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Published ahead of print on November 19, 2004, doi:10.1164/rccm.200407-928OC
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American Journal of Respiratory and Critical Care Medicine Vol 171. pp. 282-286, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200407-928OC

Original Article

Morning Levels of C-Reactive Protein in Children with Obstructive Sleep-disordered Breathing

Athanasios G. Kaditis, Emmanouel I. Alexopoulos, Efthimia Kalampouka, Eleni Kostadima, Anastasios Germenis, Elias Zintzaras and Konstantinos Gourgoulianis

Departments of Pediatrics, Pediatric Pulmonology Unit, Immunology, and Biomathematics, and Sleep Disorders Laboratory, University of Thessaly School of Medicine and Larissa University Hospital, Larissa, Greece

Correspondence and requests for reprints should be addressed to Athanasios Kaditis, M.D., Larissa University Hospital, Department of Pediatrics, P.O. Box 1425, Larissa 41110, Greece. E-mail: kaditia{at}hotmail.com


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Obstructive sleep-disordered breathing is associated with cardiovascular disease in adults, and elevated C-reactive protein (CRP) has been proposed as a link between the two disorders. We hypothesized that children with sleep-disordered breathing have higher CRP values than do control subjects. CRP was measured in 39 children (mean age ± SD: 6.9 ± 3.2 years) without snoring (controls) and in 102 children (6.2 ± 2.2 years) with habitual snoring who underwent polysomnography. No significant differences were found in mean CRP values between control subjects (0.12 ± 0.16 mg/dl; n = 39) and snorers with an apnea-hypopnea index of less than 1 episode/hour (0.15 ± 0.26; n = 18), snorers with an index of 1 or more and less than 5 (0.15 ± 0.26; n = 54), and snorers with an index of 5 or more (0.22 ± 0.43; n = 30; p > 0.05). There was no correlation between CRP or log-transformed CRP values and apnea–hypopnea index, respiratory movement/arousal index, SaO2 nadir, oxygen desaturation (>= 4%) of hemoglobin index, or percentage of sleep time with saturation less than 95% (p > 0.05). Thus, findings of higher CRP values in adults with sleep-disordered breathing and correlations of these values with polysomnography indices were not confirmed in children.

Key Words: atherosclerosis • obstructive sleep apnea • snoring

Recent studies have identified significant correlations between obstructive sleep-disordered breathing and cardiovascular disease in adults. Obstructive sleep apnea–hypopnea (OSAH) correlates at least modestly with systemic hypertension, coronary artery disease, congestive heart failure, and stroke (1–3). Cardiovascular morbidity is increased even in subjects with mild elevations (1–10 episodes/hour) of the apnea–hypopnea index (AHI) (1).

Chronic inflammatory processes participate in the pathogenesis of cardiovascular events (4, 5). In addition, OSAH in adults has been related to increased levels of C-reactive protein (CRP), a marker of inflammation and cardiovascular risk (6, 7). A CRP value of more than 0.2 mg/dl is a predictor of cardiovascular events in apparently healthy men and women (4, 5). Therefore, CRP may be one of the links between OSAH and cardiovascular disease (CVD) (6, 7). Several other risk factors for cardiovascular disease, such as obesity, diabetes mellitus, and hyperlipidemia, are also correlated with CRP levels (4, 5, 8).

Similarly to adults, OSAH can affect the cardiovascular system of children (9–13). In a recent pediatric report (14), significant associations have been described between CRP levels and indices of severity of sleep-disordered breathing. The aim of the present investigation was to compare morning levels of CRP in children, with and without habitual snoring, and to confirm the recently described associations between these levels and polysomnography indices (14). Our hypothesis was that children with snoring have higher CRP values than control subjects. Some of the results of this study have been previously reported in the form of an abstract (15).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Design
The study protocol was approved by the ethics committee of the Larissa University Hospital. Consecutive children who were referred to the Sleep Disorders Laboratory because of habitual snoring (> 3 nights/week) that had been present for at least 6 months were considered for participation in the study. Healthy children without a history of snoring who presented to the General Pediatrics clinic for well child visits and who had blood drawn for routine measurement of hematocrit were also recruited as control subjects. Exclusion criteria for children with snoring and for control subjects were as follows: (1) symptoms or signs of acute or chronic inflammation, (2) use of corticosteroids or antibiotics for the 4 weeks preceding recruitment in the study, (3) cardiovascular disease or diabetes mellitus, and (4) neuromuscular or genetic disorders.

