Exercise Challenge Test in 3- to 6-Year- Old Asthmatic Children*

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1 Original Research ASTHMA Exercise Challenge Test in 3- to 6-Year- Old Asthmatic Children* Daphna Vilozni, PhD; Lea Bentur, MD; Ori Efrati, MD; Asher Barak, MD; Amir Szeinberg, MD; David Shoseyov, MD; Yaacov Yahav, MD; and Arie Augarten, MD Rationale: The exercise challenge test (ECT) is a common tool to assess exercise-induced asthma (EIA) in school-aged children. EIA has not been explored in the early childhood setting. Objective: To assess the existence of EIA in children in this age group. Measurements and main results: A 6-min, controlled, free-run test was performed in 55 children (age range, 3 to 6 years old) who were classified into the following groups: 30 children in whom asthma had been previously diagnosed (group A); and 25 children with prolonged coughing (group B). Spirometry measurements were obtained before the run, and at 1, 2, 3, 5, 10, and 20 min after the run. A positive finding of EIA was defined as a 13% decrease from baseline FEV 1 or baseline forced expiratory volume in the first 0.5 s (FEV 0.5 ). The actual duration of each run was age-related (mean [ SD] duration, min). The nadir in indexes occurred after a mean time of min. A positive EIA finding determined by FEV 1 was present in 15 children, and by FEV 0.5 in 34 children. Twenty-six children were from group A, but only 8 children were from group B. Wheezing and/or prolonged expiration were associated with a positive test result in 31 of 34 children. Coughing was frequent in children with both negative and positive ECT findings. Conclusion: The present study documents for the first time the presence of EIA in response to a free-run test in early childhood. Our findings suggest that a free-run test for the presence of EIA is suitable, but that the running duration is limited by age. The duration of airflow limitation after exercise is significantly earlier and shorter in young children with asthma compared with older children. FEV 0.5 is a better index than the traditional FEV 1 for describing positive ECT results in young children. The association of wheezing and/or prolonged expiration may help in defining EIA in early childhood in the absence of a spirometer. (CHEST 2007; 132: ) Key words: early childhood; exercise challenge; exercise-induced asthma; spirometry Abbreviations: ECT exercise challenge test; EIA exercise-induced asthma; FEF average forced expiratory flow over the middle half of the FVC maneuver; FEV 0.5 forced expiratory volume in the first 0.5 s; PEFR peak expiratory flow rate Vigorous exercise is known to cause transient bronchoconstriction in 40 to 80% of school-age children with asthma, many of whom have normal lung function at rest. 1 This can be disabling, resulting *From the Pediatric Pulmonary Unit (Drs. Vilozni, Efrati, Barak, Szeinberg, Yahav, and Augarten), Edmond and Lily Safra Children s Hospital, Chaim Sheba Medical Center, Tel-HaShomer, Ramat-Gan, Israel; Pediatric Pulmonology Unit (Dr. Bentur), Meyer Children s Hospital Rambam Medical Center, Technion- Israel Institute of Technology, Haifa, Israel; and Pediatric Department (Dr. Shoseyov), Hadassah Medical Center, Mount Scopus, Jerusalem, Israel. This study was funded by the Israel Lung Association, Tel-Aviv, Israel. in exclusion or withdrawal from physical activity. 2 The bronchial exercise challenge test (ECT) is well standardized, 3,4 and the mechanism of exercise- The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Manuscript received January 8, 2007; revision accepted May 1, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Daphna Vilozni, PhD, Pediatric Pulmonary Unit, The Edmond and Lily Safra Children s Hospital, Chaim Sheba Medical Center, Tel HaShomer, Ramat-Gan 52621, Israel; daphna.vilozni@sheba.health.gov.il DOI: /chest CHEST / 132 / 2/ AUGUST,

