Associations of Obesity, Sleep-disordered Breathing, and Wheezing in Children
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美国呼吸和危急护理医学 2005年第3期
Case School of Medicine, Cleveland, Ohio
ABSTRACT
Although it has been speculated that rising asthma rates may be partly due to increasing obesity, the causal mechanisms that relate these conditions are unclear. We assessed the extent to which sleep-disordered breathing (SDB) may explain associations between obesity and wheezing/asthma. A total of 788 participants (aged 8eC11 years) in a community-based cohort study were classified according to two outcomes: wheezing and asthma. Sleep apnea was defined as an increased number of apneas and hypopneas on overnight monitoring. SDB was identified on the basis of either sleep apnea or habitual snoring. Multiple logistic regression models showed that children with wheeze were significantly more likely to be male (odds ratio [OR] 1.62; confidence interval [CI] 1.15, 2.29), black (OR 1.90; CI 1.35, 2.29), obese (OR 1.57; CI 1.10, 2.44), and have a maternal history of asthma (OR 1.93; CI 1.16, 3.22). Further adjustment for SDB attenuated the association between obesity and wheeze (OR 1.45; CI 0.93, 2.26), but did not substantially alter the association between obesity and asthma. We conclude that SDB and obesity each are associated with asthma and wheeze. The relationship between obesity and wheeze may be partly mediated by factors associated with SDB.
Key Words: asthma obesity sleep-disordered breathing
Asthma and obesity are increasingly prevalent conditions in both adults and children (1eC5). Several reports indicate an association between body mass and asthma and/or frequent wheeze (6eC9). These associations have been postulated to be caused by several factors (10). Both conditions may have common risk factors, such as minority ethnicity and lower socioeconomic status (2, 3, 11, 12). In addition, genetic factors, common biomediators, and hormonal influences may contribute to both obesity and lung function impairment (10, 13eC18). Causal pathways may also link these conditions. Although there has been speculation that asthma predisposes to obesity by reducing physical activity (19), this has not been shown to be the case. Rather, recent research has suggested that obesity precedes the development of asthma (20, 21). However, the mechanistic basis for this association is unclear.
Sleep-disordered breathing (SDB), a condition increasingly recognized in obese children, also may explain some of the association between asthma and obesity, as well as the potential heterogeneity in the literature in the reported association between these conditions. SDB is characterized by snoring, repetitive upper airway collapse, marked swings in intrathoracic pressure, and intermittent hypoxemia and upregulated inflammatory pathways (22). It also is more prevalent in minority children (18, 23, 24). Pathophysiologically, SDB could be in the causal pathway mediating obesity and asthma, with its effects possibly associated with SDB-mediated gastric reflux, enhanced vagal tone, or airway and systemic inflammation (10, 25). However, there has been a paucity of asthma research that has explicitly addressed SDB as a risk factor for lower respiratory symptoms, such as wheezing, and its potential role in the obesityeCasthma relationship.
To address this knowledge gap, we analyzed data from a community-based cohort from the Cleveland area and assessed the relationships between obesity with two outcomes: wheeze and current asthma. We hypothesized that obesity is associated with asthma and asthma symptoms, and that these associations are partially explained by SDB.
METHODS
Study Sample
The Cleveland Children's Sleep and Health Study is an urban, community-based cohort of 907 children studied at ages 8 to 11 years. This cohort was originally assembled as a stratified random sample of full-term and preterm (< 37 weeks' gestational age) children born between 1988 and 1993. The cohort was assembled to overrepresent African American and former preterm children to have internal validity and stable estimates of the relationship of these factors to SDB and other health outcomes as previously reported (24). Institutional review boards at participating hospitals approved the protocol. The child's legal guardian provided informed written consent and the child gave assent.
Measures
Children were studied in their homes or other convenient locations when they were 8 to 11 years old. Demographic and medical data were assessed with the Child Sleep Questionnaire (26). Direct measurements at the time of study included the following: spirometry, a home-sleep study, height, and weight. Spirometry was performed by trained research assistants. Predicted values of FEV1 and FVC are based on published equations (27). Sleep apnea was assessed with in-home cardiorespiratory monitoring of thoracic and abdominal inductance plethysmography, pulse oximetry, heart rate, and body position (PT-2 system; SensorMedics, Yorba Linda, CA). Details on the methods for spirometry, the overnight in-home cardiorespiratory studies, and their validation compared with in-laboratory polysomnography, and scoring of respiratory events can be found on the online supplement and in previous reports (24, 28).
Definitions
Outcome variables.
Children were classified as having "wheezing" if the parent reported that the child had wheezy symptoms (i.e., child's chest sounding wheezy or whistling occasionally apart from colds, most days or nights or during the night during the past year) or if asthma medication was used in the past 3 months (n = 188). Children who met the criteria for active wheeze were also classified as having "asthma" if the child was also reported to have asthma (n = 121). Children were classified as "no active wheeze/asthma" if asthma medication use, wheezy symptoms, and diagnosis of asthma were not reported by the parent (n = 600).
Predictors.
Obstructive sleep apnea (OSA) was defined as an obstructive apneaeChypopnea index of five events or more per hour and/or an obstructive apnea index of one event or more per hour (24, 29). Children without OSA were categorized as habitual snorers if the caregiver reported that the child snored loudly in the last month, at least one to two times per week. Children who habitually snored and/or had OSA were categorized as "SDB," and children who neither snored nor had OSA were categorized as "no SDB." Body mass index (BMI) was calculated as weight (kg)/height (m2), and obesity was defined as a BMI in the 95th percentile or higher for age and sex (30). Atopy was considered present if the parent reported that the child had hayfever, eczema, a positive skin test for allergies, or an allergy to mold, dust, cats, roaches, or pollen.
Statistical Analysis
Group differences were compared using two sample t tests, Wilcoxon rank-sum tests, and the Pearson 2 test for normally distributed, skewed, and categorical data, respectively. Logistic regression was used to assess the relationship between obesity and two outcomes, wheeze and asthma, controlling for traditional risk factors (age, sex, race, term status, and maternal history of asthma), as well as SDB. Main effects for covariates of secondary interest (caregiver education, caregiver marital status, smoker in the household) and all two-way interactions with SDB were evaluated using a stepwise method, and significant effects (p < 0.05) were retained. To determine the appropriate functional form of obesity, preliminary models, including traditional risk factors and various parameterizations of BMI percentile (including linear, quadratic, ordinal, and categorical terms) were fitted and compared using Akaike's information criteria (31). The results show that obesity defined as BMI in the 95th percentile or higher was the best fit to the data and the only obesity term that was a significant predictor of either outcome. Thus, obesity defined as BMI in the 95th percentile or higher was used in subsequent models. The final model was fitted with and without SDB, and SDB was considered to be a confounder of the obesity association if the estimated regression coefficient of obesity changed by at least 15%.
