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Original Research |

Obesity-Associated Asthma in ChildrenObesity-Associated Asthma in Children: A Distinct Entity FREE TO VIEW

Deepa Rastogi, MBBS; Stephen M. Canfield, MD, PhD; Andrea Andrade, BA; Carmen R. Isasi, MD, PhD; Charles B. Hall, PhD; Arye Rubinstein, MD; Raanan Arens, MD
Author and Funding Information

From the Department of Pediatrics (Drs Rastogi, Rubinstein, and Arens and Ms Andrade) and the Department of Epidemiology and Population Health (Dr Canfield), Albert Einstein College of Medicine, Bronx; and the Department of Medicine (Dr Canfield) and Department of Epidemiology and Population Health (Drs Isasi and Hall), College of Physicians and Surgeons, Columbia University, New York, NY.

Correspondence to: Deepa Rastogi, MBBS, Joseph S. Blume Faculty Scholar, Albert Einstein College of Medicine, Children’s Hospital at Montefiore, 3415 Bainbridge Ave, Bronx, NY 10467; e-mail: drastogi@montefiore.org


Ms Andrade is currently at The American University of the Caribbean (St. Maarten, Netherland Antilles).

Funding/Support: This study was funded by a grant-in-aid from the Stony-Wold Herbert Fund, New York.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2012 American College of Chest Physicians


Chest. 2012;141(4):895-905. doi:10.1378/chest.11-0930
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Background:  Obesity-associated asthma has been proposed to be a distinct entity, differing in immune pathogenesis from atopic asthma. Both obesity-mediated inflammation and increase in adiposity are potential mechanistic factors that are poorly defined among children. We hypothesized that pediatric obesity-associated asthma would be characterized by T helper (Th) 1, rather than the Th2 polarization associated with atopic asthma. Moreover, we speculated that Th1 biomarkers and anthropometric measures would correlate with pulmonary function tests (PFTs) in obese asthmatic children.

Methods:  We recruited 120 children, with 30 in each of the four study groups: obese asthmatic children, nonobese asthmatic children, obese nonasthmatic children, and nonobese nonasthmatic children. All children underwent pulmonary function testing. Blood was collected for measurement of serum cytokines. T-cell responses to mitogen, phorbol 12-myristate 13-acetate (PMA), or antigens tetanus toxoid or Dermatophagoides farinae were obtained by flow cytometric analysis of intracellular cytokine staining for interferon-γ (IFN-γ) (Th1) or IL-4 (Th2) within the CD4 population.

Results:  Obese asthmatic children had significantly higher Th1 responses to PMA (P < .01) and tetanus toxoid (P < .05) and lower Th2 responses to PMA (P < .05) and D farinae (P < .01) compared with nonobese asthmatic children. Th-cell patterns did not differ between obese asthmatic children and obese nonasthmatic children. Obese asthmatic children had lower FEV1/FVC (P < .01) and residual volume/total lung capacity ratios (P < .005) compared with the other study groups, which negatively correlated with serum interferon-inducible protein 10 and IFN-γ levels, respectively. PFTs, however, did not correlate with BMI z score or waist to hip ratio.

Conclusions:  We found that pediatric obesity-associated asthma differed from atopic asthma and was characterized by Th1 polarization. The altered immune environment inversely correlated with PFTs in obese asthmatic children.

Figures in this Article

Obesity-associated asthma has been proposed to be a distinct entity,1 but its underlying mechanisms are not well elucidated, particularly among children.2 Inflammation associated with obesity and an increase in adiposity-related mechanical fat load may both contribute to the pathogenesis of obesity-associated asthma.1

Obesity is a chronic inflammatory state characterized by elevated leptin levels.3 Leptin promotes T helper (Th)1-cell differentiation,4 associated with elevated levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and IL-6.5 In contrast, “classic” childhood asthma is predominantly atopic in nature,6 with a relative bias toward a Th2 phenotype characterized by increases in IL-4, IL-5, and IL-13.7 It is not clear whether atopic Th2 responses or obese Th1 responses predominate in obese asthmatic children. Pediatric population-based studies have yielded conflicting results, with some suggesting an increase in atopy8,9 and others, an absence of atopy, in obese asthmatic children.1012 Because Th1 and Th2 inflammatory patterns are mutually inhibitory, they promote the recruitment of different cell populations, namely neutrophils13 vs eosinophils,14 in the asthmatic airway. Hence, determining the T-cell response and systemic cytokine milieu in children with obesity-associated asthma is critical to understanding the underlying pathophysiology and, therefore, developing optimal treatment strategies.