2 induced asthma (EIA) has been extensively studied. 5,6 The ECT is used to make a diagnosis of asthma because it can discriminate between asthma and other chronic breathing illnesses of childhood, 7 9 and a positive ECT finding is related to asthma severity. 10,11 The ECT is also used for the determination of the effectiveness and optimal dosages of medications prescribed to prevent EIA. 12,13 Preschool-aged children participate in vigorous activities all day long. This may cause a severe asthma attack and may provoke a crucial disabling condition in the young child. The presence and extent of EIA in early childhood is difficult to recognize. 14 Several reasons may account for this, as follows: EIA may not limit the child s performance; the child may fail to notice the symptoms of EIA until taking part in organized or competitive sports; and poor perception of the symptoms of EIA is common. Moreover, exercise is often repeated throughout the entire day in young children, and asthma symptoms may not occur on all occasions, as the children may enter the refractory to bronchoconstriction effects period. 15 According to the recommendations for the ECT, 3,4 the preferred mode of exercise in school children is the motor-driven treadmill or cycle ergometer with adjustable speed and grade, which will produce 4 to 6 min of exercise at 80 to 90% of the predicted maximal heart rate. Postexercise spirometry testing in children is performed at 3, 5, 10, 15, 20, and 30 min after the cessation of exercise. The presence of EIA is defined by a fall in FEV 1 to below 10 to 15% of baseline values. The evaluation of EIA in early childhood by the methods cited above may not be suitable. We assumed that a free-run test, as used in epidemiologic studies for EIA diagnosis in school-aged children, 16 combined with measurements of duplicate spirometry sets 17 would be the most convenient way to test young children. The aims of this study were to examine the feasibility of a free-run protocol followed by spirometry measurements in early childhood, in order to explore the occurrence of EIA in young children with respiratory symptoms. Subjects Children who were referred to the pediatric pulmonary clinic over a 1-year period were recruited for the study, which was a cross-sectional, single-occasion, observational study. The cohort included children 3.0 to 6.9 years old who had been referred for ECT by pediatric physicians. Exclusion criteria were as follows: the presence of other chronic respiratory conditions (eg, cystic fibrosis or bronchopulmonary dysplasia); oral or inhaled steroids taken during the previous week; a bronchodilator taken within 24 h prior to the ECT; wheezing at physical examination prior to the exercise test; and a predicted baseline FEV 1 of 70% predicted. The Sheba Medical Center Ethics Board approved the study. Parental consent was obtained for each child. Materials and Methods The children were asked to arrive for the ECT in comfortable clothes and running shoes, having consumed no more than a light meal and having had therapy with pulmonary medications withdrawn, as described above. A parent, a pediatric pulmonary physician, and a technician were present throughout the ECT. Each child underwent a physical examination to exclude evidence of wheezing, and baseline spirometry was performed. The children were asked to run freely back and forth in a 50-m-long corridor next to the pulmonary laboratory. The mean relative humidity in the corridor was 30 to 40%, and the temperature was 22 to 28 C throughout the year. The target was to achieve 6 min of free running by increasing the heart rate to 80% of its maximum (0.8 [220 age]) for at least 4 min. 3,4 An adult (parent/technician/physician) ran with the child to encourage the continuation of running. After each round was completed, everybody cheered. We did not allow false starts or several opportunities to begin the run unless they were shorter than a few seconds, as we feared the child might enter a refractory period. Heart rate and O 2 saturation were monitored continuously throughout the run using a portable mobile pulse oximeter monitor (model 2500; Nonin Medical, Inc; Minneapolis, MN). In the present study, we used a commercial spirometer (ZAN100; ZAN Messgerate GmbH; Oberthulba, Germany) with built-in incentives. The incentives comprised the following two targets: peak flow and FVC. Spirometry tests were performed in the pediatric pulmonary laboratories by a skilled technician. The technician was unaware of the prerun diagnosis of the children. Baseline forced expiratory flow volume curve measurements were performed with the child in the standing position, without a nose clip (for the child s comfort), until two consecutive technically acceptable curves were achieved. The forced expiratory flow volume was measured in duplicate sets (after regular breathing was restored) at 1 to 2, 3, 5, 10, and 20 min