RESULTS
Of the 907 participants in this cohort, 835 had both a valid sleep study and height/weight measurements, enabling us to determine SDB and obesity status, respectively. We had sufficient questionnaire data to categorize 788 as wheezy/not wheezy and 721 as asthmatic/nonasthmatic. Descriptive statistics by asthma and wheeze status are shown in Table 1. These unadjusted results show that, compared with those without wheeze/asthma, a significantly greater proportion of children with wheeze were male, African American, were born prematurely, had a primary caregiver with a high school education or less, had a maternal history of asthma, were atopic, and had evidence of greater airflow obstruction on spirometry. Furthermore, compared with those with neither wheeze nor asthma, children with active wheeze had a significantly higher BMI and a greater prevalence of obesity (21.3 vs. 13.8%, p = 0.0141) and were more likely to have OSA (9.0 vs. 3.8%, p = 0.0045) and SDB (30.9 vs. 15.3%, p < 0.0001). There were no statistically significant group differences for underweight status.
Parallel analyses (Table 1) with asthma as the outcome variable yielded similar results. Compared with children without wheezing/asthma, children with asthma were significantly more likely to be obese (23.1 vs. 13.8%, p = 0.0097). Children with asthma had an almost twofold greater prevalence of both SDB and OSA; the latter association, however, was based on small numbers of children with asthma with OSA and did not reach statistical significance.
Logistic regression was used to model the association between obesity and wheeze (Table 2) and asthma (Table 3), while adjusting for potential confounders. A main effects model that included traditional risk factors for wheezing or asthma (age, race, sex, term status, and maternal history of asthma) in addition to obesity (BMI 95th percentile) was first fit without considering the effect of SDB. The results show that, with the exception of age, all traditional risk factors were significantly associated with both outcomes, with odds ratios (ORs) ranging from 1.62 to 3.40. Moreover, obesity also was significantly associated with each outcome, with ORs of 1.57 and 1.82 for wheeze and asthma, respectively. When SDB was added to the model predicting wheeze, there was an 18.4% reduction in the regression coefficient for obesity and the effect of obesity was no longer statistically significant (OR 1.45; 95% confidence interval [CI] 0.93, 2.26). This finding suggests that the relationship between obesity and wheeze was partially explained by confounding with SDB. In contrast, the other traditional risk factors remained statistically significant predictors for active wheeze, even after considering both SDB and obesity in the model. Moreover, SDB is a significant predictor of wheeze, such that children with SDB have nearly twice the odds of wheeze compared with those without SDB (OR 1.89; 95% CI 1.26, 2.85). SDB was also significantly confounded with race; when SDB was added to the model, the regression coefficient for African American race was reduced by 15.6% (OR 1.72; 95% CI 1.21, 2.46).
When SDB was added to the model predicting asthma, there was only an 8.0% reduction in the regression coefficient for obesity, and obesity remained statistically associated with asthma (OR 1.73; 95% CI 1.03, 2.90). This modest reduction in the regression coefficient suggests that the relationship between obesity and asthma is not substantially confounded by SDB. After considering obesity and traditional risk factors, SDB was not significantly associated with asthma (OR 1.38; 95% CI 0.84, 2.28) and was not a significant confounder with the other traditional risk factors.
Alternative models that added atopy as a covariate to the final models were also fitted. As expected, atopy was significantly associated with both wheeze (OR 3.63; CI 2.52, 5.23) and asthma (OR 5.32; CI 3.41, 8.30). Similar trends were observed in the association of obesity and SDB with each outcome when atopy was included as a covariate. SDB remained a statistically significant predictor of wheeze, and the coefficient for obesity decreased by 12.5% and was no longer a statistically significant predictor of wheeze. When SDB was included in the model, obesity remained a statistically significant predictor of asthma, with the coefficient decreasing by only 2.7%.
Because our cohort was oversampled for preterm, we performed sensitivity analyses restricted to full-term children. Qualitatively similar findings were observed for the association of wheezing/asthma, SDB, and obesity in the restricted sample compared with the full sample. In addition, because it is possible that guardians may nonspecifically overreport "breathing" symptoms, such as wheezing and snoring, we repeated analyses defining our exposure as those with OSA who do not snore (n = 18) and excluded the 22 (55%) children with OSA with habitual snoring. In this subanalysis, children with OSA (without reported snoring) tended to have a higher prevalence of active wheeze compared with children without OSA (38.9 vs. 20.4%, p = 0.074), suggesting that nonspecific overreporting did not account for the observed associations between SDB and wheezing.
DISCUSSION
In this study, we confirmed that traditional risk factors, such as male sex, African American race, and prematurity, are positively associated with asthma and wheeze. We further assessed the nature of the association between obesity and wheeze/asthma and quantified the extent to which SDB contributed to this relationship. We observed a statistically significant increased prevalence of both wheeze and asthma in obese children (identified as those with a BMI percentile 95%), with little evidence of linear or bimodal relationships of asthma/wheeze with changing BMI levels. Finally, our analyses suggested that SDB is associated with wheeze/asthma and that SDB may explain a part of the relationship between obesity and wheeze.
The basis for an increase of asthma in obesity is an area of active research. The rising prevalence of obesity in both children and adults highlights the public health importance of this area of research. There are several potential mechanisms that have been postulated for this association, including inflammation, mechanical factors, and common genetic factors. Leptin, a hormone produced by adipocytes with inflammatory and possibly immunoregulatory functions, is elevated in obesity and has been postulated to modulate the expression of the asthma phenotype (32eC34). Obesity may induce mechanical airway changes, such as "latch state," which is related to stiffening of the smooth airway muscle from reduced tidal volume and functional residual capacity, increasing airway narrowing (15). Common genetic influences, including those that influence estrogen receptor expression and receptors, also may explain obesityeCasthma associations (10). Nonetheless, the relative importance of these factors in the link between obesity and asthma is unclear.
Some studies have demonstrated a doseeCresponse relationship between weight and asthma, whereas other studies have demonstrated a possible quadratic relationship, with the highest risk of asthma at both extremes of body weight (6, 35). Different doseeCresponse relationships have been reported for boys as compared with girls (36). It is possible that some of the between-study differences in the reported doseeCresponse relationship between obesity and asthma could be from the inclusion of different population subsets in various reports with other potential sources of heterogeneity, including ethnicity, preterm status, atopic background, or presence of SDB. In this sample, after considering potential confounders or effect modifiers, such as sex and race, we only observed an association between asthma/wheeze with obesity, as defined as a BMI in the 95th percentile or higher, with insufficient evidence of a linear association with BMI percentile and increased asthma/wheeze prevalence in children with BMI levels classified as "at risk" for obesity (BMI 85eC95th percentile) compared with those not at risk (BMI < 85th percentile). We also did not observe evidence of increased asthma/wheeze in underweight children; however, the relatively small numbers of children with low BMI levels limited this analysis.
We based our measurements of SDB using both objective (i.e., an elevated apneaeChypopnea or apnea index) and subjective measurements (i.e., habitual snoring). Including snoring, a cardinal symptom of SDB, in our exposure definition may have reduced misclassification of children who may have had an unrepresentative single-night sleep study or who were in the lower spectrum of disease severity. However, the finding of similar behavioral morbidities in children classified on the basis of snoring compared with objective criteria (37eC40) suggests similar or overlapping underlying physiology in both groups of children.