Pulmonary mechanics are influenced by inflammation and an increase in adiposity. Adult studies suggest a greater role of mechanical fat load,15 because obesity is associated with reduced FVC and FEV1,16 which improve with weight loss.17 Results from pediatric studies suggest that there may be important differences between children and adults. Although obese nonasthmatic children are similar to their adult counterparts,18 obese asthmatic children exhibit an increase in FVC and FEV1,19 suggesting that factors other than mechanical fat load may play a prominent role in modulating pulmonary function in this group.

Given the paucity of data in pediatric populations, and the epidemic of obesity and asthma in our population, in which 17% of all children are asthmatic20 and 21% are obese,21 we undertook a cross-sectional study to characterize the T-cell population, circulating cytokines, and lung function in pediatric cohorts of obese and nonobese asthmatic children, and included obese and nonobese nonasthmatic control subjects. We predicted that obesity-associated asthma would be characterized by Th1-polarized systemic inflammation, and that these children would have greater lower-airway obstruction as measured by lower FEV1/FVC ratios and midexpiratory flow rates (forced expiratory flow 25% to 75% [FEF25%-75%]) compared with nonobese asthmatic children and obese nonasthmatic children, which would independently correlate with measures of inflammation and adiposity.

Study Population

One hundred twenty children aged 7 to 11 years were recruited from the outpatient clinics at Children’s Hospital at Montefiore, Bronx, New York, between July 2008 and August 2009. The study population was composed of 30 obese asthmatic children and 30 in each of the following comparison groups: atopic nonobese asthmatic children, obese nonasthmatic children, and nonobese nonasthmatic control subjects. The Montefiore Medical Center institutional review board approved the study (No. 08-04-107E); informed consent and assent were obtained from all parents and participants, respectively. The groups were matched for sex and ethnicity.

Obesity was defined as a BMI > 95th percentile for age, and nonobese as BMI < 85th percentile. Asthmatic children were those given the diagnosis by their primary care physicians, as per the National Asthma Education and Prevention Program guidelines.22 Additional details are in e-Appendix 1.

Anthropometric Measures

Anthropometric measurements, including height, weight, and waist and hip circumference, were obtained from all participants by a single research assistant. Additional details are in e-Appendix 1.

Asthma Severity

The National Asthma Education and Prevention Program guidelines were used to classify asthma severity.22 Parents reported the frequency of daytime and nighttime symptoms, exercise limitation, and albuterol use. The preventative medication regimen and the degree of adherence to it were recorded.

Pulmonary Function Testing

All children underwent pulmonary function testing (PFT) in a sitting position as per American Thoracic Society guidelines.23 Lung volume measures were obtained by the nitrogen washout technique. Additional details about PFTs are in e-Appendix 1.

Cytokine Assays

Cytokines and leptin were measured in serum obtained from fasting blood using a Bioluminex 100 system (Bioluminex) and were analyzed with StarStation (version 2.0; Applied Cytometry Systems). The cytokines included those linked with obesity-mediated inflammation (TNF-α, IL-6, IFN-γ, and interferon-inducible protein 10 [IP-10])5 and those with a Th2 phenotype (IL-4, IL-5, and IL-13).7 Additional details are in e-Appendix 1.

Quantification of Systemic Th-Cell Responses

Th-cell responses were obtained by performing flow cytometric analysis of intracellular cytokine staining for IFN-γ (Th1) or IL-4 (Th2) within the CD4 population. Th-cell proliferation was measured in response to polyclonal nonspecific mitogen phorbol 12-myristate 13-acetate (PMA).24,25 It was also measured in response to monoclonal antigens, tetanus toxoid, and Dermatophagoides farinae. Tetanus was chosen to study Th1 responses26,27 because it is part of universal childhood immunization. D farinae was chosen to study Th2-cell responses, given the high prevalence of sensitization to dust mite among urban minority children.28,29 Additional details are in e-Appendix 1.

