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Original Research: SLEEP MEDICINE |

Sleep-Disordered Breathing, Obesity, and Airway Inflammation in Children and Adolescents FREE TO VIEW

Stijn L. Verhulst, MD, MSc; Liselotte Aerts, BSc; Sarah Jacobs, BSc; Nancy Schrauwen; Dominique Haentjens, MD; Rita Claes; Hilde Vaerenberg; Luc F. Van Gaal, MD, PhD; Wilfried A. De Backer, MD, PhD; Kristine N. Desager, MD, PhD
Author and Funding Information

*From the Departments of Pediatrics (Drs. Verhulst, Haentjens, and Desager, Ms. Aerts, Ms. Jacobs, and Ms. Schrauwen), Respiratory Medicine (Dr. De Backer, Ms. Claes, and Ms. Vaerenberg), and Endocrinology, Diabetology, and Metabolism (Dr. Van Gaal), Antwerp University Hospital, Belgium.

Correspondence to: Stijn Verhulst, MD, MSc, University of Antwerp, Department of Pediatrics, Universiteitsplein 1, 2610 Wilrijk, Belgium; e-mail: stijn.verhulst@ua.ac.be


The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2008;134(6):1169-1175. doi:10.1378/chest.08-0535
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Background:  To investigate the relationship between obstructive sleep apnea syndrome (OSAS) and exhaled nitric oxide (eNO) in overweight children and adolescents without asthma or atopy and to assess whether obesity per se is associated with increased airway inflammation.

Methods:  Consecutive overweight subjects without symptoms of asthma or allergy were recruited at a pediatric obesity clinic. A normal-weight control group without OSAS and asthma or allergy was also recruited. All subjects underwent polysomnography and two measurements of eNO (afternoon and morning after polysomnography).

Results:  Controlling for age, the mean (± SD) afternoon eNO concentration was significantly higher in the snoring group (14.1 ± 1.1 parts per billion [ppb]) compared with the normal-weight group (10.1 ± 0.8 ppb; p = 0.03) and with the overweight group with normal polysomnography findings (8.9 ± 0.8 ppb; p = 0.007). The afternoon eNO concentration was also different between the OSAS group (11.9 ± 1.0 ppb) and the overweight group with normal polysomnography findings (p = 0.03). Morning eNO values were higher in the OSAS group (12.3 ± 1.1 ppb) than in the normal weight group (9.9 ± 0.8 ppb; p = 0.047) and in the overweight control group (9.7 ± 0.7 ppb; p = 0.02). BMI z score was not significantly correlated with afternoon eNO concentration or with morning eNO concentration.

Conclusion:  This study illustrates that both habitual snoring and OSAS are associated with increased airway inflammation in overweight children as assessed by higher eNO levels. Furthermore, it was demonstrated that childhood obesity in the absence of sleep-disordered breathing is not associated with increased airway inflammation.

Figures in this Article

Obstructive sleep apnea syndrome (OSAS) is characterized by recurrent events of partial and/or complete upper airway obstruction resulting in a disruption of normal ventilation and sleep.1 Obstructive sleep-disordered breathing (SDB) also encompasses habitual snoring, which is considered to be a relatively more benign expression of increased upper airway resistance.2 Childhood obesity is increasingly becoming a predisposing factor for OSAS. While the prevalence of OSAS in the general population is estimated at 1 to 2%,36 it reaches 13 to 59% in obese children.7 Several studies811 in adults have shown increased airway inflammation in subjects with OSAS, as assessed by increased levels of exhaled nitric oxide (eNO). To date, there have been no studies assessing eNO levels in obese children with OSAS. On the other hand, there have been studies that have demonstrated lower airway inflammation in children with OSAS using induced sputum samples12 and exhaled breath condensate samples.13 However, these studies did not rule out the possible association of obesity with airway inflammation. Indeed, longitudinal studies1418 in children and adolescents have shown an association between obesity and asthma, but the mechanisms explaining this association remain unclear.19 One of the proposed mechanisms is that obesity causes increased airway inflammation. It is indeed documented that obesity is associated with increased levels of systemic proinflammatory mediators that could potentially influence airway smooth muscle.20,21 However, studies investigating the association between childhood obesity and airway inflammation are scarce. Leung et al22 demonstrated higher levels of eNO and leukotriene B4 in children with asthma, but no relation between these markers of airway inflammation and the degree of obesity was found. The primary aim of our study was therefore to investigate the relation between obstructive SDB and eNO in overweight children and adolescents without asthma and allergy. Second, we assessed whether obesity per se is associated with increased airway inflammation, using a normal-weight control group.

