Exercise-Induced Bronchoconstriction in School-Aged Children Who Had Chronic Lung Disease in Infancy

Suchita Joshi, PhD, MRCPaed1, Thomas Powell, PhD2, William J. Watkins, PhD1, Mark Drayton, MD, FRCPCH3, E. Mark Williams, PhD2, and Sailesh Kotecha, PhD, FRCPCH1 Objectives To assess for exercise-induced bronchoconstriction in 8- to 12-year-old children who had chronic lung disease (CLD) in infancy, and to evaluate the response of bronchoconstriction to bronchodilation with albuterol in comparison with preterm and term controls. Study design Ninety-two children, including 29 with CLD, 33 born preterm at #32 weeks gestation, and 30 born at term, underwent lung spirometry before and after cycle ergometry testing and after postexercise bronchodilation with albuterol. Results Doctor-diagnosed asthma and exercise-induced wheeze were reported more frequently in the CLD group than in the preterm and term groups, but only 10% were receiving a bronchodilator. There were no differences among the groups in peak minute ventilation, oxygen uptake, or carbon dioxide output at maximum exercise. After maximal exercise, predicted forced expiratory volume in 1 second (FEV1) decreased from a mean baseline value of 81.9% (95% CI, 76.6-87.0%) to 70.8% (95% CI, 65.5-76.1%) after exercise in the CLD group, from 92.0% (95% CI, 87.2-96.8%) to 84.3% (95% CI, 79.1-89.4%) in the preterm group, and from 97.5% (95% CI, 92.5-102.6%) to 90.3% (95% CI, 85.1-95.5%) in the term group. After albuterol administration, FEV1 increased to 86.8% (95% CI, 81.7-92.0%) in the CLD group, 92.1% (95% CI, 87.3-96.9%) in the preterm group, and 97.1% (95% CI, 92.0102.3%) in the term group. The decrease in predicted FEV1 after exercise and increase in predicted FEV1 after bronchodilator use were greatest in the CLD group (11.0% [95% CI, 18.4 to 3.6%] and 16.0% [95% CI, 8.6-23.4%], respectively; P < .005 for both), with differences of <8% in the 2 control groups. Conclusion School-age children who had CLD in infancy had signicant exercise-induced bronchoconstriction that responded signicantly to bronchodilation. Reversible exercise-induced bronchoconstriction is common in children who experienced CLD in infancy and should be actively assessed for and treated. (J Pediatr 2013;162:813-8).
urvivors of chronic lung disease (CLD) of prematurity, often also called bronchopulmonary dysplasia (BPD), have increased respiratory morbidity,1,2 increased hospitalization,3-5 and poor lung function during infancy and early childhood.6,7 Children who had CLD in infancy exhibit evidence of airway obstruction,7-9 bronchial hyperreactivity,10,11 and air-trapping8 compared with term-born controls at school age and in early adulthood.12 Lung function abnormalities in childhood and early adulthood have been reported in preterm-born children without CLD as well.13,14 The increased airway obstruction is thought to be due to increased airway muscle mass,15 but data on whether the airway obstruction is reversible in childhood survivors of CLD are very limited. The EpiCure group studying preterm infants at the edge of viability (ie, #25 weeks gestation at birth) recently reported that 56% of 11-year old survivors had abnormal airway obstruction and 27% had a positive bronchodilator response at rest, but many of these children were not receiving appropriate treatment.9 These _ 2) during infants also were found to have lower lung diffusion capacity of CO (DLCO) and lower peak oxygen consumption (VO exercise.16 Balinotti et al17 reported signicantly lower DLCO and DLCO/alveolar volume ratio in infancy in preterm infants with CLD compared with term controls, suggesting impaired alveolar development. Other studies of DLCO, including those conducted in preterm-born children and young adults, have reported varying results.13,18-20 Current data on cardiopulmonary exercise testing (CPET) in school-aged children15,21-23 and young adults who had been born preterm are inconsistent.13,18 These differences may be related to variation among study groups and CPET methods. Furthermore, it is unclear whether exercise is associated with bronchoconstriction in children who had CLD in infancy, and whether this bronchoconstriction responds to bronchodilator therapy.
BPD CPET CLD DLCO FEV1 MVV _E V _ VCO 2 _ 2 VO Bronchopulmonary dysplasia Cardiopulmonary exercise testing Chronic lung disease Lung diffusion capacity of carbon monoxide Forced expiratory volume in 1 second Maximum voluntary ventilation Minute ventilation Carbon dioxide output Oxygen consumption