Statistical Analysis

Variables for asthma severity, including symptom frequency and medication use, were compared among asthma groups using Pearson χ2 test. Although the pulmonary function variables were approximately normally distributed, the percentage of Th1 and Th2 cells, cytokines, and leptin were logarithmically transformed to approach a normal distribution. The study groups were compared by analysis of variance. Between-group comparisons were done using Bonferroni post hoc analysis to adjust for multiple comparisons. Bonferroni post hoc analysis was done only when the analysis of variance was statistically significant. The T-cell IFN-γ/IL-4 ratio was calculated as a surrogate measure of the Th1/Th2 ratio. The Th1/Th2 ratio and pulmonary function variables were correlated with serum biomarker levels using Pearson’s correlation. All tests of association were two tailed and were conducted with significance set a priori at 0.05. Analyses were performed using STATA statistical software, version-10.

Demographics, Anthropometrics, and Asthma Severity

The mean age and height of the children in the four study groups were not significantly different (Table 1), but as per study design, weight, BMI z score, waist and hip circumference and their ratio were significantly higher among the obese asthmatic children and obese nonasthmatic children compared with their nonobese counterparts. There were no significant differences between the two obese groups or between the two nonobese groups in these parameters. There were also no differences between the obese and nonobese asthmatic children with respect to asthma severity, use of inhaled steroids, or leukotriene antagonists (Table 2).

Table Graphic Jump Location
Table 1 —Comparison of Demographics and Anthropometrics Among the Four Study Groups

Data are presented as mean ± SD.

Table Graphic Jump Location
Table 2 —Comparison of Asthma Characteristics Between the Two Asthma Groups

Data are presented as No. (%) or mean (95% CI).

a 

The groups were compared using the χ test for the categorical variables and Student t test for the continuous variables. There were no differences in symptom frequency or medication use between the two asthmatic study groups.

Th-Cell Responses and Serum Cytokines/Chemokines

As expected, serum IL-4 and IL-13 were higher among nonobese asthmatic children, consistent with the Th2 phenotype that characterizes atopic asthma. In contrast, obese asthmatic children had lower levels of IL-13 and higher levels of TNF-α and IL-6, Th1 cytokines known to be elevated with obesity-associated inflammation (Table 3). Furthermore, the CD4+ IFN-γ+ (Th1) response to PMA and tetanus was significantly greater in obese asthmatic children than in nonobese asthmatic children and nonobese nonasthmatic children but did not differ between the two obese groups (Fig 1). Conversely, the obese asthmatic children mounted a lower CD4+ IL-4+ (Th2) response to PMA, tetanus toxoid, and D farinae compared with nonobese asthmatic children but, again, did not differ from obese nonasthmatic children (Fig 1).

Table Graphic Jump Location
Table 3 —Comparison of Leptin, Th1, and Th2 Cytokine Levels Among the Four Study Groups

Data are presented as mean ± SD. P values indicate comparisons of cytokine values between study groups. All cytokines were log10 transformed. Cytokine levels were compared among the study groups using analysis of variance followed by Bonferroni post hoc analysis in those cytokine comparisons in which analysis of variance was statistically significant. Similar letters in each row of the table denote significant differences in the cytokine values between those two study groups. TNF-α and IL-6 were significantly higher among obese asthmatic children than nonobese nonasthmatic control subjects. IL-4 and IL-13 levels were significantly higher among nonobese asthmatic children than nonobese nonasthmatic children. Further, IL-13 levels among nonobese asthmatic children were higher than those in obese asthmatic children. In keeping with the BMI z score, leptin levels in the obese groups were significantly higher than in their nonobese counterparts. IFN-γ = interferon-γ; IP-10 = interferon-inducible protein 10; Th = T helper; TNF-α = tumor necrosis factor-α.

a 

P < .05.

b 

P < .001.

c 

P < .01.