Study Population

Consecutive overweight or obese children and adolescents aged 6 to 17 years were recruited between March 2005 and October 2007 at the Pediatric Obesity Clinic of the Antwerp University Hospital. Normal-weight children were also recruited as part of a previously published study23 regarding normative data on SDB in children and adolescents. The exclusion criteria were a history of asthma, chronic lung disease, neuromuscular disease, laryngomalacia, any genetic or craniofacial syndrome, and the use of antiinflammatory medication. Furthermore, patients with any symptoms suggesting asthma and/or respiratory allergies, as assessed by the International Study of Asthma and Allergies in Childhood questionnaire,24 were excluded from this study. All children had to be free of any acute disease at the moment of polysomnography. This study was approved by the ethics committee of the Antwerp University Hospital, and informed consent was obtained from the subjects and their parents.

Questionnaire

A questionnaire regarding sleep disturbance and related symptoms was administered to our subjects.25 Habitual snoring was defined if the answer to the question “How often does your child snore?” was “often or always.”

Anthropometry

Height and weight were obtained and the body mass index (BMI) was calculated and further analyzed as BMI z score based on Flemish growth curves (Auxology 1.1; Pfizer; New York, NY).26 Children were classified as overweight according to the criteria of the International Obesity Task Force.27

Spirometry and eNO Measurement

FEV1, FVC, peak expiratory flow (PEF), and mid-expiratory flow were measured using a spirometer (Jaeger Masterscreen; Cardinal Health; Dublin, OH). Values for FEV1, FVC, and maximum MEF were expressed as a percentage of the predicted value. The eNO concentration was measured online (Niox Nitric Oxide Analyser; Aerocrine; Stockholm, Sweden) according to American Thoracic Society recommendations.28 The subjects were measured while in the seated position. After full exhalation, the subjects inhaled nitric oxide (NO)-free air from the apparatus to total lung capacity and then immediately exhaled slowly at a constant flow rate of 50 mL/s. The exhalation breathing maneuver lasted for 10 s, and the measurement was accepted when there was a NO plateau during the last 3 s of the measurement. The exhalation was performed against a fixed external resistance that ensured a positive mouth pressure of 5 to 20 cm H2O so that the soft palate was closed to prevent contamination with nasal NO. A visual biofeedback helped the subjects to achieve the desired expiratory flow of 50 mL/s (± 10%). The maneuver was repeated with 30 s of relaxed breathing between the measurements until three reproducible NO values were obtained.28 The mean NO value of these three maneuvers was used for further analysis. All subjects were put on a nitrate-free diet during their hospital admission.29

Polysomnography

A detailed description of the standard polysomnography procedure was given previously.30 Obstructive apnea was defined as the cessation of air flow in the presence of chest and/or abdominal wall motion. Central apnea was defined as the cessation of air flow, and the absence of chest and/or abdominal wall motion lasting ≥ 10 s or of any length but associated with ≥ 4% desaturation. Hypopnea was defined as a ≥ 50% decrease in the amplitude of the air flow signal with a concurrent arousal and/or fall of > 3% in arterial oxygen saturation (Sao2) from baseline levels.1 Hypopnea was further characterized as obstructive if the reduction in air flow was associated with paradoxical breathing effort or as central if associated with an in-phase reduction in the amplitude of chest and abdominal signals.1 The obstructive apnea-hypopnea index (OAHI) was defined as the number of obstructive and mixed apneas and hypopneas per hour of sleep. The respiratory disturbance index (RDI) was defined as the sum of all respiratory events, as defined above, per hour of sleep. All desaturations, with desaturation defined as decreases of ≥ 4% from baseline Sao2, were quantified (using the oxygen desaturation index). Measurements associated with poor pulse tracings or following movement were excluded. For each child, the mean Sao2, Sao2 nadir, and total duration of desaturation, expressed as the percentage of total sleep time, were recorded. Arousals were defined according to the recommendations of the American Sleep Disorders Association Task Force report31 using the 3-s rule and/or the presence of movement arousal,32 and the respiratory arousal index was calculated. An OAHI of ≥ 1 was used as the diagnostic threshold for obstructive sleep apnea.23 Habitual snoring subjects were defined as frequent snorers as assessed by questionnaire with an OAHI of < 1. Subjects with central sleep apnea30 were not included in this study.