The role of SDB as a potential mediator between obesity and asthma has thus far received little attention. Most research in this area has addressed the association between SDB and lower respiratory symptoms without explicitly considering SDB as a confounder (or link) in obesity and asthma associations. Larsson and colleagues (41) have shown an increase in reported snoring and witnessed apneas in subjects with asthma compared with subjects without asthma. A British study showed that young wheezers and subjects with asthma have a higher prevalence of snoring compared with subjects without asthma (42). Teculescu and coworkers (43) suggested that snoring in French children was associated with exercise-induced asthma and a history of allergy. In a different population of family members of patients with OSA, we previously found that, after adjusting for obesity and race, persistent wheezing was a significant predictor of SDB (18). Although these reports underscore the potential importance of linked pathologies in the upper and lower airway, none explicitly addressed the interrelationships of obesity, asthma/wheeze, and SDB.
SDB may modify the expression of asthma in the setting of obesity for several reasons. Gastroesophageal reflux occurs commonly in SDB (44) because of intrathoracic pressure swings that accompany intermittent upper airway obstruction, favoring acid refluxeCinduced bronchoconstriction (25). Abnormalities in common biomediators may explain some of this relationship. Augmented levels of leptin, elevated in obesity and considered to have immunomodulating functions, have been demonstrated in sleep apnea (45eC48). SDB, obesity, and asthma also are each associated with augmented inflammatory states. In SDB, the oxidative stress during repetitive apneas may upregulate inflammatory cytokines and subsequent airway inflammation and smooth muscle constriction. A small, but intriguing, literature that has reported improved asthma control in patients with asthma with sleep apnea after treatment with nasal continuous positive airway pressure suggests that SDB may play a causal role in exacerbating asthma (49, 50).
SDB and asthma also may share common risk factors as proposed by the "unified airway" theory (51). Generalized abnormalities of the nasopharynx and lower airway may coexist either because of common airway responses to inflammatory or atopic stimuli, or because of other developmental factors that similarly affect the upper and lower airways. Although it is unclear how obesity might mediate common effects on both the upper and lower airways, it is possible that children with both upper and lower airway disease may be less physically active and thus be predisposed to obesity. In this study, the lack of objective measurements of physical activity prevented us from assessing this as a potential confounder.
The observed differences in the relative impact of SDB as a risk factor and confounder for our wheeze and asthma outcomes raise several interesting questions. It is possible that some of the small differences in parameter estimates are caused by chance, especially given the smaller sample of children classified as asthmatic compared with those classified as wheezing. However, if a failure to receive an asthma diagnosis despite wheezing or asthma medication use indicates a more atypical condition, then SDB may play a more prominent role in "atypical asthma" or "nonasthmatic wheezing." Alternatively, the absence of physician-diagnosed asthma in wheezing children may represent a diagnostic bias occurring in children of lower socioeconomic status, who may be at greater risk of SDB. Future studies that use refined assessments of asthma and atopy, relating these to measures of SDB and obesity, may ultimately produce improved phenotype descriptions that enable better descriptions of underlying pathophysiologic processes.
The strengths of this study include the collection of standardized, objective measures of SDB in a large sample of children representing population subgroups at increased risk for asthma. A study limitation is the lack of objective data on atopy, preventing us from fully describing the asthma phenotype and assessing differences in obesity and asthma between atopic and nonatopic subgroups. Another limitation relates to including parent-reported data on both wheezing and snoring in defining our outcome and predictors, respectively, with the potential for reporting biases. Exploratory analyses, however, showed an increased prevalence of wheezing among children with objectively measured OSA (without parent-reported snoring). These analyses suggested that the wheezingeCsnoring relationships were not solely an artifact of reporting bias.
In conclusion, we have confirmed that obesity, defined as BMI in the 95th percentile or higher for age and sex, is significantly associated with asthma and wheezing among a large, diverse pediatric population. Furthermore, our data indicate that unrecognized SDB may explain a portion of the association of obesity and childhood wheezing. Future epidemiologic studies of childhood asthma should minimally consider use of snoring data in assessments of obesityeCasthma/wheeze relationships. Additional research is needed to address the extent to which SDB exacerbates the expression of asthma, and whether SDB treatment may lead to improvement of asthma in children with both conditions.
Acknowledgments
The authors thank Sarah Bivins, Judith Emancipator, Najla Golebiewski, Heather Rosebrock, and Dina Tell for their expert assistance with data collection and processing. The authors also thank the participating families who made this study possible.
Supported, in part, by National Institutes of Health grants NIH HL60957, K23 HL04426, M01 RR00080-39, RO1 NR02707, RO1070916, NIHT 23HL03650, and K30 HL04140.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
REFERENCES
Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC. Surveillance for asthma—United States, 1980eC1999. MMWR Surveill Summ 2002;51:1eC13.
Strauss RS, Pollack HA. Epidemic increase in childhood overweight, 1986eC1998. JAMA 2001;286:2845eC2848.
Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight among US children and adolescents, 1999eC2000. JAMA 2002;288:1728eC1732.
Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, 1960eC1994. Int J Obes Relat Metab Disord 1998;22:39eC47.
Mannino DM, Homa DM, Pertowski CA, Ashizawa A, Nixon LL, Johnson CA, Ball LB, Jack E, Kang DS. Surveillance for asthma—United States, 1960eC1995. MMWR CDC Surveill Summ 1998;47:1eC27.
Celedon JC, Palmer LJ, Litonjua AA, Weiss ST, Wang B, Fang Z, Xu X. Body mass index and asthma in adults in families of subjects with asthma in Anqing, China. Am J Respir Crit Care Med 2001;164:1835eC1840.
Shaheen SO, Sterne JA, Montgomery SM, Azima H. Birth weight, body mass index and asthma in young adults. Thorax 1999;54:396eC402.
von Mutius E, Schwartz J, Neas LM, Dockery D, Weiss ST. Relation of body mass index to asthma and atopy in children: the National Health and Nutrition Examination Study III. Thorax 2001;56:835eC838.
Schwartz J, Gold D, Dockery DW, Weiss ST, Speizer FE. Predictors of asthma and persistent wheeze in a national sample of children in the United States: association with social class, perinatal events, and race. Am Rev Respir Dis 1990;142:555eC562.
Tantisira KG, Weiss ST. Complex interactions in complex traits: obesity and asthma. Thorax 2001;56(Suppl 2):ii64eCii73.
Lundback B. Epidemiology of rhinitis and asthma. Clin Exp Allergy 1998;28:3eC10.
Akinbami LJ, Schoendorf KC. Trends in childhood asthma: prevalence, health care utilization, and mortality. Pediatrics 2002;110:315eC322.
Fredberg JJ, Inouye D, Miller B, Nathan M, Jafari S, Raboudi SH, Butler JP, Shore SA. Airway smooth muscle, tidal stretches, and dynamically determined contractile states. Am J Respir Crit Care Med 1997;156:1752eC1759.
Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, D'Andrea F, Molinari AM, Giugliano D. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002;105:804eC809.
Fredberg JJ, Jones KA, Nathan M, Raboudi S, Prakash YS, Shore SA, Butler JP, Sieck GC. Friction in airway smooth muscle: mechanism, latch, and implications in asthma. J Appl Physiol 1996;81:2703eC2712.
Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292eC295.
Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS, Bulkley GB, Bao C, Noble PW, et al. Leptin regulates proinflammatory immune responses. FASEB J 1998;12:57eC65.
Redline S, Tishler PV, Schluchter M, Aylor J, Clark K, Graham G. Risk factors for sleep-disordered breathing in children: associations with obesity, race, and respiratory problems. Am J Respir Crit Care Med 1999;159:1527eC1532.
Castro-Rodriguez JA, Holberg CJ, Morgan WJ, Wright AL, Martinez FD. Increased incidence of asthmalike symptoms in girls who become overweight or obese during the school years. Am J Respir Crit Care Med 2001;163:1344eC1349.
Camargo CA Jr, Weiss ST, Zhang S, Willett WC, Speizer FE. Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med 1999;159:2582eC2588.
Beckett WS, Jacobs DR Jr, Yu X, Iribarren C, Williams OD. Asthma is associated with weight gain in females but not males, independent of physical activity. Am J Respir Crit Care Med 2001;164:2045eC2050.
Redline S, Strohl KP. Recognition and consequences of obstructive sleep apnea hypopnea syndrome. Clin Chest Med 1998;19:1eC19.
Marcus CL. Sleep-disordered breathing in children. Am J Respir Crit Care Med 2001;164:16eC30.
Rosen CL, Larkin EK, Kirchner HL, Emancipator JL, Bivins SF, Surovec SA, Martin RJ, Redline S. Prevalence and risk factors for sleep-disordered breathing in 8- to 11-year-old children: association with race and prematurity. J Pediatr 2003;142:383eC389.
Patterson PE, Harding SM. Gastroesophageal reflux disorders and asthma. Curr Opin Pulm Med 1999;5:63eC67.
Kump K, Whalen C, Tishler P, Browner I, Ferrette V, Strohl K, Rosenberg C, Redline S. Assessment of the validity and utility of a sleep symptom questionnaire in a community sample. Am J Respir Crit Care Med 1994;150:735eC741.
Knudson R. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 1983;127:725eC734.
Tang JP, Rosen CL, Larkin EK, DiFiore JM, Arnold JL, Surovec SA, Youngblut JM, Redline S. Identification of sleep-disordered breathing in children: variation with event definition. Sleep 2002;25:72eC79.
Marcus CL, Omlin KJ, Basinki DJ, Bailey SL, Rachal AB, Von Pechmann WS, Keens TG, Ward SL. Normal polysomnographic values for children and adolescents. Am Rev Respir Dis 1992;146:1235eC1239.
National Center for Health Statistics. CDC growth charts: United States (2002). Available from: www.cdc.gov/growthcharts (accessed March 2002).
Sakamoto Y, Ishiguro M, Kitagawa G. Akaike information criterion statistics. New York: Springer; 1986.
Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995;1:1155eC1161.
Johnston RA, Schwartzman IN, Shore SA. Macrophage inflammatory protein-2 levels are associated with changes in serum leptin concentrations following ozone-induced airway inflammation. Chest 2003;123(3 Suppl):369SeC370S.
Weiss ST, Shore S. Obesity and asthma: directions for research. Am J Respir Crit Care Med 2004;169:963eC968.
Guerra S, Sherrill DL, Bobadilla A, Martinez FD, Barbee RA. The relation of body mass index to asthma, chronic bronchitis, and emphysema. Chest 2002;122:1256eC1263.
Chen Y, Dales R, Tang M, Krewski D. Obesity may increase the incidence of asthma in women but not in men: longitudinal observations from the Canadian National Population Health surveys. Am J Epidemiol 2002;155:191eC197.
Urschitz MS, Guenther A, Eggebrecht E, Wolff J, Urschitz-Duprat PM, Schlaud M, Poets CF. Snoring, intermittent hypoxia and academic performance in primary school children. Am J Respir Crit Care Med 2003;168:464eC468.
O'Brien LM, Holbrook CR, Mervis CB, Klaus CJ, Bruner JL, Raffield TJ, Rutherford J, Mehl RC, Wang M, Tuell A, et al. Sleep and neurobehavioral characteristics of 5- to 7-year-old children with parentally reported symptoms of attention-deficit/hyperactivity disorder. Pediatrics 2003;111:554eC563.
Ferreira AM, Clemente V, Gozal D, Gomes A, Pissarra C, Cesar H, Coelho I, Silva CF, Azevedo MH. Snoring in Portuguese primary school children. Pediatrics 2000;106:E64.
Rosen CL, Storfer-Isser A, Taylor HG, Kirchner HL, Emancipator JL, Redline S. Increased behavioral morbidity in school-aged children with sleep-disordered breathing. Pediatrics 2004;114:1640eC1648.
Larsson LG, Lindberg A, Franklin KA, Lundback B. Symptoms related to obstructive sleep apnoea are common in subjects with asthma, chronic bronchitis and rhinitis in a general population. Respir Med 2001;95:423eC429.
Fitzpatrick MF, Martin K, Fossey E, Shapiro CM, Elton RA, Douglas NJ. Snoring, asthma and sleep disturbance in Britain: a community-based survey. Eur Respir J 1993;6:531eC535.
Teculescu DB, Caillier I, Perrin P, Rebstock E, Rauch A. Snoring in French preschool children. Pediatr Pulmonol 1992;13:239eC244.
Gislason T, Janson C, Vermeire P, Plaschke P, Bjornsson E, Gislason D, Boman G. Respiratory symptoms and nocturnal gastroesophageal reflux: a population-based study of young adults in three European countries. Chest 2002;121:158eC163.
Ozturk L, Unal M, Tamer L, Celikoglu F. The association of the severity of obstructive sleep apnea with plasma leptin levels. Arch Otolaryngol Head Neck Surg 2003;129:538eC540.
Chin K, Nakamura T, Takahashi K, Sumi K, Ogawa Y, Masuzaki H, Muro S, Hattori N, Matsumoto H, Niimi A, et al. Effects of obstructive sleep apnea syndrome on serum aminotransferase levels in obese patients. Am J Med 2003;114:370eC376.
Ip MS, Lam KS, Ho C, Tsang KW, Lam W. Serum leptin and vascular risk factors in obstructive sleep apnea. Chest 2000;118:580eC586.
Phillips BG, Kato M, Narkiewicz K, Choe I, Somers VK. Increases in leptin levels, sympathetic drive, and weight gain in obstructive sleep apnea. Am J Physiol Heart Circ Physiol 2000;279:H234eCH237.
Chan CS, Woolcock AJ, Sullivan CE. Nocturnal asthma: role of snoring and obstructive sleep apnea. Am Rev Respir Dis 1988;137:1502eC1504.
Guilleminault C, Quera-Salva MA, Powell N, Riley R, Romaker A, Partinen M, Baldwin R, Nino-Murcia G. Nocturnal asthma: snoring, small pharynx and nasal CPAP. Eur Respir J 1988;1:902eC907.
