Journal of Asthma
ISSN: 0277-0903 (Print) 1532-4303 (Online) Journal homepage: http://www.tandfonline.com/loi/ijas20
The effect of exercise on exhaled nitric oxide depends on allergic rhinoconjunctivitis in children Bjørg Evjenth MD, PhD, Tonje E. Hansen MD & Jan Holt MD, PhD To cite this article: Bjørg Evjenth MD, PhD, Tonje E. Hansen MD & Jan Holt MD, PhD (2015) The effect of exercise on exhaled nitric oxide depends on allergic rhinoconjunctivitis in children, Journal of Asthma, 52:8, 795-800, DOI: 10.3109/02770903.2015.1014099 To link to this article: http://dx.doi.org/10.3109/02770903.2015.1014099
Published online: 19 May 2015.
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Date: 06 November 2015, At: 03:07
http://informahealthcare.com/jas ISSN: 0277-0903 (print), 1532-4303 (electronic) J Asthma, 2015; 52(8): 795–800 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/02770903.2015.1014099
ORIGINAL ARTICLE
The effect of exercise on exhaled nitric oxide depends on allergic rhinoconjunctivitis in children Bjørg Evjenth, MD, PhD1, Tonje E. Hansen, MD1, and Jan Holt, MD, PhD1,2 Department of Pediatrics, Division of Pediatrics, Obstetrics and Women’s Health, Nordland Hospital, Bodø, Norway and 2Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway
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Keywords
Objective: Fractional exhaled nitric oxide (FENO) and exercise testing are widely used for the evaluation of pediatric asthma. The evidence relating to the effects of strenuous exercise on FENO in children is conflicting. Little information is available on the association between exercise and FENO in relation to allergic rhinoconjunctivitis (AR). We aimed to investigate the effects of AR on children’s FENO in response to a standardized treadmill exercise test. Methods: A total of 124 children with current asthma and 124 non-asthmatic children aged 8–16 years were studied. FENO was measured at baseline, at 1 and 30 min after an exercise challenge test using the single breath technique with EcoMedics ExhalyzerÕ . A structured parental interview, spirometry, serum allergen-specific IgE and skin prick tests were performed. Results: Baseline FENO was higher in both asthmatics and non-asthmatics with AR than without AR (both p50.001). The FENO time trend was dependent on AR (p ¼ 0.039), irrespective of asthma (p ¼ 0.876). In children with AR, FENO had declined at 1 min by a mean of 6.1 ppb with a 95% confidence level of 5.1–7.5 ppb; at 30 min, the reduction was 2.8 (2.5–3.3) ppb. In children without AR, at 1 min the decline in FENO was 2.7 (2.1–3.5) ppb and by 30 min post-exercise it was 1.6 (1.3–2.0) ppb. Conclusions: The impact of exercise on FENO was dependent on the allergic phenotype, regardless of asthma status. FENO decreased immediately after exercise, and did not return to baseline level within 30 min.
Allergic rhinoconjunctivitis, asthma, exercise test, FENO, children
Introduction Exhaled nitric oxide (FENO) is widely used as a non-invasive marker of eosinophilic airway inflammation in asthma [1–3]. A variety of factors may influence its measurement. FENO levels may be altered by exercise-induced bronchoconstriction (EIB) tests, spirometry and other laboratory procedures often accompanying FENO measurements [4–6]. The American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines recommend refraining from strenuous exercise 1 h before performing a FENO test because exercise has been shown to reduce FENO levels in both healthy and asthmatic adults [7]. It has been argued that increased nitric oxide (NO) elimination from the airways during exercise and reduced airway surface during EIB is the main mechanism of FENO decline post-exercise [8–11]. Few reports regarding the effects of exercise on FENO in children have been published, and the results are conflicting [10–13]. Asthma and allergic rhinoconjunctivitis (AR) are characterized by similar inflammatory processes, and AR has been reported to aggravate bronchial inflammation [3,14]. However, most previous studies do not take account of AR. Correspondence: Bjørg Evjenth, Department of Pediatrics, Nordland Hospital, Post Box 1480, NO-8092 Bodø, Norway. Tel: +47 75534000. Fax: +47 75534013. E-mail: [email protected]
History Received 5 September 2014 Revised 25 January 2015 Accepted 28 January 2015 Published online 19 May 2015
Increased FENO has been observed in children with AR regardless of asthma [15–17], and a strong correlation between the degree of IgE sensitization and FENO levels has been demonstrated [3,15]. It has been suggested that elevated FENO in sensitized non-asthmatic subjects represents subclinical eosinophilic inflammation in the lower airways, particularly in subjects with AR [3,15]. In asthmatics, the FENO level depends on the allergic phenotype and on treatment with inhaled corticosteroids (ICS) [3,4]. In clinical practice, EIB is an important measure of asthma control. FENO is predictive of EIB, and a low baseline FENO is reported to be useful as a negative predictor for EIB [4,18,19]. Children often play and run around before FENO measurements – activities which along with exercise testing may influence the FENO level. The primary aim of this study was to determine the effect of strenuous exercise on FENO in asthmatic and non-asthmatic children with and without AR.
Methods Study design This analysis was a part of the ‘‘Asthma and allergy among schoolchildren in Nordland’’ case–control study that included children aged 8–16 years. In Phase I of the study, 4150 parents completed a questionnaire on their children’s asthma, AR and
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eczema [20]. In Phase II of the study, 801 schoolchildren (373 of them reporting asthma in Phase I) underwent a clinical examination at least 2 weeks after any suspected respiratory tract infection. The parents completed a questionnaire and a structured interview relating to asthma and AR symptoms, exposure to allergens and tobacco smoke, and the use of medications. Based on information given in the structured interview and the clinical examination the pupils were finally categorized as asthmatic or non-asthmatic. This analysis from the Phase II study included 145 pupils with current asthma (cases) and 145 non-asthmatic age- and gender-matched controls. When a subject was unable to comply with the study protocol, or a control had a positive EIB test, the pair was excluded. The study was approved by the Regional Committee for Medical and Health Research Ethics (REC North) and was performed in accordance with the ethical standards of the 2000 Declaration of Helsinki. Written informed consent was obtained from all children and their parents.