Statistical Analysis

Statistical analysis was performed with a statistical software package (Statistica, version 7.0; StatSoft; Tulsa, OK). All data are summarized as the mean ± SD or median (range). From preliminary analysis, it was estimated that the average eNO equaled 10 parts per billion (ppb) and 14 ppb in the control and OSAS group respectively (SD, 3 ppb). With a type I error rate of 5% and a power goal of 80%, the required sample size was 10 subjects in each group.

Shapiro-Wilk test was used to test for normality. Comparisons of patient characteristics between groups were performed with one-way analysis of variance or with the Kruskal-Wallis test as a nonparametric alternative. Post hoc analyses included the Tukey test or the multiple comparison of mean ranks test. Paired comparisons were made using paired t test. Associations between variables were assessed using the Pearson correlation coefficient and multiple regression analysis. Since eNO levels increase significantly with age, age was forced into each analysis with eNO as the outcome variable.33 Analysis of covariance was applied to determine whether a diagnosis of SDB was independently associated with increased eNO levels adjusted for age and other possible confounders. Pairwise comparisons were assessed with the Tukey test. The results of these analyses of covariance with Tukey post hoc testing are presented graphically. The least square means with 95% confidence intervals are presented per diagnostic group and were estimated at the average age of the study population (11.4 years). For all analyses, p < 0.05 was considered to be statistically significant.

Patient Characteristics

Subject characteristics are presented in Table 1. The study population included 13 normal-weight children, 17 overweight children with normal sleep study findings, 7 overweight children with habitual snoring, and 11 overweight children with OSAS.

Table Graphic Jump Location
Table 1 Anthropometric, Sleep, and Spirometry Characteristics*

*Values are given as the mean ± SD or median (range), unless otherwise indicated. OAI = obstructive apnea index.

Overweight children with habitual snoring had a significantly lower FEV1, FEV1/vital capacity (VC) ratio, and maximal expiratory flow at 50% (MEF50) than their overweight peers with normal polysomnography findings. Only one subject in the habitual snoring group had VC and FEV1 of < 80% predicted (77% and 72%, respectively). This subject was an influential outlier in the model for FEV1, but not in the analyses for FEV1/VC ratio and MEF50. All subjects had an FEV1/VC ratio of > 85%.

The mean eNO levels were 10.9 ± 4.2 ppb in the afternoon and 10.5 ± 4.1 ppb in the morning. Afternoon and morning eNO levels were similar between boys (11.0 ± 4.0 and 11.4 ± 4.2 ppb, respectively) and girls (10.8 ± 4.4 and 10.1 ± 4.4 ppb, respectively). Afternoon eNO levels correlated significantly with age (r = 0.59; p < 0.001), PEF (r = 0.49; p = 0.005), and maximal mid-expiratory flow between 25% and 75% (r = 0.46; p = 0.009), while there also was a trend with VC (r = 0.34; p = 0.06).

SDB and eNO

There was no difference between afternoon and morning eNO levels in any of the studied groups. Controlling for age, afternoon eNO levels were significantly higher in the overweight group with habitual snoring compared with the normal-weight group (p = 0.03) [Fig 1] and with the overweight group with normal sleep study findings (p = 0.007). Afternoon eNO levels were also different between the overweight OSAS group and the overweight group with normal sleep study findings (p = 0.03). Morning eNO values were higher in the overweight OSAS group than in the normal-weight group (p = 0.049) and in the overweight group with normal sleep study findings (p = 0.02). These differences remained significant after controlling for PEF and maximal mid-expiratory flow between 25% and 75%. There were several borderline significant correlations between afternoon eNO and percentage of sleep time with an Sao2 of ≥ 95% (r = − 0.29; p = 0.07) and between morning eNO levels and OAHI (r = 0.29; p = 0.06), percentage of sleep time with an Sao2 of ≥ 95% (r = − 0.28; p = 0.07), and respiratory arousal index (r = 0.28; p = 0.07). However, in multiple regression analysis, only age and habitual snoring were significantly associated with eNO levels (Table 2).