postexercise. The better of the two curves was selected as the representative value at each interval, but differences between the two values of FEV 1 had to be 5%. The following signs were monitored by the pulmonologist: wheezing; and prolonged expiration on auscultation over the trachea and two zones of both lungs (upper front and lower back). Coughing, shortness of breath, or perceived breathlessness within 20 min after the run were noted. Statistical Analysis Technically acceptable spirometry maneuvers (according to recommendations for the preschool-aged children 18,19 ) were analyzed. Baseline values were first compared to the spirometry values with relation to height, which was derived from indexes in 109 healthy children from our previous study. 19 Following exercise, the best spirometry values for each interval were compared to baseline values. The exercise response was defined as the greatest decrease in FEV 1, which was expressed as a percentage of the baseline values. A bronchoconstriction response to exercise was considered to be positive when the 498 Original Research

3 FEV 1 decrease from baseline was 13%. 20 Changes in other spirometry indexes (ie, forced expiratory volume in the first 0.5 s [FEV 0.5 ]; peak expiratory flow rate [PEFR]; and average forced expiratory flow over the middle half of the FVC maneuver [FEF ]) were similarly calculated. The Student paired t test was used for the comparison of data between each spirometry index recorded and the calculated values for healthy children. The children were classified into the following two groups: group A consisted of children in whom asthma had previously been diagnosed according to the Global Initiative for Asthma guidelines 7 ; and group B consisted of children with nonspecific respiratory symptoms (ie, prolonged coughing lasting 2 months). The Student unpaired t test was used to find significant differences between group A and group B in relation to anthropometric data, baseline spirometry, and positive ECT results. Data are reported as the mean SD, unless otherwise indicated. The appearance of a test positive for EIA was analyzed in relation to age group and symptoms after the ECT. A p value of 0.05 was considered to be significant. Results Of the 68 children who were recruited into the study, 6 refused to run or stopped running after 1 min. Three children did not reach the target heart rate at any time during the run, and four children refused to perform spirometry after the run. Fifty-five children (38 male children and 17 female children; mean age, years; mean height, cm; and mean weight, kg) completed the free-run test, reaching the heart rate target with spirometry performed before and after exercise. The children s age distribution was as follows: 8 children were 3 years old; 20 children were 4 years old; 16 children were 5 years old; and 11 children were 6 years old. The anthropometric data and the baseline spirometry values for all 55 children are presented in Table 1. Eight of the 55 children could not perform FEV 1 at baseline measurements but were otherwise able to perform a technically acceptable spirometry test. For the entire group, the mean baseline FVC and FEV 1 values were within the normal range, while values for FEV 0.5, PEFR, and FEF were significantly lower than those in healthy children. FEF values in the children in group A were significantly lower than those in group B. Other indexes were similar. The children tended to run at full speed from the start. The mean ( SD) exercise time was min (range, 3 to 6 min); therefore, the distance completed for each run varied. The duration of running in relation to age is presented in Figure 1. The body mass index did not correlate with the length of the run (p 0.278). The mean baseline heart rate increased from beats/min within the first 0.5 min of exercise, to beats/min at the end of the run. Pulse oximetry remained in the range of 97 to 99% throughout the test. The time taken to reach the nadir in spirometry indexes was min, with the following distribution: 8 children at 1 to 2 min; 37 children at 3 min; 9 children at 5 min; and in 1 child the nadir was observed 10 min after the run. Spirometry values had returned spontaneously to baseline values in 54 children at the subsequent measurement interval. The single child whose nadir occurred 10 min after the run needed therapy with bronchodilators following the test. The