Informed consent was obtained from parents of all participants and child assent from subjects older than 8 years. Parents were interviewed and a questionnaire (online supplement) based on previous studies was answered (16–18). Questions inquired about symptoms of sleep-disordered breathing, past medical history, and family history. All subjects underwent a physical examination, and tonsillar size was graded from 0 to 4+ (19). A tonsillar size of 2+ or greater was defined as tonsillar hypertrophy (20). Polysomnograms were performed overnight in the Sleep Disorders Laboratory for all children with snoring but not for control subjects. Polysomnography methods and analysis of data are described in the online supplement.

Venous blood was collected between 8:00 and 10:00 A.M. from all subjects. For children with snoring, venipuncture was completed after polysomnography. Serum was obtained immediately from the blood sample and was stored at –70°C until assay. CRP levels were quantified by a high-sensitivity immunonephelometric method with a lowest detection limit of 0.0175 mg/dl (N High Sensitivity CRP; Dade Behring, Marburg, Germany). All measurements were completed in 1 day using stored serum to avoid interassay variability. Serum triglycerides and cholesterol levels were also measured.

Data Analysis and Statistics
Four groups of subjects were formed: (1) healthy control subjects without snoring, (2) snorers with an AHI of less than 1 episode/hour, (3) snorers with an AHI of 1 episode/hour or more and fewer than 5 episodes/hour, and (4) snorers with an AHI of 5 or more episodes/hour. For continuous characteristics, the study groups were compared by one-way analysis of variance. For categorical characteristics, the {chi}2 test (Yate's correction) was applied.

Pearson's correlation was used to assess the association of CRP values with polysomnography indices. To identify independent predictors of CRP levels, we performed stepwise multiple linear regression analysis (SPSS version 10.0; SPSS, Chicago, IL). CRP was the dependent variable and AHI, age, sex, relative body mass index (BMI), triglycerides, and cholesterol were entered as independent variables. The relative BMI ([absolute value/value of 50th percentile] x 100) was calculated using standard growth curves (21). The previous analysis was also repeated with log-transformed CRP values for consistency to the analysis by Tauman and colleagues (14).

Sample Size Calculation
The required sample size to detect a difference of 0.25 mg/dl in CRP levels between control subjects and snorers with an AHI of 5 or more episodes/hour (which is the comparison of interest), assuming a pooled SD of 0.35 with 90% power at the 5% level, was 45 subjects in each group (22). The expected difference in CRP levels between the two groups, which might be considered clinically important, and the pooled SD were specified on the basis of the only previous published pediatric study (14).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics and Results of Polysomnography
Thirty-nine healthy control subjects without snoring (mean age ± SD: 6.9 ± 3.2 years; age range 2–13 years) were recruited together with 102 children with habitual snoring (6.2 ± 2.2 years; range 1.9–12 years). Eighteen subjects with sleep-disordered breathing had an AHI of less than 1 episode/hour; 54 subjects had an AHI of 1 or more and fewer than 5 episodes/hour; and 30 subjects had an AHI of 5 or more episodes/hour. The frequency of sleep-disordered breathing symptoms and tonsillar size in subjects with habitual snoring and in control subjects and polysomnography indices only in subjects with habitual snoring are presented in Table 1. Of the control subjects, 3 of 39 (7.6%) had tonsillar hypertrophy and 93 of 102 (91%) children with habitual snoring had this condition.


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  		TABLE 1. Summary statistics for symptoms of sleep-disordered breathing, tonsillar size, and polysomnography indices in the four study groups of participants

 
By recruiting 39 control subjects and 30 snorers with an AHI of 5 or more episodes/hour (i.e., an effective total size of 68), the probability of detecting the expected difference, which was specified in the sample size calculation, was 79% at the 5% level (22).

