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(Chest. 2005;128:1964-1967.)
© 2005 American College of Chest Physicians

Exhaled Nitric Oxide Predicts Exercise-Induced Bronchoconstriction in Asthmatic School Children*

Frederik Buchvald, MD, PhD; Mette N. Hermansen, MD; Kim G. Nielsen, MD and Hans Bisgaard, MD, DMSci

* From the Danish Pediatric Asthma Centre, Department of Pediatrics, Copenhagen University Hospital, Gentofte, Denmark.

Correspondence to: Hans Bisgaard, MD, DMSci, Danish Pediatric Asthma Centre, Copenhagen University Hospital, DK-2900 Gentofte, Niels Andersensvej 79, 2900 Hellerup, Denmark; e-mail: Bisgaard{at}copsac.dk


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Exercise-induced bronchoconstriction (EIB) is of particular importance in children with asthma. It is an important measure of asthma control and should be monitored by exercise testing. However, exercise testing puts a large demand on health-care resources and is therefore not widely used in routine monitoring of pediatric asthma control. The fractional concentration of exhaled nitric oxide (FeNO) also reflects uncontrolled asthma. We hypothesized that FeNO may be used for prescreening of asthmatic children to exclude those with good asthma control unlikely to have EIB, thereby reducing the need for exercise testing.

Objective: The aim of this study was to estimate the value of FeNO as a predictor of EIB in asthmatic children.

Methods: Stable outpatient asthmatic school children performed standard exercise challenge tests and measurement of FeNO.

Results: FeNO and response to a standardized submaximal exercise test on the treadmill were measured in 111 school children with asthma. EIB could be excluded with a probability of 90% in asthmatic children with FeNO levels < 20 parts per billion (ppb) without current inhaled corticosteroid treatment, and < 12 ppb in children with current inhaled corticosteroid treatment.

Conclusion: Measurement of FeNO is a simple, and time- and resource-efficient tool that may be used to screen for EIB testing and therefore optimizes the resources for exercise testing in pediatric asthma monitoring.

Key Words: children • exercise-induced bronchoconstriction • FeNO • prediction


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Exercise -induced bronchoconstriction (EIB) is a hallmark of asthma, and particularly it is a key symptom in pediatric asthma.1 EIB reflects uncontrolled disease and may be used to guide treatment.1 A history of EIB in children is of limited accuracy,2 and therefore there is a clinical need for the performance of EIB tests in the monitoring of childhood asthma control. However, an exercise test requires complex equipment with a treadmill, dry air supply, and pulse monitoring. In addition, it is time consuming, with large demands on health-care resources, and it may be unpleasant for some children.

The fractional concentration of exhaled nitric oxide (FeNO) reflects asthma control in children as assessed by ß2-agonist use, symptoms, and reversibility,3 and is correlated to BHR and total eosinophil count in children treated with inhaled corticosteroids.4 FeNO reflects the response to anti-inflammatory treatment5 and predicts loss of control before clinical symptoms appear.6 Measurement of FeNO is a rapid and noninvasive procedure that can be performed from the age of 5 to 7 years.7

It was the hypothesis of this study that FeNO measurements may be used to prescreen children with asthma, excluding the need for exercise testing if FeNO measurements were near normal, and focusing the suspicion of EIB on those children with elevated FeNO. The aim of this study was to evaluate FeNO as a predictor of EIB in children with a documented clinical history of asthma in order to select those who require exercise testing.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The study was approved by the local ethics committee. Written informed consent was obtained from the parents and verbal assent from the children.

Patients
Asthmatic children from 6 to 15 years old with mild-to-moderate asthma were recruited from an outpatient pediatric asthma clinic. The diagnosis was determined from a well-known symptom history compatible with asthma, response to inhaled ß2-agonists or corticosteroids, or previous significant decrease in lung function after standardized exercise testing. Asthma was stable and considered clinically well controlled in all patients. Treatment had remained unchanged within the last 4 weeks. Current smokers and children with an airway infection within the previous fortnight were excluded.

Exercise Challenge Test
Exercise challenge test was performed according to American Thoracic Society (ATS) guidelines.8 Each child exercised 6 min on a motor-driven treadmill with a 10° steepness and adjustable speed. A submaximal workload corresponding to a pulse rate of 180 beats/min was maintained during the last 4 min, and was monitored by telemetry. During exercise, the child breathed absolutely dehumidified atmospheric air through a facemask preventing nasal respiration (Hans Rudolph; Kansas City, MO). Lung function was measured before, and 1, 3, 5, and 15 min after exercise. EIB was defined as a ≥ 15% decrease in FEV1 from baseline within the first 5 min after exercise.