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(Air Liquide Deutschland GmbH, Krefeld, Germany). FENO was measured at baseline, prior to spirometry, and 1 min after exercise and 30 min later. Pulmonary function Spirometry was performed in accordance with international guidelines [21] with an ambulant electronic spirometer, Spiro USB with Spida 5 software (Micro Medical, Rochester, UK). Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were expressed as a percentage of predicted values using the global lung function 2012 equation [22]. Before testing, ICS and short acting b-2 agonists were withheld for 12 h, inhaled long acting b-2 agonists for the last 48 h, leukotriene modifiers for the last 24 h and antihistamines for the last 5 days. No children were using oral steroids. Exercise challenge test
The participants were examined at the Nordland Hospital, Bodø, and at three other locations in Nordland County from March to mid-June 2009 and from September 2009 to midJune 2010. Two of the authors (B.E. and T.E.H.) conducted all the interviews and examinations, and the same medical instruments were used to secure standardized measurement conditions.
The EIB test was performed by running for 6–8 min on a motor-driven treadmill (Woodway GmbH, Weil am Rhein, Germany) following the ATS/ERS guidelines [23]. The mean target heart rate during the last 4 min was 95% of maximum heart rate (calculated as 220 minus age in years), though a minimum heart rate of 180 beats/min (85–88%) was accepted. The EIB test was considered positive with a decrease in FEV1 15% of baseline FEV1 measured at 3, 6, 10, 15 and 20 min after the exercise. Exclusion criteria were strenuous exercise within 4 h of testing and pre-exercise FEV1 lower than 75% of the predicted value.
Definitions
Allergic sensitization
Current asthma: at least two of the following three criteria were fulfilled within the last year: (1) recurrent dyspnoea, chest tightness and/or wheeze; (2) a doctor’s diagnosis of asthma and (3) use of asthma medication (b-2 agonist, sodium chromoglycate, corticosteroids, leukotriene antagonists and/or aminophylline). AR symptoms: a history of watery rhinorrhoea, blocked nose, sneezing, nasal itching accompanied by itchy watery eyes in the absence of airway infection. AR: AR symptoms in combination with allergic sensitization. Non-AR: no AR symptoms and no sensitization to inhalant allergens. Allergic sensitization: a positive serum allergen-specific IgE and/or a positive SPT to at least one of 10 inhalant allergens.
Seroatopy was defined by a specific IgE test 0.35 kU/L [24] to at least one of the listed allergens Dermatophagoides pteronyssinus, Cladosporium herbarium, Alternaria tenius, German cockroach, cat, dog, rabbit, mugwort, birch and timothy. Allergen-specific IgE levels were analyzed using the IMMULITEÕ 2000 immunoassay (Siemens Healthcare Diagnostics Inc., Deerfield, IL). Skin prick tests (SPTs) were performed with SoluprickÕ allergens (ALK Abello, Hørsholm, Denmark). SPT was considered positive with a wheal diameter 3 mm larger than the negative control (saline) [25]. Blood samples were requested from all participants, while during the initial study period SPT was requested from all children. Thereafter, SPT was requested from children with asthma and/ or allergy symptoms. Allergic sensitization was not evaluated in 12 individuals without AR symptoms.
Research environment
Measurement of exhaled NO FENO was measured online by the single breath method with a chemiluminescence analyzer, EcoMedics ExhalyzerÕ CLD 88sp with Denox 88 (Eco Medics, Duernten, Switzerland) [detection range, 0.1–5000 parts per billion (ppb); accuracy ± 2%]. The procedure was performed in accordance with published guidelines [7]. Mean exhalation flow rate was 50 mL/s ± 10% during the NO plateau. The maneuver was repeated until two exhalations agreed to within 5% coefficient of variation (CV), or three exhalations agreed to within 10% CV. The NO concentration, FENO, was defined as the mean of these values expressed in ppb. The analyzer was calibrated daily using a standard NO calibration gas
Statistical analysis The distribution of FENO values was right skewed, and hence analyses were executed with natural log (Ln) transformed data. The results were presented as back-transformed values and expressed as geometric means with 95% confidence intervals (CIs). Inter-group comparisons were analyzed with an independent t-test for continuous variables and Pearson’s chisquare test for categorical variables. Linear mixed models were used to assess differences in time trends of FENO between the groups. The response variable in each model was LnFENO. Dependence between the three repeated time points was controlled for by including an unstructured covariance matrix
FENO, exercise, asthma and allergic phenotype
DOI: 10.3109/02770903.2015.1014099
to the model. ‘‘Matched pairs’’ were included as a random effect in the model. Bonferroni’s post hoc test was used for multiple comparisons for continuous variables. Correlations were assessed using Spearman’s correlation test. Normally distributed values were presented as means and standard deviation (SD) or 95% CI. Categorical data were presented as percentages. All tests were two-sided using a significance level of 0.05. Statistical analyses were performed using Statistical Package for Social Science (SPSS) software version 21.0 (SPSS Inc. IBM, Chicago, IL).