From the 1Department of Child Health, School of Medicine, Cardiff University, Cardiff, United Kingdom; 2 Faculty of Health, Sport and Science, University of Glamorgan, Pontypridd, United Kingdom; and 3 Department of Neonatology, University Hospital of Wales, Cardiff, United Kingdom Partially supported by Cardiff and Vale National Health Service Trust Research and Development Small Grants. The authors declare no conicts of interest.
0022-3476/$ - see front matter. Copyright 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.09.040

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Vol. 162, No. 4 Pulmonary diffusion capacity was measured using a singlebreath carbon monoxide technique29 (MS-PFT; Jaeger, Hoechberg, Germany) and corrected for the childs hemoglobin level. Each participant rested for 10-15 minutes before performing baseline spirometry testing. All subjects were trained to perform the breath-holding maneuver before testing. All subjects performed at least 3 consecutive tests, with a 4-minute interval between maneuvers. All diffusion capacity tests were performed by a single investigator (E.W.). Hemoglobin assessment was performed in 64 children (70%); average values were 13.8 mg/dL (95% CI, 13.5-14.1) in the CLD group, 13.6 mg/dL (95% CI, 13.2-14.0) in the preterm group, and 13.1 mg/dL (95% CI, 12.8-13.5) in the term group. The average hemoglobin value for each group was used to complete the missing data on 30% of the subjects who did not consent for blood testing. DLCO was adjusted for hemoglobin value using the equation recommended by the American Thoracic Society.29 To measure static lung volumes, the method of measuring mouth pressure during a brief airway occlusion was practiced by each child, until the maneuver was repeated at least three times to obtain at least 2 satisfactory tests within 10% of the mean. Baseline spirometry was performed before commencing exercise. All spirometric (Flowscreen; Viasys Healthcare) and plethysmographic (Masterscreen; Viasys Healthcare) tests were carried out by a single investigator (S.J.). CPET Maximal exercise capacity was measured using an incremental symptom limited, electrically braked cycle ergometer (Jaeger). Pedaling was started on an unloaded cycle, and then, every 3 minutes thereafter, the load was increased in 30-W increments until volitional exhaustion or until the heart rate reached 80-90% of the predicted maximum (220 - age in years). Pedaling cadence was held at approximately 60 rpm. Each child was given the same vigorous verbal encouragement to cycle as long as possible. Heart rate was monitored throughout the exercise test using a telemetric monitor (Polar t31; Polar Electro, Warwick, United Kingdom). The facemask was connected to a calibrated ow sensor and O2/CO2 breath-by-breath analysis system (MS-CPX; Jaeger). The test was continued until at least 2 of the following 4 criteria were met: (1) maximum heart rate was $80% of predicted maxi_ 2 mum; (2) respiratory exchange ratio was >1; (3) peak VO was achieved; or (4) volitional exhaustion was present, as assessed by the Borg scale of perceived exhaustion.30 At maxi_ _ 2, CO2 output (VCO mum exercise, VO 2), and minute _ ventilation (VE) were calculated as mean values of the nal 15 seconds of exercise. Maximum voluntary ventilation (MVV) was calculated as baseline FEV1 35.31 Ventilatory _ E/MVV) 100%.32 reserve was calculated as (1 peak V Postexercise Spirometry and Reversibility Test Spirometry was performed at 5, 10, 15, 30, and 40 minutes after the exercise, and the lowest FEV1 value was recorded for each child. At each stage, at least 3 spirometry maneuvers with at least 2 reproducible recordings were recorded.
Joshi et al

In this study, we compared exercise capacity in similarly aged preterm-born children with and without CLD and term-born children. We also measured airway function after exercise and after postexercise bronchodilator administration to assess whether these preterm-born children had exerciseinduced bronchoconstriction, and whether this was reversible by a b2 bronchodilator administered after exercise.