maximal nadirs in spirometry indexes according to the subgroups are presented in Table 2. An FEV 1 value positive for EIA was present in 15 of the 47 children (31.9%) in whom FEV 1 was measured. However, an FEV 0.5 value that was positive for EIA (ie, a decrease of 13% from the baseline value) was observed in 34 of 55 children (62%). A diagram of the changes in FEV 0.5 (as a percentage of baseline values) during the challenge test is presented in Figure 2. Table 1 Anthropometric Data and Baseline Spirometry Data* Variables Group A (n 30) Group B (n 25) p Value Age, yr NS Height, cm NS Weight, kg NS FVC NS FEV NS FEV 1 /FVC ratio NS FEV NS FEV 0.5 /FVC ratio NS PEFR NS FEF *Values are given as the mean SD, unless otherwise indicated. Spirometry data are presented as percentage of predicted values. 19 NS not significant. n 26. n CHEST / 132 / 2/ AUGUST,

4 Figure 1. The relation between exercise duration and age. We found no significant correlation between the nadir of the spirometry indexes and the baseline spirometry indexes. The sensitivity of FEV 1 and FEV 0.5 values to detect a positive EIA result in the different subgroups is presented in Table 3. The postexercise clinical symptoms appearing at the nadir of lung function are presented in Table 4. All of the children with FEV 0.5 values positive for EIA experienced more than one asthma symptom at the nadir of FEV 0.5 values. In contrast, the children who presented FEV 0.5 value negative for EIA experienced coughing and breathlessness but showed no evidence of wheezing or prolonged expiration. Discussion In the present study, we have documented for the first time the presence of EIA in response to free running in early childhood. The high success rate (55 of 68 children) achieved in our study demonstrates that with patience and with a suitable teaching approach, both exercise and reproducible expiratory flow-volume curves can be obtained in very young children. We found that a free run is a suitable test for children in early childhood because they spontaneously and immediately ran at their maximum speed, which allowed for the necessary recommended effort to induce constriction of the airways. Children presenting with FEV 0.5 values positive for EIA experienced wheezing or prolonged expiration and reported a feeling of shortness of breath along with the nadir of this value; most children manifested more than a single symptom of distress. We also found that an FEV 0.5 value positive for EIA was present in the majority of the children who had previously been diagnosed with asthma (group A) but was less frequent in the children from group B. The presence of EIA in early childhood is not surprising. Data suggesting that children in early childhood are not too young to experience EIA have been reported. 14 According to the children s clinical history, 60% of young children with respiratory problems report symptom exacerbation with exercise, even those 3 years of age. However, one must keep in mind that the perception of airway obstruction in children with asthma is poor even in schoolaged children. 21 Thus, the prevalence of EIA in early childhood may be higher than has been reported. We assumed that free running would be the most convenient way to test children in this age group, as running forms a part of their everyday life. Indeed, very few children did not comply with the test. We took into consideration that a free run may decrease the percentage of children presenting with values positive for EIA, because the test cannot control the speed of running and the workload. Despite these drawbacks, children tended to run at full speed from the start, reaching their target heart rate rapidly. It may be speculated that running toward a goal (ie, a finish line) could induce even higher cooperation. However, this would force us to perform the test outdoors where climate is uncontrolled, which is a less desirable situation. 22 We found that the duration of free running was age dependent, and young children (as young as 3 years of age) were not able to tolerate 6 min of running. One additional minute of exercise could be reasonable for each year of the child s age, as demonstrated in Figure 1. This is probably due to the nature of their regular lifestyle Table 2 The Nadir (as the Percentage of Baseline Values) of the Spirometry Indices at Maximal Airway Narrowing Mean SD 95% Confidence Interval Variables Group A Group B Group A Group B p Value FVC to to 1.6 NS FEV to to 4.0 NS FEV 1 /FVC ratio to to 1.1 NS FEV to to FEV 0.5 /FVC ratio to to PEFR to to FEF to to Original Research