Spirometry
Spirometry was performed (MasterScreen; Jäeger; Würzburg, Germany) in accordance with ATS guidelines.9

Exhaled NO
FeNO measurements were performed before exercise testing. Single-breath, on-line measurement of FeNO was performed in accordance with ATS10 and European Respiratory Society11 recommendations at an exhalation flow of 50 mL/s (Aerocrine NO system; Aerocrine AB; Stockholm, Sweden; and CLD 77 AM chemiluminescence analyzer; Eco Physics AG; Duernten, Switzerland). The use of this equipment is well documented.12

Statistics
Standard statistical methods were applied,13 and computer software (MedCalc version 6; MedCalc Software; Mariakerke, Belgium) was used for statistical calculations. According to whether the data represented a normal distribution or not (controlled by Kolmogorov-Smirnov test), mean (lung function data) or median (FeNO data) values with 95% confidence intervals (CIs) were calculated, respectively. Similarly, to compare groups either t test or Wilcoxon analysis were used. Proportions were tested by {chi}2 test. Sensitivity (true-positive rate), specificity (true-negative rate), and positive/negative predictive values (probability that the child has/has not EIB according to FeNO cut-off value) were calculated. Positive cases were defined as children with significant decrease in lung function after exercise. The cut-off values of FeNO were found by receiver operating characteristic (ROC) curve analysis as the values with the highest accuracy (minimal false-negative and false-positive results ie, FeNO below the cut-off value and significant EIB and vice versa). The prevalence of disease used in the analysis was estimated by the ratio of positive and negative cases in the data set. A p value < 0.05 was considered significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
One hundred twenty-two children were included in the study. All children were able to perform the FeNO measurement, but 11 children could not cooperate with the exercise test or lung function test; 111 children completed the protocol and were included in the statistical calculations. Baseline characteristics are outlined in Table 1 . The noncooperative children (n = 11) were not different in baseline characteristics except for being younger in age (6 years old).


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  		Table 1. Baseline Characteristics

 
Baseline FEV1 was lower in children with significant EIB than in nonreactive exercise-challenged children (Table 2 ). The frequency of allergy demonstrated by skin-prick testing or specific IgE (80% vs 68%) or number of children receiving regular inhaled corticosteroids (57% in both groups) were not significantly different between reactive and nonreactive children to EIB.


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  		Table 2. FeNO and Baseline Lung Function According to Bronchoconstriction

 
FeNO was significantly higher in the children with EIB (Table 2). The cut-off value of FeNO with the highest accuracy for EIB was 21 parts per billion (ppb), with an area under the curve (AUC) of 0.77 (95% CI, 0.631 to 0.876) in children not currently receiving inhaled steroids. In the steroid-treated children, the cut-off value of FeNO for prediction of significant EIB was 12 ppb (AUC, 0.744; 95% CI, 0.614 to 0.864). Separation in three dose levels (low dose ≤ 400 µg; medium dose > 400 to < 800 µg, and high dose ≥ 800 µg budesonide or equivalent) did not significantly alter the ROC curve analysis (data not shown). In children receiving ≥ 800 µg budesonide, a FeNO ≥ 10 ppb has 100% sensitivity, specificity, and positive and negative predictive value for EIB. Sensitivity and negative predictive values were higher compared to specificity and positive predictive values. The full ROC curve analysis is presented in Table 3 and Figures 1 and 2 .


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  		Table 3. ROC Curve Analysis for Exercise Test*

 


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  		Figure 1. ROC curve for FeNO predicting EIB with representative values in children treated with regular inhaled corticosteroids treatment.

 


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  		Figure 2. ROC curve for FeNO predicting EIB with representative values in steroid-naïve children.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study shows that FeNO may be used to prescreen children with recognized asthma into a group with increased FeNO, indicating the need for EIB testing, and into another group with near-normal FeNO, for whom EIB is unlikely. FeNO values < 20 ppb in children treated with ß2-agonists on demand and < 12 ppb for children receiving regular inhaled corticosteroids provided a negative predictive value of nearly 90% probability. This finding has important implications for the quality of pediatric asthma control. Simple FeNO screening may be used to increase the vigilance of EIB in children with asthma and raised FeNO. EIB is a key symptom in pediatric asthma. In addition, EIB reflects disease control and may be present despite a lack of daily symptoms and a normal lung function. A history of EIB is insensitive, and exercise testing requires resources beyond what can be accommodated in most clinics. We therefore recommend using FeNO as a screening tool for EIB in outpatient children with clinically verified asthma.

To our knowledge, this is the first study to investigate FeNO for the prediction of EIB in asthmatic children. This pediatric population had clinically verified asthma and was therefore attending our outpatient clinic. El Halawani et al14 reported a cut-off value of 12 ppb as the best predictor of a positive exercise challenge test result with sensitivity, specificity, and positive and negative predictive values of 100%, 31%, 19%, and 100%, respectively. However, in their study,14 measurement of FeNO was used as a screening tool to diagnose asthma in subjects with complaints of abnormal dyspnea on exercise but without a verified asthma diagnosis. In contrast, our aim is to use FeNO to improve quality of care in children with diagnosed asthma by identifying the subpopulation that should be evaluated by exercise testing to reveal uncontrolled EIB.