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Results Of the 801 children enrolled in Phase II of the study, 373 children reported asthma in Phase I of the study. This part of the study included 145 pupils with current asthma (cases) and 145 non-asthmatic pupils (controls) (145 matched pairs). Twenty pairs included pupils who were unable to comply with the study protocol, and one pair included a control with a positive EIB test. These pairs were excluded. Children who did not comply were younger than the included children (p ¼ 0.006). The descriptive data of the 124 pairs (i.e. 248 participants) included in statistical calculations are given in Table 1. Baseline FENO was significantly higher in asthmatics compared to non-asthmatics (Table 1) and significantly elevated in those with AR regardless of asthma status (Table 2). Baseline FENO was not significantly different among asthmatic children reporting ICS use compared with no use of ICS (data not presented). We found parallel time trends for FENO levels (ppb) between asthmatics and non-asthmatics (p ¼ 0.866). Adjustment for baseline FENO yielded no significant difference in time trends between the groups (p ¼ 0.848). The times trends were significantly different in children with AR compared to children without AR (p ¼ 0.039), irrespective of asthma (p ¼ 0.876), Figure 1. In children with AR, FENO had declined at 1 min by a mean of 6.1 ppb with a 95% CI of 5.1–7.5 ppb; at 30 min, the reduction was 2.8 (2.5–3.3) ppb. In children without AR, at 1 min the decline in FENO was 2.7 (2.1–3.5) ppb and by 30 min post-exercise it was 1.6 (1.3–2.0) ppb.
The linear mixed model calculations of the effect of exercise on FENO involved a comparison of the percentage change in LnFENO from baseline to 1 and 30 min postexercise (Figure 2). The time trend was dependent on AR (p50.001), irrespective of asthma status (p ¼ 0.795). In children with AR, LnFENO declined at 1 min by a mean of 10.1% (±2.2) and was reduced by a mean of 4.5% (±2.3) at 30 min. In children without AR, LnFENO dropped by a mean of 17.7% (±2.8) at 1 min, and LnFENO was reduced by a mean of 9.4% (±2.9) at 30 min post-exercise. In asthmatics, the effects of exercise on FENO was independent on ICS treatment (p ¼ 0.583) and a positive EIB test (p ¼ 0.230). Children with AR had a mean of four positive SPT/or allergen-specific IgE tests. Based on LnFENO, the % reduction at 1 and 30 min post-exercise was less pronounced with increasing number of positive SPT/or allergen-specific IgE tests (data not presented). Of the 123 children with AR, 122 were sensitized to seasonal and 110 to perennial allergens. The time trend was significantly dependent on AR in children with perennial and seasonal AR (both p50.001). Baseline FENO correlated positively with maximal postexercise FEV1 decline in asthmatics ( ¼ 0.331, p50.001). In asthmatics with AR, a positive correlation was found ( ¼ 0.360, p50.001), but not in asthmatics without AR.
Discussion The main results of the present study were that FENO decreased immediately after a submaximal treadmill challenge and did not return to baseline value within 30 min. The time trends were parallel in asthmatic and non-asthmatic children and independent of baseline FENO. Children with AR showed a greater reduction in FENO value (ppb) post-exercise, although the effect of heavy exercise (% change in LnFENO) was more pronounced in children without AR than in children with AR. Our study demonstrates that the assessment of clinical effects differed according to whether the target parameter chosen was the absolute FENO (ppb) level, or if the effect was
Table 1. Demographic data, baseline FENO and pulmonary measurements of the study group.
N (male) Age (years)a Height (cm)a Weight (kg)a Parental smoking (%) Allergic sensitizationb (%) Allergic rhinoconjuctivitis (%) FENOc FVC (% predicted)d FEV1 (% predicted)d FEF50 (L/s)a
Current asthma
Non-asthma
p Value
124 (81) 12.6 (2.0) 156.1 (13.7) 51.4 (16.9) 39.0 80.3 71.7 21.0 (17.6–24.9) 95.6 (0.4) 90.6 (0.8) 2.9 (1.1)
124 (81) 12.6 (2.0) 156.3 (13.1) 47.8 (13.1) 28.2 45.6 27.4 11.1 (9.9–12.4) 93.1 (0.6) 94.1 (0.5) 3.4 (1.1)
0.810 0.919 0.059 0.072 50.001 50.001 50.001 0.069 0.010 0.001
FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; FEF50, forced expiratory flow after 50% of FVC. Results are given as means (SD). Allergic sensitization was defined by a positive SPT and/or specific s-IgE 0.35 kU/L to 1/10 inhalation allergens, n ¼ 236. c Geometric mean fractional FENO is expressed in ppb (95% CI). d FVC and FEV1 are given as mean % predicted values (z-scores) [22]. a
b
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Table 2. Baseline FENO measurements in subgroups according to AR. Group Current asthma Non-asthmab
b
Non-ARa
ARa
p Value
9.0 (7.1–11.3) (n ¼ 22) 8.5 (7.7–9.4) (n ¼ 61)
28.1 (23.0–34.3) (n ¼ 89) 19.3 (14.9–25.0) (n ¼ 34)
50.001 50.001
a
AR was defined by AR symptoms and allergic sensitization to 1/10 inhalant allergens. Geometric mean FENO is expressed in ppb (95% CI).
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b
Figure 1. Geometric mean FENO levels in asthmatics with AR (n ¼ 89), non-asthmatics with AR (n ¼ 34), asthmatics without AR (n ¼ 22) and non-asthmatics without AR (n ¼ 61). FENO was measured at baseline (pre) and at 1 and 30 min after a standardized exercise inducedbronchoconstriction test on a treadmill. FENO is expressed in ppb. Error bars represent 95% CIs.