Figure Jump LinkFigure 1 Differences in afternoon and morning exhaled NO between the normal-weight group (A), the overweight group with normal sleep study findings (B), the overweight group with habitual snoring (C), and the overweight group with OSAS (D). Afternoon eNO levels were estimated at a mean (± SE) age in the population of 11.4 years as follows: normal weight control subjects, 10.1 ± 0.8 ppb; overweight control subjects, 8.9 ± 0.8 ppb; overweight habitual snorers, 14.1 ± 1.1 ppb; and overweight OSAS subjects, 11.9 ± 1.0 ppb. For morning eNO levels, the estimated values were 9.9 ± 0.8, 9.7 ± 0.7, 11.8 ± 1.2, and 12.3 ± 1.1 ppb, respectively. The graph presents the least square means with 95% confidence interval for each diagnostic group. * = p < 0.05 vs normal weight group. ** = p < 0.05 vs overweight group with normal sleep study findings.Grahic Jump Location
Table Graphic Jump Location
Table 2 Multiple Regression Analyses for Afternoon and Morning eNO Levels*

*Values are given as the estimate ± SE, unless otherwise indicated.

Obesity and eNO

Both afternoon and morning eNO levels were similar in the normal-weight group and the overweight group with normal sleep study findings (p > 0.9). BMI z score was not significantly correlated with afternoon eNO level (r = 0.20; p = 0.2) or with morning eNO level (r = 0.19; p = 0.2).

In the present study, we illustrated that both habitual snoring and OSAS are associated with increased airway inflammation, as assessed by higher eNO level, in overweight children and adolescents without asthma or atopy. Furthermore, we could demonstrate that childhood obesity as such is not associated with increased airway inflammation.

Our present study using eNO levels confirmed previous reports12,13 using other techniques that SDB in children is associated with increased airway inflammation. Furthermore, the finding34 that tonsillar tissue from children with OSAS also shows distinct inflammatory patterns suggests that SDB up-regulates inflammation in both the upper and lower airway. These inflammatory changes are postulated to occur, in part, due to snoring that evokes vibration frequencies associated with soft-tissue damage.35 This hypothesis was confirmed in our study by the finding that habitual snorers and subjects with OSAS had significantly higher eNO concentrations. Of note, there was no difference in eNO levels between the snoring and OSAS group. Second, the finding that only habitual snoring and no other sleep-related variable was associated with increased eNO levels further supports the hypothesis that, at least in this study population, the presence of snoring is more important in inducing inflammation than the actual obstructive events during sleep. It is also hypothesized that inflammation of the airways plays an important role in the pathogenesis of OSAS, although the exact mechanisms remain unknown.9 These inflammatory changes have also been associated with altered innervations of the upper airway mucosa and reduced function of the upper airway musculature in adults with OSAS.36,37

A limitation of our results on the association between SDB and eNO is the cross-sectional design of the study. Therefore, it cannot be assessed whether the increased airway inflammation is a cause or a consequence of SDB. The finding that therapy with continuous positive airway pressure reduces eNO levels in adults with SDB suggests the latter.10 However, we recommend conducting further interventional studies confirming these findings in children with OSAS. Second, our subjects with OSAS had relatively mild disease. This might also explain why the univariate correlation between eNO and OAHI did not persist after controlling for habitual snoring and for the equal levels of eNO between the snoring and OSAS groups. A technical comment is that we classified events as central or obstructive using strain gauges and not by a more sensitive method such as pressure monitoring in the esophagus. In order to avoid a possible misclassification of obstructive events as central events, we also used the total RDI in our analysis. A final limitation is that asthmatic subjects were excluded from the study. Further studies are needed to assess the relation between SDB and eNO in asthmatic children.