Methods
Three groups of children aged 8-12 years were studied, including 2 preterm groups (born at #32 weeks gestation) who developed CLD (ie, oxygen-dependent or breathing air by 36 weeks gestation) and a control term group born at $37 weeks gestation. CLD was diagnosed pragmatically and would have been classied as moderate to severe using the National Institutes of Healths denition of BPD.24 Neonatal clinical records for each preterm-born child were reviewed. Children with a congenital anomaly, cardiopulmonary defect, neuromuscular disease, severe neurodevelopmental impairment, or inability to comply with the research protocol were excluded. Children with a respiratory tract infection within the previous 3 weeks were asked to return at a later date. Children with asthma or atopy were not excluded. Children receiving inhaled medication were asked to stop the treatment for at least 12 hours before attending. Ethical approval was obtained from the local Research Ethics Committee. Written informed consent was obtained for each participant. Height and weight were measured using a calibrated stadiometer and beam-balance scale (Model 424; Weylux, London, United Kingdom), and baseline pulse rate and oxygen saturation were measured with a Dinamap Procare monitor (GE Healthcare, Hateld, United Kingdom). Parents completed a modied International Study of Asthma and Allergies in Childhood questionnaire eliciting data on the childs respiratory health.25 Lung Spirometry After equipment calibration, the forced expiratory methods were demonstrated to the children who then practiced the maneuver using an animated, computer-programmed spirometer (Flowscreen; Viasys Healthcare, Basingstoke, United Kingdom). Once deemed competent, the children were assessed using a screen pneumotachograph (Masterscreen; Viasys Healthcare). Nose clips and mouthpiece bacterial lters were worn throughout all procedures. Each child performed at least 3 acceptable and reproducible spirometric maneuvers in accordance with American Thoracic Society and European Respiratory Society guidelines.26,27 Reproducibility was assessed visually by observing the ow volume curves and by ensuring that the differences in forced vital capacity and forced expiratory volume in 1 second (FEV1) between the maneuvers were within 5%. Absolute values for forced vital capacity, FEV1, forced expiratory ow at 2575% of vital capacity, and peak expiratory ow, along with percent predicted values corrected for age, sex, and height, were calculated.26,28
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April 2013 Albuterol was administered 45-60 minutes after exercise via a pediatric Aerochamber (GSK, Brentford, United Kingdom) with an appropriate-sized facemask. Four 100-mg doses (total dose, 400 mg) were administered, with the child instructed to take 10 normal breaths after each dose. Spirometry was repeated after 15 minutes. Only data from the 75 children who had data recorded at baseline, after exercise, and after albuterol administration (26 in the CLD group, 23 in the preterm group, and 26 in the term group) were included in these analyses. Statistical Analyses Because the data were normally distributed, they are presented as mean SD or 95% CI. Differences in CPET among groups were tested for using ANOVA with post hoc Bonferroni corrections. Differences in FEV1 at baseline, minimum FEV1 after exercise, and postbronchodilation FEV1 among groups were assessed by 2-way ANOVA. A P value <.05 was considered to indicate statistical signicance. SPSS 18.0 (IBM, Armonk, New York) was used for all analyses.