Figure 2. Changes in LnFENO (%) after a standardized EIB test on a treadmill in asthmatic and non-asthmatic children. Data are presented for four subgroups: asthmatics with allergic rhinoconjunctivitis (AR) (n ¼ 89), non-asthmatics with AR (n ¼ 34), asthmatics without AR (n ¼ 22) and non-asthmatics without AR (n ¼ 61). FENO was measured at baseline (pre) and at 1 and 30 min after a standardized exercise inducedbronchoconstriction test on a treadmill. Error bars represent 95% CIs.
assessed as a % change in LnFENO. The impact of exercise on FENO levels may be most relevant in clinical practice. However, assessment of effect (% change) appears to provide information on dissimilar airway inflammatory responses to exercise. Previous studies have reported contradictory results regarding the impact of exercise on FENO in children [10–13]. Differences in response were not stratified by AR or allergic sensitization in asthmatics and controls, and the number of subjects was low compared to the present study. Our finding that baseline FENO was increased in allergic asthmatics and allergic non-asthmatics agrees with previous studies [15–18]. Even though ICS treatment of asthmatics has been reported to be a marker of more severe disease [26], it did not influence baseline FENO. Similar mucosal inflammatory processes characterize children with allergic asthma and AR. Histochemical studies in subjects with AR have demonstrated the presence of eosinophilic inflammation from the nasal mucous membrane to the bronchial lining [14]. Hence, the increased FENO at baseline in non-asthmatics with AR likely reflects subclinical eosinophilic inflammation of the lower airways. FENO was reduced in all subgroups after exercise. The lower % reduction in LnFENO post-exercise found in children with AR and allergic asthma can be explained by pathophysiological differences in NO production. Eosinophilic cells are known to provoke airway-epithelium injury via oxidative damage of proteins [27] and thereby promote the release of cytokines and other pro-inflammatory mediators. The expressions of inducible NO synthase (NOS) and constitutive NOS are enhanced by pro-inflammatory mediators, and the NO production is increased by oxidative stress [28,29]. During exercise, airway inflammation is triggered by cooling and dehydration of the airway mucosa, and inflammatory mediators are released in response to a hyperosmolar stimulus [30,31]. Based on our findings (Figure 2), we hypothesise that heavy exercise aggravate NO production in asthmatics and non-asthmatics with AR leading to a less % reduction in LnFENO post-exercise compared to children without AR. The % reduction in LnFENO was less pronounced with increased number of positive SPT/or allergen specific IgE tests. These results indicate that the FENO production is more aggravated in children with greater atopy. The effect of exercise on FENO differed significantly in both seasonal AR and perennial AR compared to non-AR. A significant proportion of children with AR were sensitized to both seasonal and perennial allergens. Fourteen children with seasonal allergy were investigated within the season. The level of allergen exposure may have affected the results.
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DOI: 10.3109/02770903.2015.1014099
The overall reduction in FENO after the EIB test can be explained by alteration in NO dynamics due to a ventilation effect. Exercise increase the diffusing capacity of NO and decrease the airway wall concentration of NO (CawNO) [32]. The decreased CawNO, attributed to increased loss of NO in the exhaled air, has been explained as a washout of tissue NO stores [32]. The EIB test has been reported with different activity, intensity and threshold [10–13]. A high exercise load is essential, as it is more likely to reveal EIB and better related to inflammatory activity [33]. Likewise, ventilation is dependent on exercise load. We used a standardized exercise test with a high exercise load, which explains the marked decline in FENO value. High exercise intensity entails increased heart rate and pulmonary blood flow, which may alter pulmonary NO exchange. However, NO diffusion toward the pulmonary circulation does not increase during exercise [34]. It is unlikely that increased pulmonary vascular NO production affects FENO post-exercise due to the short half-life of NO and the high affinity of NO to hemoglobin [35]. The positive relationship between baseline FENO and the severity of bronchial hyperreactivity has also been demonstrated in other studies [4,18,36]. Bronchoconstriction could conceivably decrease the airway surface area, and thus decrease the diffusing capacity of NO. In line with other studies, the observed reduction in FENO was independent of changes in airway caliber post-exercise [10,37]. The overall decreased FENO after exercise could partially be explained by a lower contribution of nasal NO (nNO). During exercise, nNO falls rapidly and oral breathing may contribute to lessen the contamination of nNO to the lower respiratory tract [38]. Studies are conflicting as to whether nNO is altered in AR [39]. Discrepancies between studies can be attributed to differences in methodology, as different NO sampling techniques have been used [10–12]. For example, the measured FENO concentration is inversely related to the analyzer expiratory flow rate [40]. Participants were subjected to baseline FENO measurements and spirometry, which were followed by the EIB test, FENO measurements and repeated spirometry. Previous studies have reported contradictory results regarding the effect of spirometry on FENO [6,11,41]. Repeated FENO measurements may affect the within-subject variability [6]. In the present study, FENO was still at a decreased level after 30 min. In this context, we cannot draw firm conclusions as to whether reduced FENO at this time point can be solely attributed to exercise or was influenced by the repeated spirometric maneuvers. Ideally, the FENO measurements should have been repeated until normalized.
Conclusions Baseline FENO levels were increased in asthmatic and nonasthmatic children with AR compared to children without AR. The effects of exercise on FENO (% reduction in LnFENO) were less pronounced in children with AR than without AR, irrespective of asthma. This finding indicated that exercise aggravated lower airway inflammation in children with
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inhalant allergy. If children are physically active before FENO measurements, FENO values could be underestimated. This is especially pronounced in children with AR and allergic asthma who have the highest baseline FENO and greatest reduction in FENO (ppb) value post-exercise. Therefore, FENO measurements should be performed before EIB testing, and children should rest for at least 30 min before measuring FENO, since FENO is reduced after exercise and does not return to baseline level within 30 min.
Acknowledgements We thank Professor Tom Wilsgaard and PhD Tonje Braaten for statistical advice. We thank MD Sandy Goldbeck-Wood and Emeritus Professor Evert Nieboer for critically editing the article and MD Terje Tolla˚li for helpful discussions. We gratefully acknowledge the enthusiasm and cooperation of all participating children and parents.
Declaration of interest The study was supported by grants from the Northern Norway Regional Health Authority, the Norwegian Respiratory Society and the Morten Jensens foundation. The authors declare no conflicts of interest, in terms of the ICMJE definition, in respect of the authorship and/or publication of this article.