Nayak AS. A common pathway: asthma and allergic rhinitis. Allergy Asthma Proc 2002;23:359eC365.(Loreto G. Sulit, Amy Stor)
ABSTRACT
Although it has been speculated that rising asthma rates may be partly due to increasing obesity, the causal mechanisms that relate these conditions are unclear. We assessed the extent to which sleep-disordered breathing (SDB) may explain associations between obesity and wheezing/asthma. A total of 788 participants (aged 8eC11 years) in a community-based cohort study were classified according to two outcomes: wheezing and asthma. Sleep apnea was defined as an increased number of apneas and hypopneas on overnight monitoring. SDB was identified on the basis of either sleep apnea or habitual snoring. Multiple logistic regression models showed that children with wheeze were significantly more likely to be male (odds ratio [OR] 1.62; confidence interval [CI] 1.15, 2.29), black (OR 1.90; CI 1.35, 2.29), obese (OR 1.57; CI 1.10, 2.44), and have a maternal history of asthma (OR 1.93; CI 1.16, 3.22). Further adjustment for SDB attenuated the association between obesity and wheeze (OR 1.45; CI 0.93, 2.26), but did not substantially alter the association between obesity and asthma. We conclude that SDB and obesity each are associated with asthma and wheeze. The relationship between obesity and wheeze may be partly mediated by factors associated with SDB.
Key Words: asthma obesity sleep-disordered breathing
Asthma and obesity are increasingly prevalent conditions in both adults and children (1eC5). Several reports indicate an association between body mass and asthma and/or frequent wheeze (6eC9). These associations have been postulated to be caused by several factors (10). Both conditions may have common risk factors, such as minority ethnicity and lower socioeconomic status (2, 3, 11, 12). In addition, genetic factors, common biomediators, and hormonal influences may contribute to both obesity and lung function impairment (10, 13eC18). Causal pathways may also link these conditions. Although there has been speculation that asthma predisposes to obesity by reducing physical activity (19), this has not been shown to be the case. Rather, recent research has suggested that obesity precedes the development of asthma (20, 21). However, the mechanistic basis for this association is unclear.
Sleep-disordered breathing (SDB), a condition increasingly recognized in obese children, also may explain some of the association between asthma and obesity, as well as the potential heterogeneity in the literature in the reported association between these conditions. SDB is characterized by snoring, repetitive upper airway collapse, marked swings in intrathoracic pressure, and intermittent hypoxemia and upregulated inflammatory pathways (22). It also is more prevalent in minority children (18, 23, 24). Pathophysiologically, SDB could be in the causal pathway mediating obesity and asthma, with its effects possibly associated with SDB-mediated gastric reflux, enhanced vagal tone, or airway and systemic inflammation (10, 25). However, there has been a paucity of asthma research that has explicitly addressed SDB as a risk factor for lower respiratory symptoms, such as wheezing, and its potential role in the obesityeCasthma relationship.
To address this knowledge gap, we analyzed data from a community-based cohort from the Cleveland area and assessed the relationships between obesity with two outcomes: wheeze and current asthma. We hypothesized that obesity is associated with asthma and asthma symptoms, and that these associations are partially explained by SDB.
METHODS
Study Sample
The Cleveland Children's Sleep and Health Study is an urban, community-based cohort of 907 children studied at ages 8 to 11 years. This cohort was originally assembled as a stratified random sample of full-term and preterm (< 37 weeks' gestational age) children born between 1988 and 1993. The cohort was assembled to overrepresent African American and former preterm children to have internal validity and stable estimates of the relationship of these factors to SDB and other health outcomes as previously reported (24). Institutional review boards at participating hospitals approved the protocol. The child's legal guardian provided informed written consent and the child gave assent.
Measures
Children were studied in their homes or other convenient locations when they were 8 to 11 years old. Demographic and medical data were assessed with the Child Sleep Questionnaire (26). Direct measurements at the time of study included the following: spirometry, a home-sleep study, height, and weight. Spirometry was performed by trained research assistants. Predicted values of FEV1 and FVC are based on published equations (27). Sleep apnea was assessed with in-home cardiorespiratory monitoring of thoracic and abdominal inductance plethysmography, pulse oximetry, heart rate, and body position (PT-2 system; SensorMedics, Yorba Linda, CA). Details on the methods for spirometry, the overnight in-home cardiorespiratory studies, and their validation compared with in-laboratory polysomnography, and scoring of respiratory events can be found on the online supplement and in previous reports (24, 28).
Definitions
Outcome variables.
Children were classified as having "wheezing" if the parent reported that the child had wheezy symptoms (i.e., child's chest sounding wheezy or whistling occasionally apart from colds, most days or nights or during the night during the past year) or if asthma medication was used in the past 3 months (n = 188). Children who met the criteria for active wheeze were also classified as having "asthma" if the child was also reported to have asthma (n = 121). Children were classified as "no active wheeze/asthma" if asthma medication use, wheezy symptoms, and diagnosis of asthma were not reported by the parent (n = 600).
Predictors.
Obstructive sleep apnea (OSA) was defined as an obstructive apneaeChypopnea index of five events or more per hour and/or an obstructive apnea index of one event or more per hour (24, 29). Children without OSA were categorized as habitual snorers if the caregiver reported that the child snored loudly in the last month, at least one to two times per week. Children who habitually snored and/or had OSA were categorized as "SDB," and children who neither snored nor had OSA were categorized as "no SDB." Body mass index (BMI) was calculated as weight (kg)/height (m2), and obesity was defined as a BMI in the 95th percentile or higher for age and sex (30). Atopy was considered present if the parent reported that the child had hayfever, eczema, a positive skin test for allergies, or an allergy to mold, dust, cats, roaches, or pollen.
Statistical Analysis
Group differences were compared using two sample t tests, Wilcoxon rank-sum tests, and the Pearson 2 test for normally distributed, skewed, and categorical data, respectively. Logistic regression was used to assess the relationship between obesity and two outcomes, wheeze and asthma, controlling for traditional risk factors (age, sex, race, term status, and maternal history of asthma), as well as SDB. Main effects for covariates of secondary interest (caregiver education, caregiver marital status, smoker in the household) and all two-way interactions with SDB were evaluated using a stepwise method, and significant effects (p < 0.05) were retained. To determine the appropriate functional form of obesity, preliminary models, including traditional risk factors and various parameterizations of BMI percentile (including linear, quadratic, ordinal, and categorical terms) were fitted and compared using Akaike's information criteria (31). The results show that obesity defined as BMI in the 95th percentile or higher was the best fit to the data and the only obesity term that was a significant predictor of either outcome. Thus, obesity defined as BMI in the 95th percentile or higher was used in subsequent models. The final model was fitted with and without SDB, and SDB was considered to be a confounder of the obesity association if the estimated regression coefficient of obesity changed by at least 15%.
