Published ahead of print on December 10, 2004, doi:10.1164/rccm.200403-398OC
© 2005 American Thoracic Society doi: 10.1164/rccm.200403-398OC
Associations of Obesity, Sleep-disordered Breathing, and Wheezing in ChildrenCase School of Medicine, Cleveland, Ohio Correspondence and requests for reprints should be addressed to Loreto G. Sulit, M.D., Division of Clinical Epidemiology, Rainbow Babies and Children's Hospital, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106-6003. E-mail: loreto.sulit{at}case.edu
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 8–11 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 (1–5). Several reports indicate an association between body mass and asthma and/or frequent wheeze (6–9). 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, 13–18). 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 obesity–asthma 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.
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
Definitions
Predictors.
Statistical Analysis
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
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.
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 (32–34). 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 ß receptors, also may explain obesity–asthma associations (10). Nonetheless, the relative importance of these factors in the link between obesity and asthma is unclear. Some studies have demonstrated a dose–response 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 dose–response relationships have been reported for boys as compared with girls (36). It is possible that some of the between-study differences in the reported dose–response 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 85–95th 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 apnea–hypopnea 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 (37–40) 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 reflux–induced 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 (45–48). 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 wheezing–snoring 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 obesity–asthma/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.
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 Conflict of Interest Statement: L.G.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.S.-I. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.L.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; H.L.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.R. received a grant from Sepracor with payment per participant enrolled (December 2002–June 2005) to evaluate levabuterol in a randomized controlled trial, and approximate payments for cost for participants' fees and study costs were $15,000. Received in original form March 23, 2004; accepted in final form December 6, 2004
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ABSTRACT
METHODS
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 (