5 Figure 2. A representative diagram of the changes in FEV 0.5 (as a percentage of baseline values) during the ECT. (ie, playing by bursts of aerobic activity). 23 Vigorous exercise may also be limited by body mass during early childhood. 24 We found no such correlation, which could be due to the limited range of body mass in the children in our study. Since the standardized test requires performing a minimum of 4 min of exercise at 80% of the predicted maximum heart rate, 3,4 we questioned whether the shortened challenge was sufficient. Documentation of the heart rate revealed that it increased abruptly during the first 30 s and was sustained at a high level throughout the test. Moreover, bronchoconstriction was noted in 62% of all tested children. Therefore, we believe that EIA can be produced by running for even as short a timeas3to4min. In this study, we used incentives for the spirometry measurement. However, we should stress that the use of incentives is not essential, and some centers 25 have reported creditable success rates for preschool spirometry using only verbal training and encouragement. Yet, when attempting spirometry in early childhood the operator should be able to earn the child s trust and be capable of obtaining acceptable and reproducible maneuvers. The acceptability criteria for preschoolers differ from those for adults, as the shape of the descending limb of the flow-volume curve may be convex, and this pattern should not be misinterpreted as early termination. Measurement of the volume expired within 1 s, such as with FEV 0.5, may be more accurate than the use of the traditional FEV 1, and the appropriate reference values should be adopted. 26 According to the American Thoracic Society/European Respiratory Society guidelines for performing an ECT in school-aged children, it is recommended that spirometry be performed at intervals of 3, 5, 10, and 20 min after the cessation of exercise. In the young children in our study, we found that the nadir of the spirometry indexes was observed within 3 min after the cessation of exercise, disappearing at the 5-min postexercise measurement, while it was established that the nadir of FEV 1 after exercise in school-aged children is expected within 5 to 10 min after ceasing exercise. 3 Our finding that young children presented earlier and with shorter durations of bronchoconstriction after exercise, in comparison with older children, has never been explored. The findings could be explained by maturational changes in the airway smooth muscle shortening response and relaxation time. 27 One of the mechanisms producing EIA is the loss of water by evaporation from the surface of the airways. 5,6 The dehydration of the airways depends on the intensity and the duration of hyperventilation. It has been shown that increased duration of hyperventilation delays the onset of bronchoconstriction but causes greater bronchoconstriction. 28 We speculate that in young children the hyperventilation is of lower intensity and of shorter duration than in older children, with both leading to transient bronchoconstriction. We do not know whether the bronchoconstriction was accompanied by inflammation, but in our study the children who were positive for EIA experienced wheezing and/or prolonged expiration. Therefore, we assume that, despite the transient nature of the symptoms, they were related to asthma and are probably of clinical importance. One may be skeptical about whether a single drop in FEV 0.5 occurring 1 or 2 min after ceasing the run is genuine. Five of 55 children showed an FEV 0.5 nadir at that measured time. In these children, the FEF decreased markedly, up to 36%, while FVC decreased by a maximal 10% only, implying that the airway narrowing was genuine. Our findings indicate that although the recommendation regarding the postexercise timing of spirometry for school-aged children is also suitable for children in early childhood, the exclusion of measurements up to 5 min after the run may miss the bronchoconstriction event. This may explain why some investigators 29 have not previously found exercise to be a good provoking stimulus for young children. By using FEV 1 to identify EIA, we found that only a third of our population had a positive ECT result. The magnitude of the 13% decrease in FEV 1 in response to exercise may simply be too large for this parameter due to its close relation to FVC. Some Table 3 Sensitivity of a 13% Fall in FEV 0.5 and FEV 1 To Identify EIA in Group A and Group B EIA Group A Group B FEV 1 FEV 0.5 FEV 1 FEV 0.5 Positive ECT result Negative ECT result CHEST / 132 / 2/ AUGUST,