ORIGINAL ARTICLES
FEV1, forced expiratory ow at 25-75% of vital capacity, and peak expiratory ow were signicantly lower, and functional residual capacity, residual volume, and residual volume/total lung capacity ratio were signicantly higher in the CLD group compared with the preterm and term groups. Values for the preterm group were intermediate, but not signicantly different from those for the term group. Hemoglobin-adjusted DLCO values differed signicantly among the groups (P < .05 between the CLD and preterm groups [4.9 (95% CI, 4.5-5.2) mmol/min/ kPa vs 5.5 (95% CI, 5.1-5.6) mmol/min/kPa]; P < .05 between the CLD and term groups [4.9 (95% CI, 4.5-5.2) mmol/min/kPa vs 5.5 (95% CI, 5.1-6.0) mmol/min/ kPa]). However, predicted hemoglobin-adjusted DLCO was signicantly lower in the CLD group compared with the preterm group, but not compared with the term group (Table III). CPET Four children (2 CLD, 1 preterm, 1 term) of insufcient height and 8 children (3 CLD, 3 preterm, and 2 term) who did not meet the criteria for CPET were excluded from the cycle ergometry testing. Another 2 children (1 preterm, 1 term) were unable to perform the CPET because of equipment failure and 2 children from the preterm control group missed the CPET for other reasons (1 was temporarily on crutches and 1 was unable to complete due to parental time constraint). Thus, a total of 76 children completed cycle ergometry testing. Baseline heart _ 2, rate, respiratory rate, oxygen saturation, and peak VO _ _ VCO 2, and VE were similar in the 3 groups (Table IV; available at www.jpeds.com). MVV and ventilatory reserve were both markedly lower in the CLD group compared with the preterm and term groups (25.8% [95% CI, 19.7-31.9%], 37.5% [95% CI, 32.2-42.8%], and 43.7% [95% CI, 38.6-48.7%], respectively) in the term groups. Postexercise Spirometry and Reversibility Test In the CLD group, predicted FEV1 decreased from a mean baseline of 81.9% (95% CI, 76.6-87.0%) to 70.8% (95% CI, 65.5-76.1%) after maximal exercise and increased to 86.8% (95% CI, 81.7-92.0%) after albuterol administration (Figure). Corresponding data were 92.0% (95% CI, 87.296.8%), 84.3% (95% CI, 79.1-89.4%), and 92.1% (95% CI, 87.3-96.9%) in the preterm group and 97.5% (95% CI, 92.5-102.6%), 90.3% (95% CI, 85.1-95.5%), and 97.1% (95% CI, 92.0-102.3%) in the term group. The lowest postexercise FEV1 was noted at 20.2 minutes for the CLD group, 17.9 minutes for the preterm group, and 19.9 minutes for the term group. Two-way ANOVA identied signicant differences in predicted FEV1 between baseline and postexercise (11.0%; 95% CI, 18.4 to 3.6%: P < .004) and between postexercise and postbronchodilation (16.0%; 95% CI, 8.6-23.4%; P < .0001) in the children who had CLD in infancy. Corresponding differences were 7.8% (95% CI, 14.8
815

Results
We studied 92 children, including 29 with CLD, 33 born preterm, and 30 term-born controls, with 1 subject in the CLD reclassied into the preterm group after a detailed review of each subjects neonatal records. Characteristics of the study population and reported symptoms are presented in Tables I and II (Table II; available at www.jpeds.com). As expected, the CLD group was signicantly more immature and had a lower mean birth weight compared with the preterm and term groups. They also received mechanical ventilation and oxygen therapy for longer periods. All infants in the CLD group had received exogenous surfactant, compared with 45% of those in the preterm group and none in the term group. Weight at the time of lung function assessment was signicantly lower in the CLD group compared with the preterm and term groups, but height and body mass index were not statistically signicantly different among the groups. More parents smoked in the CLD and preterm groups compared with the term group. The rates of doctor-diagnosed asthma, dry cough at night, and exercise-induced wheeze were higher in the CLD group compared with the preterm and term groups (Tables I and II), but only 10% of those in the CLD group were receiving current asthma treatment. The rate of current asthma treatment was higher in the CLD group compared with the other groups, but the differences did not reach statistical signicance. Self-reported physical activity was signicantly lower in the CLD group compared with the other 2 groups. Lung Spirometry All 92 children underwent spirometry; 90 had satisfactory results on whole-body plethysmography, and 84 had satisfactory results on the single-breath maneuver (Table III). Baseline

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Table I. Baseline characteristics of the subjects

CLD group Parameter Demographic data Male sex, n (%) Gestation, weeks, mean SD Birth weight, kg, mean SD Age, years, mean SD Height, cm, mean SD Weight, kg, mean SD Body mass index, kg m2, mean SD Antenatal and postnatal respiratory status Antenatal steroid use, n (%) Postnatal steroid use, n (%) Surfactant use, n (%) Supplemental oxygen, days, median (range) Assisted ventilation, days, median (range) Reported respiratory symptomszz Asthma ever (doctor-diagnosed), n (%) Current asthma on treatment, n (%) Exercised induced wheeze in previous 12 months, n (%) Parental smoking, n (%) Self-reported physical activity per week, hours, median (range)
*P < .001 (CLD vs preterm). P < .001 (CLD vs term). zP < .01 (CLD vs preterm). xP < .05 (CLD vs term). {P < .05 (CLD vs term). **P < .01 (CLD vs term; preterm vs term). P < .05 (CLD vs preterm; CLD vs term). zzFurther details are given in Table II.