This current study also showed that childhood obesity in the absence of SDB and asthma and allergy did not result in increased eNO levels. This is an important finding, because it has been suggested that this could be one of the mechanisms linking obesity with asthma. Indeed, asthma is the most common chronic illness in childhood, with its prevalence and severity still increasing in developed countries over the last few decades. The cause of the increase in asthma is probably multifactorial, with allergic sensitization, lifestyle changes, and genetics emerging as important determinants.21 Almost in parallel with this rise in asthma prevalence has been the epidemic increase in the prevalence of childhood obesity. This has led to the hypothesis that obesity could be a risk factor for the development of asthma. Various longitudinal studies1418 in children and adolescents have shown an association between obesity and asthma, but the mechanisms explaining this association remain unclear.19 It is proposed that the obesity-related systemic inflammatory state leads to increased levels of proinflammatory mediators, which could potentially influence airway smooth muscle.20,21 Leung et al22 studied 92 asthmatic children and 23 control subjects. Although mean eNO and leukotriene B4 levels were higher in asthmatic patients, obesity itself was not associated with any alteration in these markers in asthmatic patients. Furthermore, these inflammatory marker levels did not differ between asthmatic patients in the highest and lowest quartiles of weight-for-height z score.22 Santamaria et al38 also failed to find any association between eNO level and obesity in children with and without asthma. The results of these studies indicate that eNO levels are not different between normal-weight and obese children. These findings do not suggest a role for airway inflammation in obesity, so that factors other than airway inflammation are likely responsible for the development of asthma in obese subjects. One could hypothesize that obstructive SDB could contribute to the link between childhood obesity and asthma. It has indeed been proposed39 that there is also a significant overlap between SDB and asthma, as airway obstruction, inflammation, and obesity are implicated in the development of both diseases. Our findings indicate that overweight subjects with habitual snoring have lower values of FEV1, FEV1/VC ratio, and MEF50 compared to their peers with normal sleep study findings. Unfortunately, our present study was underpowered to demonstrate a similar difference between the OSAS group and the group with normal sleep study findings (differences for FEV1 and MEF50 between both groups resulted in p = 0.1). Zerah-Lancner et al40 found similar evidence in obese adults with OSAS, adjusting for adiposity. Although there have been studies41,42 evaluating both lung function and SDB in obese children and adolescents, they did not report an association between obstructive SDB and smaller airway obstruction. Therefore, our present report warrants further studies with more extensive lung function techniques (eg, body plethysmography and airway resistance testing) on the association between obstructive SDB and lower airway dysfunction, as it could partly explain the association between obesity and asthma in children.

In conclusion, this study demonstrated that habitual snoring and OSAS in overweight children is associated with increased airway inflammation, as assessed by eNO levels. No association between airway inflammation and obesity was found.

BMI

body mass index

eNO

exhaled nitric oxide

MEF50

maximal expiratory flow at 50%

NO

nitric oxide

OAHI

obstructive apnea-hypopnea index

OSAS

obstructive sleep apnea syndrome

PEF

peak expiratory flow

ppb

parts per billion

RDI

respiratory disturbance index

Sao2

arterial oxygen saturation

SDB

sleep-disordered breathing

VC

vital capacity

The authors thank the staff of the Lung Function Laboratory of Antwerp University Hospital for obtaining the lung function and eNO measurements for this study.

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Figures

Figure Jump LinkFigure 1 Differences in afternoon and morning exhaled NO between the normal-weight group (A), the overweight group with normal sleep study findings (B), the overweight group with habitual snoring (C), and the overweight group with OSAS (D). Afternoon eNO levels were estimated at a mean (± SE) age in the population of 11.4 years as follows: normal weight control subjects, 10.1 ± 0.8 ppb; overweight control subjects, 8.9 ± 0.8 ppb; overweight habitual snorers, 14.1 ± 1.1 ppb; and overweight OSAS subjects, 11.9 ± 1.0 ppb. For morning eNO levels, the estimated values were 9.9 ± 0.8, 9.7 ± 0.7, 11.8 ± 1.2, and 12.3 ± 1.1 ppb, respectively. The graph presents the least square means with 95% confidence interval for each diagnostic group. * = p < 0.05 vs normal weight group. ** = p < 0.05 vs overweight group with normal sleep study findings.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Anthropometric, Sleep, and Spirometry Characteristics*

*Values are given as the mean ± SD or median (range), unless otherwise indicated. OAI = obstructive apnea index.

Table Graphic Jump Location
Table 2 Multiple Regression Analyses for Afternoon and Morning eNO Levels*

*Values are given as the estimate ± SE, unless otherwise indicated.

References

American Thoracic Society Standards and indications for cardiopulmonary sleep studies in children. Am J Respir Crit Care Med. 1996;153:866-878. [PubMed]
 
Greene MG, Carroll JL. Consequences of sleep-disordered breathing in childhood. Curr Opin Pulm Med. 1997;3:456-463. [PubMed] [CrossRef]
 
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