6 Table 4 Most Commonly Occurring Signs and Symptoms Appearing After Exercise at Peak Nadir of FEV 0.5 Showing EIA* EIA Prolonged Expiration Wheezing Coughing Feeling of Breathlessness No Symptoms Positive (n 34) Negative (n 21) *Values are given as the No. of patients. children could not produce FEV 1 at the baseline measurement, which is a documented phenomenon. 18,19 With a milder cutoff of a 10% decrease in FEV 1, more children (24 of 47 children; 57%) showed values that were positive for EIA. These values are similar to those previously found after a free run in a population of asthmatic school-aged children. 11,30 The percentage (62%) of children showing values positive for EIA according to a 13% decrease in FEV 0.5, was somewhat higher than that found in mildly asthmatic older children for FEV 1 values positive for EIA. 11,29 However, this drop was associated with clinical symptoms of asthma, indicating that a 13% decrease in FEV 0.5 is a relevant clinical parameter to detect the presence of EIA. PEFR is a common index for following changes in pulmonary function after exercise challenge in epidemiologic studies, 29,30 but PEFR values positive for EIA in our study were present in only 24 of the 55 children (44%). The reliability of PEFR has often been challenged as not yielding a complete picture, because it is not sufficiently sensitive in detecting small airways narrowing. 31 FEV 0.5 values positive for EIA were present in 26 of 30 children in group A, while it was found less frequently (8 of 25 children) in group B. Interestingly, baseline FEF values differed between subgroups, whereas values were significantly lower in group A. But, we could not establish any correlation between baseline FEF values and FEV 0.5 values positive for EIA or a decrease in FEV ( 31 8% of baseline values). Thus, this difference could not explain the discrepancy in the appearance of EIA between the groups. As mentioned, the nadir in spirometry was accompanied by respiratory asthma symptoms. Wheezing and/or prolonged expiration were present in most children presenting with FEV 0.5 values positive for EIA, while these two major symptoms did not appear when FEV 0.5 values were negative for EIA. Coughing and a feeling of breathlessness, however, were present in both positive and negative ECT results (Table 4). The phenomena of wheezing and prolonged expiration appearing and disappearing within 5 min after exercise may have an important clinical application in defining EIA in early childhood, in the absence of spirometry. In conclusion, our study suggests that EIA can be documented in early childhood using the free-run test, and that the prevalence of EIA in early childhood is probably similar to that in older children. The demonstration of EIA with a free-run test in preschool-aged children is not stressful for the child or the parent, and can probably be carried out in any pediatric pulmonary function laboratory after brief training of the staff to perform spirometry in preschool-aged children. The standard protocol used for ECTs in school-aged children may be used in younger children, but because the nadir is so shortlived, measurements should also be performed several times during the first 5 min after the run. FEV 0.5 describes the bronchoconstriction event better than the traditional FEV 1, but the best spirometry index for describing EIA should be explored. Larger scale studies on healthy and asthmatic children in the early childhood are needed to establish standardizations. References 1 Godfrey S. Exercise-induced asthma. In: Barnes PJ, Grunstein MM, Leff AR, et al, eds. Asthma. Philadelphia, PA: Lippincott-Raven, 1997; Mead D. Asthma, children and physical exercise. Nurs Stand 1990; 4: American Thoracic Society. Guidelines for methacholine and exercise challenge testing 1999: the official statements of the American Thoracic Society, adopted by the ATS board of directors, Am J Respir Crit Care Med 2000; 161: European Respiratory Society. Clinical exercise testing with reference