rs) analysis was performed between the bronchial response to exercise and the serum values of log IgH. The sensitivity, specificity and the predictive value of a positive and a negative test (PV + and PV —, respectively) in regard to (i) respiratory symptoms and (ii) the exercise test were calculaled as follows: (i) sensitivity (positive test and respiratory symptoms/all with positive test), speci-
Bronchial rc.spon.sivene.Ks to exerci.'ie
743
Table 1. Relationship between bronchial response to inhaled histatnine and exercise among 464 unselected children and adolescents. Subjects with a PC20 < 8 0 mg/ ml were classified as having bronchial hyperresponsiveness (BHR).
BHR—All
Non-BHR—All (n = 388)
18
9 39 340
Exercise (A%FEV,)
10
20
30
40
50
60
70
80
90
100
10-14% < 10%
1]
47
Rjise positive rate (l-specificity)
Hg. I. ROC curves for 494 children and adolescents tested with exercise challenge test using increasing fall in FEV'i as cut-off. The diagnostit: value of bronchial responsiveness at lO'i'o (•), 12"/.. (*), 15% (A) iind 20% (•) are illustrated on the curve. The heavily drawn line (45 ) indicates the state where the diagnostic test provides no more than chance inrormaiion.
licity (negative test and no respiratory symptoms/all negative test). PV + (positive test and respiratory symptoms/all with respiratory symptoms) and PV— (negative test and no respiratory symptoms/all subjects without respiratory symptoms); (ii) sensilivily (asthmatic subjects with positive test/all asthmatic subjects), specificity (nonasthmatic with negative tesl/all non-asthmatic subjects). PV-i- (asthmatic subjects with positive test/all subjects with positive test) and PV — (non asthmatic subjects with negative test/all subjects with negative test). The receiver operating characteristic (ROC) curve (Fig. I) was constructed as the relationship between true positive rate (sensitivity) and false positive-rate (I-specificity) and was calculated for asthmatic/non-asthmatic and for each percentage change in FEVj after exercise. Furthermore, differences in bronchial response to exercise (BRE). FEV|, age and height between grotips of respiratory symptoms were analysed using Kruskal-Wallis lest and when appropriate, the Mann-Whitney test was used. Results The median reduction in FEVi after exercise in this random sample of children and adolescents was 4 0 % (95% percentile - 7 i o 15). Of the 494 subjects studied, 81 (16%) subjects had bronchial hyperresponsiveness to exercise (BHR-exercise) with at least 10% reduction in FEV| (AFEVi^lO%) within 15 min after exercise, of whom 30 (6^'Ai) had exercise-induced bronchoconstruction of AFEV|>15%. Four-hundred and sixty-four (94%) of the 494 subjects had a bronchial challenge with histamine and exercise performed (Table 1). A significant relationship between the bronchial response to exercise
* P. which is in keeping with fmdings from another Scandinavian country [4]. Furthermore, 13 subjects had monosymptomatic respiratory symptoms and BHR-exercise, which suggest that they may have clinical asthma as well, as a history of respiratory symptoms and signs of airway variability are suggestive for asthma [26]. One explanation, for the differences between 5 3% and 16%, might be that a separation between asthma and non-asthma is not possible as both bronchial responsiveness and respiratory symptoms appear to be a continuum instead of an on-off phenomenon; the point at which children claim that they have respiratory symptoms might be different, and slight exercise induced dyspnoea may never be recorded. Furthermore, poor health education in the community may also lead to an underreporting of respiratory symptoms. Anyhow, the present findings suggest that \6% of the population have airways which respond abnormally, similar to findings in asthmatic
746
V. Backer and C. S. Vlrik
airways. Although these findings are not suggestive for clinical asthma they may be suggestive for increased degree of pulmonary lability. We found that the subjects with a history of clinical asthma frequently had abnomial airway variability, suggesting that a clinical diagnosis of asthma is indicative for airway variability, as a high PV+ (77%,) was found. These findings support the presumption that bronchial asthma may be associated with perception of variability of airway obstruction both at rest and after exercise. The clinical diagnosis of asthma may therefore be used as screening for airway variability, whereas lack of symptoms are highly suggestive for lack of airway variability as the P V - was high (87%). On the other hand, the predictive value of a positive exercise test in this random sample of children and adolescents was disappointingly low (25%), supporting the suggestion that not only children with current clinical asthma have substantial exercise-induced bronchoconstriction. The present findings, however, are in keeping with studies of bronchial hyperresponsiveness to inhaled histaminc in random samples [27]. Cockcroft et al. [28] concluded on behalf of the literature that BHR to inhaled histamine is insufficient to discriminate between asthma and non-asthma in population samples. With regard to the presence of clinical asthma in unselected samples, exercise testing might also be inappropriate, whereas a history of asthma seems to be suggestive for airway variability. These findings suggest that exercise testing may be suitable in the clinical situation, especially in children with a higher degree of bronchial responsiveness [29]. Furthermore, exercise tests might be helpful for identifying a subject with increased risk for subsequent development of asthma in the future, but inappropriate to distinguish clinical asthma from non-asthma in population samples. In conclusion, significantly increased bronchial responsiveness to exercise was found in 16% of a random sample of children and adolescents aged 7 16 years. Furthermore, increased airway variability was of little value in regard to the clinical diagnosis of asthma, whereas the clinical diagnosis of asthma was diagnostic for increased airway variability. On the other hand, increased bronchial responsiveness to exercise indicates abnormal airway variability irrespective of the presence or absence of respiratory symptoms. Aeknowledgments
We are indebted to the laboratory of respiratory physiology for the use of equipment and to the laboratory technician, K. Bottger, who has helped with the tests. This study was supported by Department of Virology (Statens Serum Institute), The Danish Asthma and Allergy Foun-
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