Preterm group (n = 33) 15/33 (46) 30.0 2.0 1.5 0.4 10.3 1.1 140.9 9.0 37.3 10.9 17.6 3.8 20/33 (61) 1/33 (3) 15/33 (45) 4 (0-61) 3 (0-50) 11/33 (33) 4/33 (12) 2/33 (6) 15/32 (47) 3.0 (0-10)

Term group (n = 30) 15/30 (50) 39.8 1.5 3.4 0.5 10.5 1.5 143.2 11.0 39.6 13.7 17.9 4.6 None None None None None 4/28 (14) 0/28 (0) 0/28 (0) 3/28 (11) 3.5 (0-24) P value

(n = 29) 17/29 (59) 27.3 2.1 1.1 0.4 10.2 1.4 137.1 9.6 32.1 8.2 16.3 3.2 24/29 (83) 9/29 (31) 29/29 (100) 84 (30-410) 28 (5-80) 13/29 (45) 3/29 (10) 5/29 (17) 11/27 (41) 2.0 (0-24)

*, *,
z

* * *
{ {

**

to 0.7%; P = .03) and 7.8% (95% CI, 0.8-14.8%; P = .03) for the preterm group and 7.2% (95% CI, 14.5 to 0.06%; P = .052) and 6.8% (95% CI, 0.5 to 14.2%; P = .069) for the term group. Similar magnitudes of changes were obtained by paired t test comparisons and repeated-measures ANOVA (data not shown). We also noted a moderate correlation between duration of exercise testing and the lowest FEV1 value after exercise

(R = 0.37; P = .001) and with reported physical activity (R = 0.43; P < .001).

Discussion
In this study we studied each child in detail, focusing especially on his or her ability to exercise, and on whether the CLD group exhibited exercise-induced bronchoconstriction

Table III. Pulmonary function indices

Parameter Baseline spirometry FEV1, % predicted Forced vital capacity, % predicted FEF25-75, % predicted Peak expiratory ow, % predicted Single-breath test DLCO corrected for hemoglobin, % predicted KCO corrected for hemoglobin, % predicted Whole-body plethysmography FRCpleth, % predicted TLC, % predicted RV, % predicted RV:TLC, % predicted Vital capacity, % predicted CLD n = 29 81.9 (77.1-86.7) 98.9 (94.7-103.1) 49.2 (43.1-55.4) 71.6 (64.2-79.0) n = 26 88.0 (83.7-92.3) 74.6 (69.8-79.4) n = 28 120.6 (105.9-135.3) 104.9 (96.8-112.9) 131.6 (110.0-153.1) 122 (111-133) 89.9 (85.1-94.6) Preterm group n = 33 92.0 (87.0-97.0) 100.8 (96.8-104.9) 69.2 (60.5-78.0) 82.2 (76.0-88.4) n = 32 95.9 (91.9-100.0) 89.7 (84.7-94.7) n = 33 99.4 (93.7-105.1) 96.7 (91.4-102.0) 103.2 (91.8-114.7) 107 (96-120) 92.1 (87.6-96.6) Term group n = 30 97.5 (93.2-101.9) 102.0 (97.2-106.8) 80.0 (73.6-86.4) 90.8 (84.6-97.1) n = 26 93.5 (88.6-98.4) 90.0 (83.7-96.2) n = 29 93.8 (86.8-100.7) 99.0 (94.5-103.6) 96.9 (85.6-108.1) 97 (87-107) 94.7 (89.6-99.8) P value *,
,z x ,z

*,
x,{ {

FEF25-75, forced expiratory ow at 25-75% of vital capacity; FRCpleth, functional residual capacity measured by plethysmography; KCO, DLCO/alveolar volume; RV, residual volume; TLC, total lung capacity. Data are mean (95% CI). *P < .01 (CLD vs preterm). P < .001 (CLD vs term). zP < .001 (CLD vs preterm). xP < .05 (CLD vs preterm). {P < .01 (CLD vs term).