to lung diseases: indications, standardization and interpretation strategies; ERS Task Force on Standardization of Clinical Exercise Testing. Eur Respir J 1997; 10: Anderson SD, Daviskas E. The mechanism of exerciseinduced asthma is... J Allergy Clin Immunol 2000; 106: McFadden ER, Gilbert IA. Exercise-induced asthma. N Engl J Med 1994; 330: National Asthma Education and Prevention Program, National Institutes of Health, National Heart, Lung, and Blood Institute. Practical guide for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health, Avital A, Springer C, Bar-Yishay E, et al. Adenosine, methacholine, and exercise challenges in children with asthma or paediatric chronic obstructive pulmonary disease. Thorax 1995; 50: Haby MM, Anderson SD, Peat JK, et al. An exercise challenge protocol for epidemiological studies of asthma in children: comparison with histamine challenge. Eur Respir J 1994; 7: Original Research

7 10 Avital A, Godfrey S, Springer C. Exercise, methacholine, and adenosine 5 -mono-phosphate challenges in children with asthma: relation to severity of the disease. Pediatr Pulmonol 2000; 30: Lazo-Velasquez JC, Lozada AR, Cruz HM. Evaluation of severity of bronchial asthma through an exercise bronchial challenge. Pediatr Pulmonol 2005; 40: Pajaron-Fernandez M, Garcia-Rubia S, Sanchez-Solis M, et al. Montelukast administered in the morning or evening to prevent exercise-induced bronchoconstriction in children. Pediatr Pulmonol 2006; 41: Anderson SD. Single-dose agents in the prevention of exercise-induced asthma: a descriptive review. Treat Respir Med 2004; 3: Strunk RC. Defining asthma in the preschool-aged child. Pediatrics 2002; 109: Ben-Dov I, Gur I, Bar-Yishay E, et al. Refractory period following induced asthma: contributions of exercise and isocapnic hyperventilation. Thorax 1983; 38: Haby MM, Peat JK, Mellis CM, et al. An exercise challenge for epidemiological studies of childhood asthma: validity and repeatability. Eur Respir J 1995; 8: Bentur L, Beck R, Elias N, et al. Methacholine bronchial provocation measured by spirometry versus wheezing detection in preschool children. BMC Pediatr 2005; 28: Aurora P, Stocks J, Oliver C, et al. Quality control for spirometry in preschool children with and without lung disease. Am J Respir Crit Care Med 2004; 169: Vilozni D, Barak A, Efrati O, et al. The role of computer games in measuring spirometry in healthy and asthmatic preschool children. Chest 2005; 128: Godfrey S, Springer C, Bar-Yishay E, et al. Cut-off points defining normal and asthmatic bronchial reactivity to exercise and inhalation challenges in children and young adults. Eur Respir J 1999; 14: Panditi S, Silverman M. Perception of exercise induced asthma by children and their parents. Arch Dis Child 2003; 88: Goldberg S, Schwartz S, Izbicki G, et al. Sensitivity of exercise testing for asthma in adolescents is halved in the summer. Chest 2005; 128: Bailey RC, Olson J, Pepper SL, et al. The level and tempo of children s physical activities: an observational study. Med Sci Sports Exerc 1995; 27: Krombholz H. Percept Mot Skills. Physical performance in relation to age, sex, birth order, social class, and sports activities of preschool children. Percept Mot Skills 2006; 102: Eigen H, Bieler H, Grant D et al. Spirometric pulmonary function in healthy preschool children. Am J Respir Crit Care Med 2001; 163: Aurora P, Eeigen H, Artes B, et al. An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children; recommendations on spirometry. Am J Respir Crit Care Med 2007; 175: Chitano P, Murphy TM. Maturational changes in airway smooth muscle shortening and relaxation: implications for asthma. Respir Physiol Neurobiol 2003; 16:137: Blackie SP, Hilliam C, Village R, et al. The time course of bronchoconstriction in asthmatics during and after isocapnic hyperventilation. Am Rev Respir Dis 1990; 142: Seear M, Wensley D, West N. How accurate is the diagnosis of exercise induced asthma among Vancouver school children? Arch Dis Child 2005; 90: Hammerman SI, Becker JM, Rogers J, et al. Asthma screening of high school athletes: identifying the undiagnosed and poorly controlled. Ann Allergy Asthma Immunol 2002; 88: Goldberg S, Springer C, Avital A, et al. Can peak expiratory flow measurements estimate small airway function in asthmatic children? Chest 2001; 120: CHEST / 132 / 2/ AUGUST,

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