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The effect of exercise on exhaled nitric oxide depends on allergic rhinoconjunctivitis in children Bjørg Evjenth MD, PhD, Tonje E. Hansen MD & Jan Holt MD, PhD To cite this article: Bjørg Evjenth MD, PhD, Tonje E. Hansen MD & Jan Holt MD, PhD (2015) The effect of exercise on exhaled nitric oxide depends on allergic rhinoconjunctivitis in children, Journal of Asthma, 52:8, 795-800, DOI: 10.3109/02770903.2015.1014099 To link to this article: http://dx.doi.org/10.3109/02770903.2015.1014099
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Date: 06 November 2015, At: 03:07
http://informahealthcare.com/jas ISSN: 0277-0903 (print), 1532-4303 (electronic) J Asthma, 2015; 52(8): 795–800 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/02770903.2015.1014099
ORIGINAL ARTICLE
The effect of exercise on exhaled nitric oxide depends on allergic rhinoconjunctivitis in children Bjørg Evjenth, MD, PhD1, Tonje E. Hansen, MD1, and Jan Holt, MD, PhD1,2 Department of Pediatrics, Division of Pediatrics, Obstetrics and Women’s Health, Nordland Hospital, Bodø, Norway and 2Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway
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Keywords
Objective: Fractional exhaled nitric oxide (FENO) and exercise testing are widely used for the evaluation of pediatric asthma. The evidence relating to the effects of strenuous exercise on FENO in children is conflicting. Little information is available on the association between exercise and FENO in relation to allergic rhinoconjunctivitis (AR). We aimed to investigate the effects of AR on children’s FENO in response to a standardized treadmill exercise test. Methods: A total of 124 children with current asthma and 124 non-asthmatic children aged 8–16 years were studied. FENO was measured at baseline, at 1 and 30 min after an exercise challenge test using the single breath technique with EcoMedics ExhalyzerÕ . A structured parental interview, spirometry, serum allergen-specific IgE and skin prick tests were performed. Results: Baseline FENO was higher in both asthmatics and non-asthmatics with AR than without AR (both p50.001). The FENO time trend was dependent on AR (p ¼ 0.039), irrespective of asthma (p ¼ 0.876). In children with AR, FENO had declined at 1 min by a mean of 6.1 ppb with a 95% confidence level of 5.1–7.5 ppb; at 30 min, the reduction was 2.8 (2.5–3.3) ppb. In children without AR, at 1 min the decline in FENO was 2.7 (2.1–3.5) ppb and by 30 min post-exercise it was 1.6 (1.3–2.0) ppb. Conclusions: The impact of exercise on FENO was dependent on the allergic phenotype, regardless of asthma status. FENO decreased immediately after exercise, and did not return to baseline level within 30 min.
Allergic rhinoconjunctivitis, asthma, exercise test, FENO, children
Introduction Exhaled nitric oxide (FENO) is widely used as a non-invasive marker of eosinophilic airway inflammation in asthma [1–3]. A variety of factors may influence its measurement. FENO levels may be altered by exercise-induced bronchoconstriction (EIB) tests, spirometry and other laboratory procedures often accompanying FENO measurements [4–6]. The American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines recommend refraining from strenuous exercise 1 h before performing a FENO test because exercise has been shown to reduce FENO levels in both healthy and asthmatic adults [7]. It has been argued that increased nitric oxide (NO) elimination from the airways during exercise and reduced airway surface during EIB is the main mechanism of FENO decline post-exercise [8–11]. Few reports regarding the effects of exercise on FENO in children have been published, and the results are conflicting [10–13]. Asthma and allergic rhinoconjunctivitis (AR) are characterized by similar inflammatory processes, and AR has been reported to aggravate bronchial inflammation [3,14]. However, most previous studies do not take account of AR. Correspondence: Bjørg Evjenth, Department of Pediatrics, Nordland Hospital, Post Box 1480, NO-8092 Bodø, Norway. Tel: +47 75534000. Fax: +47 75534013. E-mail: [email protected]
History Received 5 September 2014 Revised 25 January 2015 Accepted 28 January 2015 Published online 19 May 2015
Increased FENO has been observed in children with AR regardless of asthma [15–17], and a strong correlation between the degree of IgE sensitization and FENO levels has been demonstrated [3,15]. It has been suggested that elevated FENO in sensitized non-asthmatic subjects represents subclinical eosinophilic inflammation in the lower airways, particularly in subjects with AR [3,15]. In asthmatics, the FENO level depends on the allergic phenotype and on treatment with inhaled corticosteroids (ICS) [3,4]. In clinical practice, EIB is an important measure of asthma control. FENO is predictive of EIB, and a low baseline FENO is reported to be useful as a negative predictor for EIB [4,18,19]. Children often play and run around before FENO measurements – activities which along with exercise testing may influence the FENO level. The primary aim of this study was to determine the effect of strenuous exercise on FENO in asthmatic and non-asthmatic children with and without AR.
Methods Study design This analysis was a part of the ‘‘Asthma and allergy among schoolchildren in Nordland’’ case–control study that included children aged 8–16 years. In Phase I of the study, 4150 parents completed a questionnaire on their children’s asthma, AR and
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eczema [20]. In Phase II of the study, 801 schoolchildren (373 of them reporting asthma in Phase I) underwent a clinical examination at least 2 weeks after any suspected respiratory tract infection. The parents completed a questionnaire and a structured interview relating to asthma and AR symptoms, exposure to allergens and tobacco smoke, and the use of medications. Based on information given in the structured interview and the clinical examination the pupils were finally categorized as asthmatic or non-asthmatic. This analysis from the Phase II study included 145 pupils with current asthma (cases) and 145 non-asthmatic age- and gender-matched controls. When a subject was unable to comply with the study protocol, or a control had a positive EIB test, the pair was excluded. The study was approved by the Regional Committee for Medical and Health Research Ethics (REC North) and was performed in accordance with the ethical standards of the 2000 Declaration of Helsinki. Written informed consent was obtained from all children and their parents.