C-Reactive Protein Measurements
There were no significant differences between control subjects and the other three study groups regarding CRP and log-transformed CRP values (p > 0.05; Table 2). No differences were found among the study groups regarding characteristics that may affect CRP values (Table 2).


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  		TABLE 2. Summary statistics and significance of comparisons between study groups regarding c-reactive protein or log-transformed c-reactive protein values and factors that may affect these values

 
No significant relationships were identified between CRP levels and the following factors: AHI (r = 0.04, p > 0.05; Figure 1), respiratory movement/arousal index (r = –0.08, p > 0.05; Figure 2), SaO2 nadir (r = 0.05, p > 0.05; Figure 3), oxygen desaturation of hemoglobin index (r = 0.04, p > 0.05), or percentage of sleep time with SaO2 less than 95% (r = 0.06, p > 0.05). When multiple linear regression was performed, AHI, age, sex, relative BMI, serum triglycerides, and cholesterol were not significant predictors of CRP values.



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  		Figure 1. Scatterplot of C-reactive protein (CRP) values (mg/dl) plotted against the apnea–hypopnea index (AHI; episodes/hour) for 102 children with habitual snoring. *Values below 0.0175 mg/dl, which is the lowest detection limit of the high-sensitivity CRP method.

 


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  		Figure 2. Scatterplot of CRP values (mg/dl) plotted against respiratory movement/arousal index (episodes/hour) for102 children with habitual snoring. *Values below 0.0175 mg/dl, which is the lowest detection limit of the high-sensitivity CRP method.

 


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  		Figure 3. Scatterplot of CRP values (mg/dl) plotted against SaO2 nadir (%) for 102 children with habitual snoring. *Values below 0.0175 mg/dl, which is the lowest detection limit of the high-sensitivity CRP method.

 
Similarly, no significant relationships were found between log-transformed CRP levels and the following: AHI (r = 0.04, p > 0.05), respiratory movement/arousal index (r = 0.002, p > 0.05), SaO2 nadir (r = 0.04, p > 0.05), oxygen desaturation of hemoglobin index (r = 0.03, p > 0.05), or percentage of sleep time with SaO2 less than 95% (r = 0.08, p > 0.05). Multiple linear regression analysis identified relative BMI as the only significant predictor of log-transformed CRP values (p < 0.05).

Two of the children with habitual snoring had a low AHI and a high CRP values (index of 4.2 episodes/hour and CRP value of 1.80 mg/dl; index of 6.2 episodes/hour and CRP value of 2.21 mg/dl). These extreme values were excluded and statistical analysis was repeated. There were still no significant differences between control subjects and the other three study groups regarding CRP and log-transformed CRP values (p > 0.05). No significant relationships were identified between CRP or log-transformed CRP values and polysomnography indices. Multiple linear regression analysis, including AHI, age, sex, relative BMI, serum triglycerides, and cholesterol as independent variables was also repeated. Relative BMI was the only significant predictor of both CRP and log-transformed CRP levels (p < 0.05).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Studies in adults with OSAH have detected elevated values of CRP that are correlated with severity of sleep-disordered breathing (6, 7). Because CRP is a marker of inflammation and cardiovascular risk (4, 5), its association with obstructive sleep-disordered breathing could be one of the pathophysiologic links between obstructive sleep apnea and cardiovascular disease (3). CRP values in adults are also affected by other cardiovascular risk factors that are less frequently present in children, such as obesity, hyperlipidemia, and diabetes mellitus (4, 5, 8).

In this investigation of healthy children without apparent risk factors for cardiovascular disease, no statistically significant differences in CRP or log-transformed CRP values were identified between groups of habitual snorers with sleep-disordered breathing of variable severity and control subjects without snoring. All four groups were similar regarding factors that may have affected CRP values (age, sex, relative BMI, serum triglycerides, or cholesterol) (23, 24). Our findings differ from those of previous reports in adults (6, 7) and children (14).