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ORIGINAL ARTICLES
at 32 weeks gestation, and were oxygen-dependent only until age 28 days. More recently, underdiagnosed reversible airway disease in extremely preterm infants, including those with and without lung disease, has been reported.9 Whether earlier intervention with bronchodilators improves the long-term respiratory outlook for these children remains to be seen, but we recommend that reversible bronchoconstriction be actively assessed for and treated, given that such basic treatment is likely to improve their quality of life. Antenatal maternal smoking and postnatal passive exposure34,35 could possibly play a role in the observed lung function decits. Children in the CLD and preterm groups had a greater rate of current parental smoking compared with the term-born children, suggesting greater exposure at least during postnatal life, but we did not have sufcient data documented during the perinatal period to determine whether children in the CLD group had greater exposure to antenatal maternal smoking. _ _ _ 2, peak VCO For the exercise tests, peak VO 2, and peak VE values did not differ signicantly among our 3 study groups. The values are lower than some reported previously20,36 but similar to others,13,21,23 possibly reecting differences in choice of protocol, participants, or equipment used for assessment. We found signicant differences in the self-reported hours of physical activity per week between the CLD and control groups, however. In view of the explicit large and small airway obstruction and the drop in FEV1 after exercise in the CLD group, the previously reported lack of limited exercise capacity in this group13,18,21,23 is perhaps surprising. Most interestingly, however, both MVV and ventilatory capacity were markedly decreased in the CLD group, with intermediate values noted in the preterm group compared with the term controls. Thus, the CLD and preterm groups were able to exercise similarly to the term infants but with the need to use a greater proportion of their ventilatory reserve. Whether lesser ventilatory reserve is used after satisfactory treatment of the reversible exercise-induced bronchoconstriction is open to speculation and will need further study. In the present study, hemoglobin-corrected DLCO was lower in the CLD group compared with both the preterm and term groups, but percent predicted values were lower in the CLD group compared only with the preterm group, but not the term group. Our data are consistent with results reported by Tepper et al,17 data for 8-year-old ex-preterm subjects in the EPICure cohort,16 and data for a cohort of 19-year-olds in a Dutch study.13 Thus, there is evidence of limitations in alveolarcapillary gas exchange in the expreterm children with CLD. Narang et al18 measured DLCO combined with effective pulmonary blood ow at rest and during exercise in preterm-born young adults in the presurfactant era. Although DLCO was reduced in the preterm group compared with the control population at rest, it normalized during exercise. The investigators suggested that the rise of DLCO during exercise may be a mechanical consequence of increased effective pulmonary blood ow, not a true increase. In conclusion, 8- to 12-year-old children who had CLD in infancy achieved a similar exercise load as control children with exercise testing, but with the need to use greater
817

Figure. Mean (95% CI) percentage of predicted FEV1 at baseline, after exercise, and after bronchodilator use. Solid line, CLD; dashed line, preterm; dotted line, term controls.

that was responsive to bronchodilation. We conrmed previous reports of airway obstruction in the CLD group, but also _ 2 values were similar in the 3 found that although peak VO groups after exercise, the children in the CLD group used more ventilatory reserve. In the CLD group, FEV1 decreased signicantly after exercise and improved markedly after albuterol administration. Modest decreases (<8%) were seen in the preterm and term groups after exercise and after bronchodilator administration. Children born preterm are known to have higher incidence of respiratory illness during infancy and early childhood.1-5 In our study cohort, 45% of the CLD group and 33% of the preterm group had been diagnosed with asthma, compared with only 13% of the term group. Only 10% of the CLD and 12% of the preterm group, but no children in the term group, were receiving medication for asthma or, more correctly, for airway symptoms, such as wheeze. However, the prevalence of such respiratory symptoms as exerciseinduced wheeze and night cough was still higher in the CLD group compared with the term group (31% vs 4%). Clearly, these children have persistent respiratory symptoms that they perceive as limiting their activities, and these symptoms should be actively assessed for and treated. We assessed both the effect of maximum exercise on FEV1 and the response to bronchodilator administered at 45-60 minutes after exercise. We noted signicant decrease in predicted FEV1 after exercise in the CLD group, which was signicantly greater than for the preterm and term groups. After exercise, the response to bronchodilator was much greater in the CLD group compared with the 2 control groups, suggesting markedly underdiagnosed reversible exercise-induced bronchoconstriction in the CLD group. Gross et al4 reported reversible postexercise bronchoconstriction in survivors of BPD from the presurfactant era. In a study from Brazil, however, Abreu et al33 observed no bronchoconstriction or response to bronchodilators administered after exercise, but the 13 children in the CLD/BPD group had mild lung disease in infancy as suggested by the normal FEV1 of 99% (12%), were more mature