J Asthma, 2015; 52(8): 795–800
(Air Liquide Deutschland GmbH, Krefeld, Germany). FENO was measured at baseline, prior to spirometry, and 1 min after exercise and 30 min later. Pulmonary function Spirometry was performed in accordance with international guidelines [21] with an ambulant electronic spirometer, Spiro USB with Spida 5 software (Micro Medical, Rochester, UK). Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were expressed as a percentage of predicted values using the global lung function 2012 equation [22]. Before testing, ICS and short acting b-2 agonists were withheld for 12 h, inhaled long acting b-2 agonists for the last 48 h, leukotriene modifiers for the last 24 h and antihistamines for the last 5 days. No children were using oral steroids. Exercise challenge test
The participants were examined at the Nordland Hospital, Bodø, and at three other locations in Nordland County from March to mid-June 2009 and from September 2009 to midJune 2010. Two of the authors (B.E. and T.E.H.) conducted all the interviews and examinations, and the same medical instruments were used to secure standardized measurement conditions.
The EIB test was performed by running for 6–8 min on a motor-driven treadmill (Woodway GmbH, Weil am Rhein, Germany) following the ATS/ERS guidelines [23]. The mean target heart rate during the last 4 min was 95% of maximum heart rate (calculated as 220 minus age in years), though a minimum heart rate of 180 beats/min (85–88%) was accepted. The EIB test was considered positive with a decrease in FEV1 15% of baseline FEV1 measured at 3, 6, 10, 15 and 20 min after the exercise. Exclusion criteria were strenuous exercise within 4 h of testing and pre-exercise FEV1 lower than 75% of the predicted value.
Definitions
Allergic sensitization
Current asthma: at least two of the following three criteria were fulfilled within the last year: (1) recurrent dyspnoea, chest tightness and/or wheeze; (2) a doctor’s diagnosis of asthma and (3) use of asthma medication (b-2 agonist, sodium chromoglycate, corticosteroids, leukotriene antagonists and/or aminophylline). AR symptoms: a history of watery rhinorrhoea, blocked nose, sneezing, nasal itching accompanied by itchy watery eyes in the absence of airway infection. AR: AR symptoms in combination with allergic sensitization. Non-AR: no AR symptoms and no sensitization to inhalant allergens. Allergic sensitization: a positive serum allergen-specific IgE and/or a positive SPT to at least one of 10 inhalant allergens.
Seroatopy was defined by a specific IgE test 0.35 kU/L [24] to at least one of the listed allergens Dermatophagoides pteronyssinus, Cladosporium herbarium, Alternaria tenius, German cockroach, cat, dog, rabbit, mugwort, birch and timothy. Allergen-specific IgE levels were analyzed using the IMMULITEÕ 2000 immunoassay (Siemens Healthcare Diagnostics Inc., Deerfield, IL). Skin prick tests (SPTs) were performed with SoluprickÕ allergens (ALK Abello, Hørsholm, Denmark). SPT was considered positive with a wheal diameter 3 mm larger than the negative control (saline) [25]. Blood samples were requested from all participants, while during the initial study period SPT was requested from all children. Thereafter, SPT was requested from children with asthma and/ or allergy symptoms. Allergic sensitization was not evaluated in 12 individuals without AR symptoms.
Research environment
Measurement of exhaled NO FENO was measured online by the single breath method with a chemiluminescence analyzer, EcoMedics ExhalyzerÕ CLD 88sp with Denox 88 (Eco Medics, Duernten, Switzerland) [detection range, 0.1–5000 parts per billion (ppb); accuracy ± 2%]. The procedure was performed in accordance with published guidelines [7]. Mean exhalation flow rate was 50 mL/s ± 10% during the NO plateau. The maneuver was repeated until two exhalations agreed to within 5% coefficient of variation (CV), or three exhalations agreed to within 10% CV. The NO concentration, FENO, was defined as the mean of these values expressed in ppb. The analyzer was calibrated daily using a standard NO calibration gas
Statistical analysis The distribution of FENO values was right skewed, and hence analyses were executed with natural log (Ln) transformed data. The results were presented as back-transformed values and expressed as geometric means with 95% confidence intervals (CIs). Inter-group comparisons were analyzed with an independent t-test for continuous variables and Pearson’s chisquare test for categorical variables. Linear mixed models were used to assess differences in time trends of FENO between the groups. The response variable in each model was LnFENO. Dependence between the three repeated time points was controlled for by including an unstructured covariance matrix
FENO, exercise, asthma and allergic phenotype
DOI: 10.3109/02770903.2015.1014099
to the model. ‘‘Matched pairs’’ were included as a random effect in the model. Bonferroni’s post hoc test was used for multiple comparisons for continuous variables. Correlations were assessed using Spearman’s correlation test. Normally distributed values were presented as means and standard deviation (SD) or 95% CI. Categorical data were presented as percentages. All tests were two-sided using a significance level of 0.05. Statistical analyses were performed using Statistical Package for Social Science (SPSS) software version 21.0 (SPSS Inc. IBM, Chicago, IL).