CRP or log-transformed CRP values did not show any association with several different indices of severity of sleep-disordered breathing, whereas relative BMI was the only significant predictor of log-transformed CRP values, but not of raw CRP values. This discrepancy occurred because when the data are log-transformed, the linear fit is improved (25). The improvement was mainly related to the two subjects with high CRP levels. After excluding the two subjects, relative BMI was a significant predictor of both raw CRP values and log-transformed CRP values.

Higher serum CRP levels have been reported in adults with OSAH than in control subjects (6, 7). CRP levels ranged from 0.09 to 2.73 mg/dl (median 0.33 mg/dl) in 22 adult subjects with an AHI of 20 or more episodes/hour and from 0.02 to 0.9 mg/dl (median 0.09 mg/dl) in 20 control subjects with an AHI of 5 or fewer episodes/hour (6). CRP was positively associated with AHI.

In a second report, which included 30 adult patients with obstructive sleep apnea syndrome and 14 obese control subjects, mean CRP values (± SD) were as follows: 0.27 ± 0.03 mg/dl in patients with an AHI of 20 or more episodes/hour, 0.13 ± 0.03 mg/dl in those with an AHI of 5 or more and fewer than 20 episodes/hour, and 0.07 ± 0.0001 mg/dl in obese control subjects (7). Levels of CRP were positively correlated with AHI, percentage of sleep time with SaO2 less than 90%, BMI, and serum triglycerides levels, and negatively correlated with SaO2 nadir during sleep.

In the pediatric report by Tauman and colleagues (14), mean log-transformed plasma CRP levels (± SD) were higher in children with an AHI of 5 or more episodes/hour (mean log-transformed CRP: –0.51 ± 0.4; mean CRP: 0.46 ± 0.39 mg/dl) than in subjects with an AHI of 1 or more episodes/hour and fewer than 5 episodes/hour (mean log-transformed CRP: –0.91 ± 0.28; mean CRP: 0.15 ± 0.12 mg/dl) and in those with an AHI of less than 1 episode/hour (control subjects; mean log-transformed CRP: –0.8 ± 0.33; mean CRP: 0.22 ± 0.27 mg/dl). Log-transformed CRP values were positively correlated with AHI and arousal index and negatively correlated with SaO2.

Raw CRP values in the present report and in the report by Tauman and colleagues (14) were similar in subjects with an AHI of fewer than 5 episodes/hour. However, in the present study, children with an AHI of 5 or more episodes/hour had lower CRP values (mean CRP: 0.22 ± 0.43 mg/dl) compared with children with the same AHI in the published pediatric report (mean CRP: 0.46 ± 0.39 mg/dl). In contrast to the report by Tauman and colleagues, CRP and log-transformed CRP values in our subjects were not associated with any polysomnography indices.

When comparing the present investigation to the study by Tauman and colleagues (14) regarding subjects' characteristics, female-to-male ratio, cholesterol levels, and severity of sleep-disordered breathing were the same. For example, in this series, children with an AHI of 5 or more episodes/hour had a mean (± SD) AHI of 12.3 ± 8.9 episodes/hour and an SaO2 nadir of 83.1 ± 4.4%; in the series by Tauman and colleagues, however, children with an AHI of 5 or more episodes/hour had a mean AHI of 14.6 ± 14 episodes/hour and a mean SaO2 nadir of 83.4 ± 7.8%.

Major discrepancies in the results between the two studies may be because of differences in subjects' age and in obesity. The children in the present investigation were younger, leaner, and had lower serum triglyceride levels than participants in the study by Tauman and colleagues (14). The duration of the disorder in respiration could affect CRP values. Because children in the study by Tauman and colleagues were older than subjects in this report, they conceivably had sleep-disordered breathing for more years. The lower relative BMI and serum triglycerides in our subjects may reflect differences in prevalence of childhood obesity between the two populations from which children for each study were recruited (Thessaly, Greece, and Kentucky).