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longitudinal lung spirometry in school age children and adolescents. Thorax 2012;67:54-61. Tiddens HA, Hofhuis W, Casotti V, Hop WC, Hulsmann AR, de Jongste JC. Airway dimensions in bronchopulmonary dysplasia: implications for airow obstruction. Pediatr Pulmonol 2008;43:1206-13. Welsh L, Kirkby J, Lum S, Odendaal D, Marlow N, Derrick G, et al. The EPICure study: maximal exercise and physical activity in school children born extremely preterm. Thorax 2010;65:165-72. Balinotti JE, Chakr VC, Tiller C, Kimmel R, Coates C, Kisling J, et al. Growth of lung parenchyma in infants and toddlers with chronic lung disease of infancy. Am J Respir Crit Care Med 2010;181:1093-7. Narang I, Bush A, Rosenthal M. Gas transfer and pulmonary blood ow at rest and during exercise in adults 21 years after preterm birth. Am J Respir Crit Care Med 2009;180:339-45. Mitchell SH, Teague WG. Reduced gas transfer at rest and during exercise in school-age survivors of bronchopulmonary dysplasia. Am J Respir Crit Care 1998;157:1406-12. Smith LJ, van Asperen PP, McKay KO, Selvadurai H, Fitzgerald DA. Reduced exercise capacity in children born very preterm. Pediatrics 2008; 122:e287-93. Jacob SV, Lands LC, Coates AL, Davis GM, MacNeish CF, Hornby L, et al. Exercise ability in survivors of severe bronchopulmonary dysplasia. Am J Respir Crit Care Med 1997;155:1925-9. Pianosi PT, Fisk M. Cardiopulmonary exercise performance in prematurely born children. Pediatr Res 2000;47:653-8. Kriemler S, Keller H, Saigal S, Bar-Or O. Aerobic and lung performance in premature children with and without chronic lung disease of prematurity. Clin J Sport Med 2005;15:349-55. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9. Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 1995;8:483-91. Rosenthal M, Bain SH, Cramer D, Helms P, Denison D, Bush A, et al. Lung function in white children aged 4 to 19 years: I-Spirometry. Thorax 1993;48:794-802. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A. Standardisation of spirometry. Eur Respir J 2005;26:319-38. Stanojevic S, Wade A, Cole TJ, Lum S, Custovic A, Silverman M, et al. Spirometry centile charts for young Caucasian children: the Asthma UK Collaborative Initiative. Am J Respir Crit Care Med 2009;180: 547-52. Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CP, Brusasco V, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 2005; 26:720-35. Borg G. Perceived exertion as an indicator of somatic stress. Scand J Rehabil Med 1970;2:92-8. Stein R, Selvadurai H, Coates A, Wilkes DL, Schneiderman-Walker J, Corey M. Determination of maximal voluntary ventilation in children with cystic brosis. Pediatr Pulmonol 2003;35:467-71. Medoff BD, Oelberg DA, Kanarek DJ, Systrom DM. Breathing reserve at the lactate threshold to differentiate a pulmonary mechanical from cardiovascular limit to exercise. Chest 1998;113:913-8. Abreu LR, Costa-Rangel RCA, Gastaldi AC, Guimaraes RC, Cravo SL, Sologuren MJJ. Cardio-respiratory capacity assessment in children with bronchopulmonary dysplasia. Rev Bras Fisioter S~ ao Carlos 2007; 11:95-100. Hayatbakhsh MR, Sadasivam S, Mamun AA, Najman JM, Williams GM, OCallaghan MJ. Maternal smoking during and after pregnancy and lung function in early adulthood: a prospective study. Thorax 2009;64:810-4. Milner AD, Rao H, Greenough A. The effects of antenatal smoking on lung function and respiratory symptoms in infants and children. Early Hum Dev 2007;83:707-11. Clemm H, Rksund O, Thorsen E, Eide GE, Markestad T, Halvorsen T. Aerobic capacity and exercise performance in young people born extremely preterm. Pediatrics 2012;129:e97-105.