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Results Of the 801 children enrolled in Phase II of the study, 373 children reported asthma in Phase I of the study. This part of the study included 145 pupils with current asthma (cases) and 145 non-asthmatic pupils (controls) (145 matched pairs). Twenty pairs included pupils who were unable to comply with the study protocol, and one pair included a control with a positive EIB test. These pairs were excluded. Children who did not comply were younger than the included children (p ¼ 0.006). The descriptive data of the 124 pairs (i.e. 248 participants) included in statistical calculations are given in Table 1. Baseline FENO was significantly higher in asthmatics compared to non-asthmatics (Table 1) and significantly elevated in those with AR regardless of asthma status (Table 2). Baseline FENO was not significantly different among asthmatic children reporting ICS use compared with no use of ICS (data not presented). We found parallel time trends for FENO levels (ppb) between asthmatics and non-asthmatics (p ¼ 0.866). Adjustment for baseline FENO yielded no significant difference in time trends between the groups (p ¼ 0.848). The times trends were significantly different in children with AR compared to children without AR (p ¼ 0.039), irrespective of asthma (p ¼ 0.876), Figure 1. In children with AR, FENO had declined at 1 min by a mean of 6.1 ppb with a 95% CI of 5.1–7.5 ppb; at 30 min, the reduction was 2.8 (2.5–3.3) ppb. In children without AR, at 1 min the decline in FENO was 2.7 (2.1–3.5) ppb and by 30 min post-exercise it was 1.6 (1.3–2.0) ppb.
The linear mixed model calculations of the effect of exercise on FENO involved a comparison of the percentage change in LnFENO from baseline to 1 and 30 min postexercise (Figure 2). The time trend was dependent on AR (p50.001), irrespective of asthma status (p ¼ 0.795). In children with AR, LnFENO declined at 1 min by a mean of 10.1% (±2.2) and was reduced by a mean of 4.5% (±2.3) at 30 min. In children without AR, LnFENO dropped by a mean of 17.7% (±2.8) at 1 min, and LnFENO was reduced by a mean of 9.4% (±2.9) at 30 min post-exercise. In asthmatics, the effects of exercise on FENO was independent on ICS treatment (p ¼ 0.583) and a positive EIB test (p ¼ 0.230). Children with AR had a mean of four positive SPT/or allergen-specific IgE tests. Based on LnFENO, the % reduction at 1 and 30 min post-exercise was less pronounced with increasing number of positive SPT/or allergen-specific IgE tests (data not presented). Of the 123 children with AR, 122 were sensitized to seasonal and 110 to perennial allergens. The time trend was significantly dependent on AR in children with perennial and seasonal AR (both p50.001). Baseline FENO correlated positively with maximal postexercise FEV1 decline in asthmatics ( ¼ 0.331, p50.001). In asthmatics with AR, a positive correlation was found ( ¼ 0.360, p50.001), but not in asthmatics without AR.
Discussion The main results of the present study were that FENO decreased immediately after a submaximal treadmill challenge and did not return to baseline value within 30 min. The time trends were parallel in asthmatic and non-asthmatic children and independent of baseline FENO. Children with AR showed a greater reduction in FENO value (ppb) post-exercise, although the effect of heavy exercise (% change in LnFENO) was more pronounced in children without AR than in children with AR. Our study demonstrates that the assessment of clinical effects differed according to whether the target parameter chosen was the absolute FENO (ppb) level, or if the effect was
Table 1. Demographic data, baseline FENO and pulmonary measurements of the study group.
N (male) Age (years)a Height (cm)a Weight (kg)a Parental smoking (%) Allergic sensitizationb (%) Allergic rhinoconjuctivitis (%) FENOc FVC (% predicted)d FEV1 (% predicted)d FEF50 (L/s)a
Current asthma
Non-asthma
p Value
124 (81) 12.6 (2.0) 156.1 (13.7) 51.4 (16.9) 39.0 80.3 71.7 21.0 (17.6–24.9) 95.6 (0.4) 90.6 (0.8) 2.9 (1.1)
124 (81) 12.6 (2.0) 156.3 (13.1) 47.8 (13.1) 28.2 45.6 27.4 11.1 (9.9–12.4) 93.1 (0.6) 94.1 (0.5) 3.4 (1.1)
0.810 0.919 0.059 0.072 50.001 50.001 50.001 0.069 0.010 0.001
FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; FEF50, forced expiratory flow after 50% of FVC. Results are given as means (SD). Allergic sensitization was defined by a positive SPT and/or specific s-IgE 0.35 kU/L to 1/10 inhalation allergens, n ¼ 236. c Geometric mean fractional FENO is expressed in ppb (95% CI). d FVC and FEV1 are given as mean % predicted values (z-scores) [22]. a
b
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Table 2. Baseline FENO measurements in subgroups according to AR. Group Current asthma Non-asthmab
b
Non-ARa
ARa
p Value
9.0 (7.1–11.3) (n ¼ 22) 8.5 (7.7–9.4) (n ¼ 61)
28.1 (23.0–34.3) (n ¼ 89) 19.3 (14.9–25.0) (n ¼ 34)
50.001 50.001
a
AR was defined by AR symptoms and allergic sensitization to 1/10 inhalant allergens. Geometric mean FENO is expressed in ppb (95% CI).
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b
Figure 1. Geometric mean FENO levels in asthmatics with AR (n ¼ 89), non-asthmatics with AR (n ¼ 34), asthmatics without AR (n ¼ 22) and non-asthmatics without AR (n ¼ 61). FENO was measured at baseline (pre) and at 1 and 30 min after a standardized exercise inducedbronchoconstriction test on a treadmill. FENO is expressed in ppb. Error bars represent 95% CIs.