Differences in subjects' relative BMI between the two reports (higher in the study by Tauman and colleagues) were more apparent in children with an AHI of 5 or more episodes/hour. Serum CRP in adults has been positively associated with BMI (23), and this association has been attributed to secretion of interleukin 6 (IL-6) by adipose tissue (26), which regulates CRP production in the liver (27). CRP values in the two studies were controlled statistically for BMI. Nevertheless, the difference in subjects' mean relative BMI between the two reports may still be one of the reasons that children with snoring and an AHI of 5 or more episodes/hour in the series by Tauman and colleagues had higher CRP values than participants with a similar AHI in this investigation.

Furthermore, adipocytes produce adiponectin, a hydrophilic protein with protective metabolic and antiinflammatory properties (28). Adiponectin plasma levels and gene expression are significantly reduced in obese adults (29). An independent inverse correlation between plasma adiponectin levels and CRP has been documented in obese adults (29). This correlation may also be present in children and may contribute to the higher CRP values in subjects of the study by Tauman and colleagues compared with children in the present report, who had a lower relative BMI.

Finally, a recent report demonstrated that severity of sleep-disordered breathing relates to fasting insulin levels in obese children, a proxy measure of insulin resistance (30). Increasing levels of CRP are associated with elevated fasting insulin among nondiabetic women (31). Because children in the study by Tauman and colleagues (14) were more obese than our subjects, sleep-disordered breathing in those children may be correlated with higher insulin, IL-6, and CRP levels.

In subjects with habitual snoring, IL-6 could also be released by the intensely working respiratory muscles that try to overcome the increased upper airway resistance during sleep. Strenuous resistive breathing in both animals and humans increases IL-6 levels if a certain inspiratory threshold is exceeded (32, 33). If IL-6 is released from the respiratory muscles in children with sleep-disordered breathing, this could also explain why mean CRP values are not consistently higher in subjects with an AHI of 5 or more episodes/hour compared with children with an AHI of fewer than 5 episodes/hour or with control subjects.

Although the AHI describes the frequency of apneas and hypopneas, it does not accurately reflect the work of breathing in children whose disordered respiration during sleep is characterized by hypopneas of variable duration. Therefore, the absence of correlation between AHI and levels of CRP is not surprising. Two children with the same AHI value could differ in the degree of upper airway obstruction, work of breathing, IL-6, and CRP levels during sleep. Confirmation of this speculation requires the concomitant determination of IL-6 and CRP values together with measurement of work of breathing using an esophageal balloon.

The role of CRP in adults with sleep-disordered breathing is still uncertain. CRP could simply be a marker of chronic vascular inflammation and/or an active participant in processes leading to atherosclerosis (4, 5, 34, 35). Published reports from adult subjects have associated obstructive sleep-disordered breathing with the following: (1) increased expression of adhesion molecules on monocytes; (2) increased serum levels of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and L-selectin; and (3) increased adherence of monocytes to endothelial cells in cultures (36–38). These findings together with the increased production of reactive oxygen species by monocytes and granulocytes exposed to recurrent hypoxia (39) indicate that sleep-disordered breathing promotes vascular inflammation and atherosclerosis (40, 41).

CRP is elevated in the presence of acute or chronic inflammation and therefore children with any symptoms or signs of an inflammatory process were excluded from participation in the study (42). A possible limitation of the present study would be that polysomnography was not performed in control subjects because this was not acceptable by their parents. In addition, thermistors were used to detect decreases in airflow instead of measuring end-tidal CO2 as an index of hypoventilation. In previous studies (6, 7), subjects with snoring and a low AHI (< 5 episodes/hour) have been recruited as controls instead of including healthy subjects without snoring. In this report, children without snoring were an additional control group supplementary to the group of snorers with a low AHI (< 1 episode/hour).

In conclusion, findings of higher CRP values in adults with obstructive sleep-disordered breathing and correlations of these values with polysomnography indices are not consistently present in children. The reported results may indicate that not all children with sleep-disordered breathing have associated vascular inflammation.


   FOOTNOTES
 
Supported by the University of Thessaly Research Committee.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Conflict of Interest Statement: A.G.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; E.I.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; E.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; E.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; E.Z. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form July 18, 2004; accepted in final form November 15, 2004


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 DISCUSSION
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