We analyzed the data in steroid-naïve and corticosteroid-treated children separately. Analysis of the ROC curve in steroid-naïve children suggested a cut-off value of approximately 20 ppb, which, coincidentally, is similar to the upper limit (mean + 2 SD) of normal values in healthy children.15 FeNO is decreased by anti-inflammatory treatment16; hence, the cut-off for children receiving inhaled corticosteroids was lower (12 ppb) than in steroid-naïve children. Nearly 50% of the steroid-treated children reactive to exercise have increased FeNO (> 20 ppb) despite current inhaled corticosteroid treatment (data not shown), and the predicted FeNO cut-off values were not significantly affected by current dose of inhaled corticosteroid (the daily dose of budesonide ranged from 100 to 1,600 µg). This confirms the results from our previous study15 that FeNO in some children was not affected by treatment with inhaled corticosteroids.

In our study, all subjects included were tested irrespective of a history of respiratory symptoms during exercise. Despite apparently being well controlled, > 25% of this unselected population of asthmatic children showed EIB, which emphasizes the relevance of such exercise testing, but also suggests that a large number of tests could have been avoided by screening with FeNO. Even though the study population differed in asthma severity, all children were clinically stable at the time of measurement, and we believe that the results can be directly applied to clinical practice and used as guidance for a more accurate selection of asthmatic children eligible for exercise testing. In conclusion, FeNO measurement is a cost-saving procedure that can be used in pediatric asthma management as a rapid and feasible screening tool to assess the need for exercise testing in children with asthma.


   Footnotes
 
Abbreviations: AUC = area under the curve; CI = confidence interval; EIB = exercise-induced bronchoconstriction; FeNO = fractional concentration of exhaled nitric oxide; ppb = parts per billion; ROC = receiver operating characteristic

Received for publication December 4, 2004. Accepted for publication February 25, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Price, JF (2001) Choices of therapy for exercise-induced asthma in children. Allergy 56,12-17[CrossRef]
  2. Panditi, S, Silverman, M Perception of exercise induced asthma by children and their parents. Arch Dis Child 2003;88,807-811[Abstract/Free Full Text]
  3. Meyts, I, Proesmans, M, De Boeck, K Exhaled nitric oxide corresponds with office evaluation of asthma control. Pediatr Pulmonol 2003;36,283-289[Medline]
  4. Covar, RA, Szefler, SJ, Martin, RJ, et al Relations between exhaled nitric oxide and measures of disease activity among children with mild-to-moderate asthma. J Pediatr 2003;142,469-475[CrossRef][ISI][Medline]
  5. Szefler, SJ, Martin, RJ, King, TS, et al Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol 2002;109,410-418[CrossRef][ISI][Medline]
  6. Jones, SL, Kittelson, J, Cowan, JO, et al The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 2001;164,738-743[Abstract/Free Full Text]
  7. Kharitonov, SA, Gonio, F, Kelly, C, et al Reproducibility of exhaled nitric oxide measurements in healthy and asthmatic adults and children. Eur Respir J 2003;21,433-438[Abstract/Free Full Text]
  8. Crapo, RO, Casaburi, R, Coates, AL, et al Guidelines for methacholine and exercise challenge testing-1999: this official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 2000;161,309-329[Free Full Text]
  9. American Thoracic Society.. Standardization of spirometry, 1994 update. Am J Respir Crit Care Med 1995;152,1107-1136[ISI][Medline]
  10. Recommendations for standardized procedures for the on-line and off-line measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children-1999: this official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 1999;160,2104-2117[Free Full Text]
  11. Kharitonov, S, Alving, K, Barnes, PJ Exhaled and nasal nitric oxide measurements: recommendations: The European Respiratory Society Task Force. Eur Respir J 1997;10,1683-1693[CrossRef][ISI][Medline]
  12. Bisgaard, H, Loland, L, Anhoj, J NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast. Am J Respir Crit Care Med 1999;160,1227-1231[Abstract/Free Full Text]
  13. Altman, DG Practical statistics for medical research 1st ed. 1999 Chapman and Hall/CRC. London, UK:
  14. El Halawani, SM, Ly, NT, Mahon, RT, et al Exhaled nitric oxide as a predictor of exercise-induced bronchoconstriction. Chest 2003;124,639-643[Abstract/Free Full Text]
  15. Buchvald, F, Eiberg, H, Bisgaard, H Heterogeneity of FeNO response to inhaled steroid in asthmatic children. Clin Exp Allergy 2003;33,1735-1740[CrossRef][Medline]
  16. Silkoff, PE, McClean, P, Spino, M, et al Dose-response relationship and reproducibility of the fall in exhaled nitric oxide after inhaled beclomethasone dipropionate therapy in asthma patients. Chest 2001;119,1322-1328[Abstract/Free Full Text]



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