ventilatory reserve. These children had more respiratory symptoms, were generally not receiving bronchodilator treatment, and had signicant exercise-induced bronchoconstriction that demonstrated a better response to bronchodilator therapy compared with preterm and term controls. Our data suggest that exercise-induced bronchoconstriction is common in children who had CLD in infancy and, most importantly, that this bronchoconstriction is responsive to bronchodilator therapy. We therefore recommend the active assessment for and treatment of reversible bronchoconstriction in these children, which is likely to improve their quality of life. n
We would like to thank the children and their parents for taking part in the study.
Submitted for publication Mar 26, 2012; last revision received Aug 7, 2012; accepted Sep 18, 2012. Reprint requests: Sailesh Kotecha, PhD, FRCPCH, Department of Child Health, Cardiff University School of Medicine, Cardiff CF14 4XN, UK. E-mail: kotechas@cardiff.ac.uk

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ORIGINAL ARTICLES

Table II. Prevalence of parent-reported respiratory symptoms

CLD group (n = 29) Dry cough at night in the previous 12 months, n (%) Eczema ever, n (%) Eczema in the previous 12 months, n (%) Family history of asthma, n (%) Family history of eczema, n (%) Family history of hay fever, n (%) 9 (31) 7 (24) 4 (14) 11 (38) 10 (34) 9 (31) Preterm group (n = 33) 9 (27) 12 (36) 6 (18) 12 (36) 12 (36) 18 (55) Term group (n = 28) 1 (4) 9 (32) 4 (14) 9 (32) 11 (39) 16 (57) P value *

Results were expressed in count (%). Two children born at term did not ll their questionairre. *P<.05.

Table IV. CPET results

Parameter Baseline oxygen saturation, % Baseline respiratory rate, breaths min1 Maximum respiratory rate, breaths min1 Baseline heart rate, beats min1 Maximum heart rate, beats min1 Exercise duration, seconds Load, W Load, W kg1 _ 2, mL kg min1 Peak VO _ 2, mL kg min1 Peak VCO _ E, L min1 V _ 2 _ 2/VO RER, VCO MVV, L min1 Ventilatory reserve, % Borg score RER at ventilatory aerobic threshold CLD group (n = 24) 99.2 (98.8-99.6) 25.2 (22.0-28.5) 53.8 (49.0-58.6) 81.3 (76.7-85.9) 175.3 (171.5-179.1) 553.8 (511.6-596.1) 78.8 (71.5-86.0) 2.4 (2.2-2.7) 35.4 (33.0-37.7) 37.2 (34.1-40.2) 40.7 (37.4-44.0) 1.04 (1.01-1.06) 56.1 (50.7-61.4) 25.8 (19.7-31.9) 16.2 (14.6-17.8) 0.89 (0.86-0.92) Preterm group (n = 26) 99.6 (99.3-99.8) 26.9 (24.5-29.3) 52.5 (47.7-57.3) 76.7 (71.8-82.5) 178.7 (175.1-182.3) 613.6 (559.8-667.5) 84.4 (74.9-93.9) 2.3 (2.1-2.6) 35.0 (32.0-37.9) 36.9 (33.1-40.8) 41.0 (37.5-44.4) 1.05 (1.01-1.09) 67.5 (61.0-74.0) 37.5 (32.2-42.8) 14.6 (12.9-16.3) 0.90 (0.87-0.93) Term group (n = 26) 99.2 (98.8-99.6) 25.2 (22.9-27.5) 48.1 (43.6-52.6) 77.6 (73.2-82.0) 171.4 (165.0-177.8) 625.2 (576.6-673.9) 86.4 (77.4-95.4) 2.2 (1.9-2.4) 31.1 (27.8-34.5) 32.6 (28.6-36.6) 40.9 (37.6-44.2) 1.07 (1.05-1.1) 74.6 (68.4-80.7) 43.7 (38.6-48.7) 15.6 (14.5-16.7) 0.94 (0.92-0.96) P value

*,
,z x

_ 2/VO _ 2). RER, respiratory exchange ratio (VCO Data are mean (95% CI). All values are reported at maximum exercise unless stated otherwise. *P < .05 (CLD vs preterm). P < .001 (CLD vs term). zP < .01 (CLD vs preterm). xP < .05 (CLD vs term).

Exercise-Induced Bronchoconstriction in School-Aged Children Who Had Chronic Lung Disease in Infancy

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