RESULTS
Of the 907 participants in this cohort, 835 had both a valid sleep study and height/weight measurements, enabling us to determine SDB and obesity status, respectively. We had sufficient questionnaire data to categorize 788 as wheezy/not wheezy and 721 as asthmatic/nonasthmatic. Descriptive statistics by asthma and wheeze status are shown in Table 1. These unadjusted results show that, compared with those without wheeze/asthma, a significantly greater proportion of children with wheeze were male, African American, were born prematurely, had a primary caregiver with a high school education or less, had a maternal history of asthma, were atopic, and had evidence of greater airflow obstruction on spirometry. Furthermore, compared with those with neither wheeze nor asthma, children with active wheeze had a significantly higher BMI and a greater prevalence of obesity (21.3 vs. 13.8%, p = 0.0141) and were more likely to have OSA (9.0 vs. 3.8%, p = 0.0045) and SDB (30.9 vs. 15.3%, p < 0.0001). There were no statistically significant group differences for underweight status.
Parallel analyses (Table 1) with asthma as the outcome variable yielded similar results. Compared with children without wheezing/asthma, children with asthma were significantly more likely to be obese (23.1 vs. 13.8%, p = 0.0097). Children with asthma had an almost twofold greater prevalence of both SDB and OSA; the latter association, however, was based on small numbers of children with asthma with OSA and did not reach statistical significance.
Logistic regression was used to model the association between obesity and wheeze (Table 2) and asthma (Table 3), while adjusting for potential confounders. A main effects model that included traditional risk factors for wheezing or asthma (age, race, sex, term status, and maternal history of asthma) in addition to obesity (BMI 95th percentile) was first fit without considering the effect of SDB. The results show that, with the exception of age, all traditional risk factors were significantly associated with both outcomes, with odds ratios (ORs) ranging from 1.62 to 3.40. Moreover, obesity also was significantly associated with each outcome, with ORs of 1.57 and 1.82 for wheeze and asthma, respectively. When SDB was added to the model predicting wheeze, there was an 18.4% reduction in the regression coefficient for obesity and the effect of obesity was no longer statistically significant (OR 1.45; 95% confidence interval [CI] 0.93, 2.26). This finding suggests that the relationship between obesity and wheeze was partially explained by confounding with SDB. In contrast, the other traditional risk factors remained statistically significant predictors for active wheeze, even after considering both SDB and obesity in the model. Moreover, SDB is a significant predictor of wheeze, such that children with SDB have nearly twice the odds of wheeze compared with those without SDB (OR 1.89; 95% CI 1.26, 2.85). SDB was also significantly confounded with race; when SDB was added to the model, the regression coefficient for African American race was reduced by 15.6% (OR 1.72; 95% CI 1.21, 2.46).
When SDB was added to the model predicting asthma, there was only an 8.0% reduction in the regression coefficient for obesity, and obesity remained statistically associated with asthma (OR 1.73; 95% CI 1.03, 2.90). This modest reduction in the regression coefficient suggests that the relationship between obesity and asthma is not substantially confounded by SDB. After considering obesity and traditional risk factors, SDB was not significantly associated with asthma (OR 1.38; 95% CI 0.84, 2.28) and was not a significant confounder with the other traditional risk factors.
Alternative models that added atopy as a covariate to the final models were also fitted. As expected, atopy was significantly associated with both wheeze (OR 3.63; CI 2.52, 5.23) and asthma (OR 5.32; CI 3.41, 8.30). Similar trends were observed in the association of obesity and SDB with each outcome when atopy was included as a covariate. SDB remained a statistically significant predictor of wheeze, and the coefficient for obesity decreased by 12.5% and was no longer a statistically significant predictor of wheeze. When SDB was included in the model, obesity remained a statistically significant predictor of asthma, with the coefficient decreasing by only 2.7%.
Because our cohort was oversampled for preterm, we performed sensitivity analyses restricted to full-term children. Qualitatively similar findings were observed for the association of wheezing/asthma, SDB, and obesity in the restricted sample compared with the full sample. In addition, because it is possible that guardians may nonspecifically overreport "breathing" symptoms, such as wheezing and snoring, we repeated analyses defining our exposure as those with OSA who do not snore (n = 18) and excluded the 22 (55%) children with OSA with habitual snoring. In this subanalysis, children with OSA (without reported snoring) tended to have a higher prevalence of active wheeze compared with children without OSA (38.9 vs. 20.4%, p = 0.074), suggesting that nonspecific overreporting did not account for the observed associations between SDB and wheezing.
DISCUSSION
In this study, we confirmed that traditional risk factors, such as male sex, African American race, and prematurity, are positively associated with asthma and wheeze. We further assessed the nature of the association between obesity and wheeze/asthma and quantified the extent to which SDB contributed to this relationship. We observed a statistically significant increased prevalence of both wheeze and asthma in obese children (identified as those with a BMI percentile 95%), with little evidence of linear or bimodal relationships of asthma/wheeze with changing BMI levels. Finally, our analyses suggested that SDB is associated with wheeze/asthma and that SDB may explain a part of the relationship between obesity and wheeze.
The basis for an increase of asthma in obesity is an area of active research. The rising prevalence of obesity in both children and adults highlights the public health importance of this area of research. There are several potential mechanisms that have been postulated for this association, including inflammation, mechanical factors, and common genetic factors. Leptin, a hormone produced by adipocytes with inflammatory and possibly immunoregulatory functions, is elevated in obesity and has been postulated to modulate the expression of the asthma phenotype (32eC34). Obesity may induce mechanical airway changes, such as "latch state," which is related to stiffening of the smooth airway muscle from reduced tidal volume and functional residual capacity, increasing airway narrowing (15). Common genetic influences, including those that influence estrogen receptor expression and receptors, also may explain obesityeCasthma associations (10). Nonetheless, the relative importance of these factors in the link between obesity and asthma is unclear.
Some studies have demonstrated a doseeCresponse relationship between weight and asthma, whereas other studies have demonstrated a possible quadratic relationship, with the highest risk of asthma at both extremes of body weight (6, 35). Different doseeCresponse relationships have been reported for boys as compared with girls (36). It is possible that some of the between-study differences in the reported doseeCresponse relationship between obesity and asthma could be from the inclusion of different population subsets in various reports with other potential sources of heterogeneity, including ethnicity, preterm status, atopic background, or presence of SDB. In this sample, after considering potential confounders or effect modifiers, such as sex and race, we only observed an association between asthma/wheeze with obesity, as defined as a BMI in the 95th percentile or higher, with insufficient evidence of a linear association with BMI percentile and increased asthma/wheeze prevalence in children with BMI levels classified as "at risk" for obesity (BMI 85eC95th percentile) compared with those not at risk (BMI < 85th percentile). We also did not observe evidence of increased asthma/wheeze in underweight children; however, the relatively small numbers of children with low BMI levels limited this analysis.
We based our measurements of SDB using both objective (i.e., an elevated apneaeChypopnea or apnea index) and subjective measurements (i.e., habitual snoring). Including snoring, a cardinal symptom of SDB, in our exposure definition may have reduced misclassification of children who may have had an unrepresentative single-night sleep study or who were in the lower spectrum of disease severity. However, the finding of similar behavioral morbidities in children classified on the basis of snoring compared with objective criteria (37eC40) suggests similar or overlapping underlying physiology in both groups of children.