Figure 2. Changes in LnFENO (%) after a standardized EIB test on a treadmill in asthmatic and non-asthmatic children. Data are presented for four subgroups: asthmatics with allergic rhinoconjunctivitis (AR) (n ¼ 89), non-asthmatics with AR (n ¼ 34), asthmatics without AR (n ¼ 22) and non-asthmatics without AR (n ¼ 61). FENO was measured at baseline (pre) and at 1 and 30 min after a standardized exercise inducedbronchoconstriction test on a treadmill. Error bars represent 95% CIs.
assessed as a % change in LnFENO. The impact of exercise on FENO levels may be most relevant in clinical practice. However, assessment of effect (% change) appears to provide information on dissimilar airway inflammatory responses to exercise. Previous studies have reported contradictory results regarding the impact of exercise on FENO in children [10–13]. Differences in response were not stratified by AR or allergic sensitization in asthmatics and controls, and the number of subjects was low compared to the present study. Our finding that baseline FENO was increased in allergic asthmatics and allergic non-asthmatics agrees with previous studies [15–18]. Even though ICS treatment of asthmatics has been reported to be a marker of more severe disease [26], it did not influence baseline FENO. Similar mucosal inflammatory processes characterize children with allergic asthma and AR. Histochemical studies in subjects with AR have demonstrated the presence of eosinophilic inflammation from the nasal mucous membrane to the bronchial lining [14]. Hence, the increased FENO at baseline in non-asthmatics with AR likely reflects subclinical eosinophilic inflammation of the lower airways. FENO was reduced in all subgroups after exercise. The lower % reduction in LnFENO post-exercise found in children with AR and allergic asthma can be explained by pathophysiological differences in NO production. Eosinophilic cells are known to provoke airway-epithelium injury via oxidative damage of proteins [27] and thereby promote the release of cytokines and other pro-inflammatory mediators. The expressions of inducible NO synthase (NOS) and constitutive NOS are enhanced by pro-inflammatory mediators, and the NO production is increased by oxidative stress [28,29]. During exercise, airway inflammation is triggered by cooling and dehydration of the airway mucosa, and inflammatory mediators are released in response to a hyperosmolar stimulus [30,31]. Based on our findings (Figure 2), we hypothesise that heavy exercise aggravate NO production in asthmatics and non-asthmatics with AR leading to a less % reduction in LnFENO post-exercise compared to children without AR. The % reduction in LnFENO was less pronounced with increased number of positive SPT/or allergen specific IgE tests. These results indicate that the FENO production is more aggravated in children with greater atopy. The effect of exercise on FENO differed significantly in both seasonal AR and perennial AR compared to non-AR. A significant proportion of children with AR were sensitized to both seasonal and perennial allergens. Fourteen children with seasonal allergy were investigated within the season. The level of allergen exposure may have affected the results.
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DOI: 10.3109/02770903.2015.1014099
The overall reduction in FENO after the EIB test can be explained by alteration in NO dynamics due to a ventilation effect. Exercise increase the diffusing capacity of NO and decrease the airway wall concentration of NO (CawNO) [32]. The decreased CawNO, attributed to increased loss of NO in the exhaled air, has been explained as a washout of tissue NO stores [32]. The EIB test has been reported with different activity, intensity and threshold [10–13]. A high exercise load is essential, as it is more likely to reveal EIB and better related to inflammatory activity [33]. Likewise, ventilation is dependent on exercise load. We used a standardized exercise test with a high exercise load, which explains the marked decline in FENO value. High exercise intensity entails increased heart rate and pulmonary blood flow, which may alter pulmonary NO exchange. However, NO diffusion toward the pulmonary circulation does not increase during exercise [34]. It is unlikely that increased pulmonary vascular NO production affects FENO post-exercise due to the short half-life of NO and the high affinity of NO to hemoglobin [35]. The positive relationship between baseline FENO and the severity of bronchial hyperreactivity has also been demonstrated in other studies [4,18,36]. Bronchoconstriction could conceivably decrease the airway surface area, and thus decrease the diffusing capacity of NO. In line with other studies, the observed reduction in FENO was independent of changes in airway caliber post-exercise [10,37]. The overall decreased FENO after exercise could partially be explained by a lower contribution of nasal NO (nNO). During exercise, nNO falls rapidly and oral breathing may contribute to lessen the contamination of nNO to the lower respiratory tract [38]. Studies are conflicting as to whether nNO is altered in AR [39]. Discrepancies between studies can be attributed to differences in methodology, as different NO sampling techniques have been used [10–12]. For example, the measured FENO concentration is inversely related to the analyzer expiratory flow rate [40]. Participants were subjected to baseline FENO measurements and spirometry, which were followed by the EIB test, FENO measurements and repeated spirometry. Previous studies have reported contradictory results regarding the effect of spirometry on FENO [6,11,41]. Repeated FENO measurements may affect the within-subject variability [6]. In the present study, FENO was still at a decreased level after 30 min. In this context, we cannot draw firm conclusions as to whether reduced FENO at this time point can be solely attributed to exercise or was influenced by the repeated spirometric maneuvers. Ideally, the FENO measurements should have been repeated until normalized.
Conclusions Baseline FENO levels were increased in asthmatic and nonasthmatic children with AR compared to children without AR. The effects of exercise on FENO (% reduction in LnFENO) were less pronounced in children with AR than without AR, irrespective of asthma. This finding indicated that exercise aggravated lower airway inflammation in children with
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inhalant allergy. If children are physically active before FENO measurements, FENO values could be underestimated. This is especially pronounced in children with AR and allergic asthma who have the highest baseline FENO and greatest reduction in FENO (ppb) value post-exercise. Therefore, FENO measurements should be performed before EIB testing, and children should rest for at least 30 min before measuring FENO, since FENO is reduced after exercise and does not return to baseline level within 30 min.
Acknowledgements We thank Professor Tom Wilsgaard and PhD Tonje Braaten for statistical advice. We thank MD Sandy Goldbeck-Wood and Emeritus Professor Evert Nieboer for critically editing the article and MD Terje Tolla˚li for helpful discussions. We gratefully acknowledge the enthusiasm and cooperation of all participating children and parents.
Declaration of interest The study was supported by grants from the Northern Norway Regional Health Authority, the Norwegian Respiratory Society and the Morten Jensens foundation. The authors declare no conflicts of interest, in terms of the ICMJE definition, in respect of the authorship and/or publication of this article.
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