The role of SDB as a potential mediator between obesity and asthma has thus far received little attention. Most research in this area has addressed the association between SDB and lower respiratory symptoms without explicitly considering SDB as a confounder (or link) in obesity and asthma associations. Larsson and colleagues (41) have shown an increase in reported snoring and witnessed apneas in subjects with asthma compared with subjects without asthma. A British study showed that young wheezers and subjects with asthma have a higher prevalence of snoring compared with subjects without asthma (42). Teculescu and coworkers (43) suggested that snoring in French children was associated with exercise-induced asthma and a history of allergy. In a different population of family members of patients with OSA, we previously found that, after adjusting for obesity and race, persistent wheezing was a significant predictor of SDB (18). Although these reports underscore the potential importance of linked pathologies in the upper and lower airway, none explicitly addressed the interrelationships of obesity, asthma/wheeze, and SDB.
SDB may modify the expression of asthma in the setting of obesity for several reasons. Gastroesophageal reflux occurs commonly in SDB (44) because of intrathoracic pressure swings that accompany intermittent upper airway obstruction, favoring acid refluxeCinduced bronchoconstriction (25). Abnormalities in common biomediators may explain some of this relationship. Augmented levels of leptin, elevated in obesity and considered to have immunomodulating functions, have been demonstrated in sleep apnea (45eC48). SDB, obesity, and asthma also are each associated with augmented inflammatory states. In SDB, the oxidative stress during repetitive apneas may upregulate inflammatory cytokines and subsequent airway inflammation and smooth muscle constriction. A small, but intriguing, literature that has reported improved asthma control in patients with asthma with sleep apnea after treatment with nasal continuous positive airway pressure suggests that SDB may play a causal role in exacerbating asthma (49, 50).
SDB and asthma also may share common risk factors as proposed by the "unified airway" theory (51). Generalized abnormalities of the nasopharynx and lower airway may coexist either because of common airway responses to inflammatory or atopic stimuli, or because of other developmental factors that similarly affect the upper and lower airways. Although it is unclear how obesity might mediate common effects on both the upper and lower airways, it is possible that children with both upper and lower airway disease may be less physically active and thus be predisposed to obesity. In this study, the lack of objective measurements of physical activity prevented us from assessing this as a potential confounder.
The observed differences in the relative impact of SDB as a risk factor and confounder for our wheeze and asthma outcomes raise several interesting questions. It is possible that some of the small differences in parameter estimates are caused by chance, especially given the smaller sample of children classified as asthmatic compared with those classified as wheezing. However, if a failure to receive an asthma diagnosis despite wheezing or asthma medication use indicates a more atypical condition, then SDB may play a more prominent role in "atypical asthma" or "nonasthmatic wheezing." Alternatively, the absence of physician-diagnosed asthma in wheezing children may represent a diagnostic bias occurring in children of lower socioeconomic status, who may be at greater risk of SDB. Future studies that use refined assessments of asthma and atopy, relating these to measures of SDB and obesity, may ultimately produce improved phenotype descriptions that enable better descriptions of underlying pathophysiologic processes.
The strengths of this study include the collection of standardized, objective measures of SDB in a large sample of children representing population subgroups at increased risk for asthma. A study limitation is the lack of objective data on atopy, preventing us from fully describing the asthma phenotype and assessing differences in obesity and asthma between atopic and nonatopic subgroups. Another limitation relates to including parent-reported data on both wheezing and snoring in defining our outcome and predictors, respectively, with the potential for reporting biases. Exploratory analyses, however, showed an increased prevalence of wheezing among children with objectively measured OSA (without parent-reported snoring). These analyses suggested that the wheezingeCsnoring relationships were not solely an artifact of reporting bias.
In conclusion, we have confirmed that obesity, defined as BMI in the 95th percentile or higher for age and sex, is significantly associated with asthma and wheezing among a large, diverse pediatric population. Furthermore, our data indicate that unrecognized SDB may explain a portion of the association of obesity and childhood wheezing. Future epidemiologic studies of childhood asthma should minimally consider use of snoring data in assessments of obesityeCasthma/wheeze relationships. Additional research is needed to address the extent to which SDB exacerbates the expression of asthma, and whether SDB treatment may lead to improvement of asthma in children with both conditions.
Acknowledgments
The authors thank Sarah Bivins, Judith Emancipator, Najla Golebiewski, Heather Rosebrock, and Dina Tell for their expert assistance with data collection and processing. The authors also thank the participating families who made this study possible.
Supported, in part, by National Institutes of Health grants NIH HL60957, K23 HL04426, M01 RR00080-39, RO1 NR02707, RO1070916, NIHT 23HL03650, and K30 HL04140.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
REFERENCES
Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC. Surveillance for asthma—United States, 1980eC1999. MMWR Surveill Summ 2002;51:1eC13.
Strauss RS, Pollack HA. Epidemic increase in childhood overweight, 1986eC1998. JAMA 2001;286:2845eC2848.
Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight among US children and adolescents, 1999eC2000. JAMA 2002;288:1728eC1732.
Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, 1960eC1994. Int J Obes Relat Metab Disord 1998;22:39eC47.
Mannino DM, Homa DM, Pertowski CA, Ashizawa A, Nixon LL, Johnson CA, Ball LB, Jack E, Kang DS. Surveillance for asthma—United States, 1960eC1995. MMWR CDC Surveill Summ 1998;47:1eC27.
Celedon JC, Palmer LJ, Litonjua AA, Weiss ST, Wang B, Fang Z, Xu X. Body mass index and asthma in adults in families of subjects with asthma in Anqing, China. Am J Respir Crit Care Med 2001;164:1835eC1840.
Shaheen SO, Sterne JA, Montgomery SM, Azima H. Birth weight, body mass index and asthma in young adults. Thorax 1999;54:396eC402.
von Mutius E, Schwartz J, Neas LM, Dockery D, Weiss ST. Relation of body mass index to asthma and atopy in children: the National Health and Nutrition Examination Study III. Thorax 2001;56:835eC838.
Schwartz J, Gold D, Dockery DW, Weiss ST, Speizer FE. Predictors of asthma and persistent wheeze in a national sample of children in the United States: association with social class, perinatal events, and race. Am Rev Respir Dis 1990;142:555eC562.
Tantisira KG, Weiss ST. Complex interactions in complex traits: obesity and asthma. Thorax 2001;56(Suppl 2):ii64eCii73.
Lundback B. Epidemiology of rhinitis and asthma. Clin Exp Allergy 1998;28:3eC10.
Akinbami LJ, Schoendorf KC. Trends in childhood asthma: prevalence, health care utilization, and mortality. Pediatrics 2002;110:315eC322.
Fredberg JJ, Inouye D, Miller B, Nathan M, Jafari S, Raboudi SH, Butler JP, Shore SA. Airway smooth muscle, tidal stretches, and dynamically determined contractile states. Am J Respir Crit Care Med 1997;156:1752eC1759.
Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, D'Andrea F, Molinari AM, Giugliano D. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002;105:804eC809.
Fredberg JJ, Jones KA, Nathan M, Raboudi S, Prakash YS, Shore SA, Butler JP, Sieck GC. Friction in airway smooth muscle: mechanism, latch, and implications in asthma. J Appl Physiol 1996;81:2703eC2712.
Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292eC295.
Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS, Bulkley GB, Bao C, Noble PW, et al. Leptin regulates proinflammatory immune responses. FASEB J 1998;12:57eC65.
Redline S, Tishler PV, Schluchter M, Aylor J, Clark K, Graham G. Risk factors for sleep-disordered breathing in children: associations with obesity, race, and respiratory problems. Am J Respir Crit Care Med 1999;159:1527eC1532.
Castro-Rodriguez JA, Holberg CJ, Morgan WJ, Wright AL, Martinez FD. Increased incidence of asthmalike symptoms in girls who become overweight or obese during the school years. Am J Respir Crit Care Med 2001;163:1344eC1349.
Camargo CA Jr, Weiss ST, Zhang S, Willett WC, Speizer FE. Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med 1999;159:2582eC2588.
Beckett WS, Jacobs DR Jr, Yu X, Iribarren C, Williams OD. Asthma is associated with weight gain in females but not males, independent of physical activity. Am J Respir Crit Care Med 2001;164:2045eC2050.
Redline S, Strohl KP. Recognition and consequences of obstructive sleep apnea hypopnea syndrome. Clin Chest Med 1998;19:1eC19.
Marcus CL. Sleep-disordered breathing in children. Am J Respir Crit Care Med 2001;164:16eC30.
Rosen CL, Larkin EK, Kirchner HL, Emancipator JL, Bivins SF, Surovec SA, Martin RJ, Redline S. Prevalence and risk factors for sleep-disordered breathing in 8- to 11-year-old children: association with race and prematurity. J Pediatr 2003;142:383eC389.
Patterson PE, Harding SM. Gastroesophageal reflux disorders and asthma. Curr Opin Pulm Med 1999;5:63eC67.
Kump K, Whalen C, Tishler P, Browner I, Ferrette V, Strohl K, Rosenberg C, Redline S. Assessment of the validity and utility of a sleep symptom questionnaire in a community sample. Am J Respir Crit Care Med 1994;150:735eC741.
Knudson R. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 1983;127:725eC734.
Tang JP, Rosen CL, Larkin EK, DiFiore JM, Arnold JL, Surovec SA, Youngblut JM, Redline S. Identification of sleep-disordered breathing in children: variation with event definition. Sleep 2002;25:72eC79.
Marcus CL, Omlin KJ, Basinki DJ, Bailey SL, Rachal AB, Von Pechmann WS, Keens TG, Ward SL. Normal polysomnographic values for children and adolescents. Am Rev Respir Dis 1992;146:1235eC1239.
National Center for Health Statistics. CDC growth charts: United States (2002). Available from: www.cdc.gov/growthcharts (accessed March 2002).
Sakamoto Y, Ishiguro M, Kitagawa G. Akaike information criterion statistics. New York: Springer; 1986.
Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995;1:1155eC1161.
Johnston RA, Schwartzman IN, Shore SA. Macrophage inflammatory protein-2 levels are associated with changes in serum leptin concentrations following ozone-induced airway inflammation. Chest 2003;123(3 Suppl):369SeC370S.
Weiss ST, Shore S. Obesity and asthma: directions for research. Am J Respir Crit Care Med 2004;169:963eC968.
Guerra S, Sherrill DL, Bobadilla A, Martinez FD, Barbee RA. The relation of body mass index to asthma, chronic bronchitis, and emphysema. Chest 2002;122:1256eC1263.
Chen Y, Dales R, Tang M, Krewski D. Obesity may increase the incidence of asthma in women but not in men: longitudinal observations from the Canadian National Population Health surveys. Am J Epidemiol 2002;155:191eC197.
Urschitz MS, Guenther A, Eggebrecht E, Wolff J, Urschitz-Duprat PM, Schlaud M, Poets CF. Snoring, intermittent hypoxia and academic performance in primary school children. Am J Respir Crit Care Med 2003;168:464eC468.
O'Brien LM, Holbrook CR, Mervis CB, Klaus CJ, Bruner JL, Raffield TJ, Rutherford J, Mehl RC, Wang M, Tuell A, et al. Sleep and neurobehavioral characteristics of 5- to 7-year-old children with parentally reported symptoms of attention-deficit/hyperactivity disorder. Pediatrics 2003;111:554eC563.
Ferreira AM, Clemente V, Gozal D, Gomes A, Pissarra C, Cesar H, Coelho I, Silva CF, Azevedo MH. Snoring in Portuguese primary school children. Pediatrics 2000;106:E64.
Rosen CL, Storfer-Isser A, Taylor HG, Kirchner HL, Emancipator JL, Redline S. Increased behavioral morbidity in school-aged children with sleep-disordered breathing. Pediatrics 2004;114:1640eC1648.
Larsson LG, Lindberg A, Franklin KA, Lundback B. Symptoms related to obstructive sleep apnoea are common in subjects with asthma, chronic bronchitis and rhinitis in a general population. Respir Med 2001;95:423eC429.
Fitzpatrick MF, Martin K, Fossey E, Shapiro CM, Elton RA, Douglas NJ. Snoring, asthma and sleep disturbance in Britain: a community-based survey. Eur Respir J 1993;6:531eC535.
Teculescu DB, Caillier I, Perrin P, Rebstock E, Rauch A. Snoring in French preschool children. Pediatr Pulmonol 1992;13:239eC244.
Gislason T, Janson C, Vermeire P, Plaschke P, Bjornsson E, Gislason D, Boman G. Respiratory symptoms and nocturnal gastroesophageal reflux: a population-based study of young adults in three European countries. Chest 2002;121:158eC163.
Ozturk L, Unal M, Tamer L, Celikoglu F. The association of the severity of obstructive sleep apnea with plasma leptin levels. Arch Otolaryngol Head Neck Surg 2003;129:538eC540.
Chin K, Nakamura T, Takahashi K, Sumi K, Ogawa Y, Masuzaki H, Muro S, Hattori N, Matsumoto H, Niimi A, et al. Effects of obstructive sleep apnea syndrome on serum aminotransferase levels in obese patients. Am J Med 2003;114:370eC376.
Ip MS, Lam KS, Ho C, Tsang KW, Lam W. Serum leptin and vascular risk factors in obstructive sleep apnea. Chest 2000;118:580eC586.
Phillips BG, Kato M, Narkiewicz K, Choe I, Somers VK. Increases in leptin levels, sympathetic drive, and weight gain in obstructive sleep apnea. Am J Physiol Heart Circ Physiol 2000;279:H234eCH237.
Chan CS, Woolcock AJ, Sullivan CE. Nocturnal asthma: role of snoring and obstructive sleep apnea. Am Rev Respir Dis 1988;137:1502eC1504.
Guilleminault C, Quera-Salva MA, Powell N, Riley R, Romaker A, Partinen M, Baldwin R, Nino-Murcia G. Nocturnal asthma: snoring, small pharynx and nasal CPAP. Eur Respir J 1988;1:902eC907.
Nayak AS. A common pathway: asthma and allergic rhinitis. Allergy Asthma Proc 2002;23:359eC365.(Loreto G. Sulit, Amy Stor)