Figure Jump LinkFigure 1. A, Comparison of CD4+ Th-cell responses to PMA/ionomycin. The bar represents the mean values. Mean IFNγ+ CD4+ Th cells were significantly higher in the obese asthmatic children than in the nonobese asthmatic children and nonobese nonasthmatic children. Mean IL-4+ CD4+ cells were lower in the obese asthmatic children and nonobese nonasthmatic children than in the nonobese asthmatic children. The mean IFNγ/IL-4 ratio was higher among the obese asthmatic children than among the nonobese asthmatic children. B, Comparison of CD4+ Th-cell responses to tetanus toxoid. Mean IFNγ+ CD4+ Th cells were significantly higher in the obese asthmatic children, obese nonasthmatic children, and nonobese nonasthmatic children than in the nonobese asthmatic children. Mean IL-4+ CD4+ cells were lower in the obese asthmatic children than in the nonobese asthmatic children. The mean IFNγ/IL-4 ratio was higher among the obese asthmatic children and obese nonasthmatic children than among the nonobese asthmatic children. C, Comparison of CD4+ Th-cell responses to Dermatophagoides farinae stimulation. Mean IFNγ+ CD4+ Th cells were significantly higher in the nonobese nonasthmatic children than in the nonobese asthmatic children. Mean IL-4+ CD4+ cells were lower in the obese asthmatic children than in the nonobese asthmatic children. The mean IFNγ/IL-4 ratio was higher among the obese asthmatic children than among the nonobese asthmatic children. *P < .05; **P < .01. The bar represents the mean values. IFNγ = interferon-γ; NOA = nonobese asthmatic children; NONA = nonobese nonasthmatic children; OA = obese asthmatic children; ONA = obese nonasthmatic children; Th = T helper.Grahic Jump Location

Investigating the Th-cell patterns among nonasthmatic children, we found a higher Th1 response to PMA in obese nonasthmatic children than in nonobese nonasthmatic children, suggestive of baseline Th1 polarization, although this difference did not reach statistical significance (P = .08). In keeping with the absence of atopy in the nonasthmatic groups per the study design, both obese (P < .01) and nonobese nonasthmatic children (P = .03) mounted a higher Th1 response to tetanus than did nonobese asthmatic children. There was also a higher Th1 response to D farinae among the nonobese nonasthmatic children (0.01) and a borderline significant response among the obese nonasthmatic children (0.06) compared with the nonobese asthmatic children.

The IFN-γ/IL-4 Th-cell ratio in response to all three stimulation conditions was higher among obese asthmatic children than among nonobese asthmatic children, but it did not differ from obese nonasthmatic children. The IFN-γ/IL-4 Th-cell ratio in response to PMA/ionomycin stimulation, a potential biomarker of baseline systemic Th1/Th2 balance, correlated with serum leptin levels (r = 0.35, P = .04), and approached significance with serum IL-6 levels (r = 0.36, P = .05) only in obese asthmatic children (Fig 2).

Figure Jump LinkFigure 2. Correlation between measures of Th1/Th2-cell ratio in response to PMA/ionomycin stimulation and serum. A, Leptin levels. B, IL-6 levels. *Leptin and IL-6 levels were log10 transformed. PMA = phorbol 12-myristate 13-acetate. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Pulmonary Function Tests

The results of PFT are shown in Figure 3. The mean spirometric indices, including FVC, FEV1, FEV1/FVC ratio, and FEF25%-75%, were within normal range in all four study groups. However, the FEV1/FVC ratio was statistically significantly lower among obese asthmatic children than among nonobese asthmatic children (P = .049), obese nonasthmatic children (P = .005), and nonobese nonasthmatic children (P = .03). Similarly, although the mean FEF25%-75% was within the normal range, it was the lowest among obese asthmatic children compared with the other three study groups; however, this difference did not reach statistical significance (P = .3), possibly because of the higher variability of this spirometry index.

Figure Jump LinkFigure 3. Comparison of pulmonary function tests. A, Spirometry indices. B, Lung volume indices among the four study groups. *P < .05; **P < .01; #P < .001. FEF25-75% = forced expiratory flow 25% to 75%; FRC = functional residual capacity; RV = residual volume; TLC = total lung capacity.Grahic Jump Location

Mean functional residual capacity (FRC) was lower among obese asthmatic children than among nonobese asthmatic children (P = .05) and obese nonasthmatic children (P < .005) (Fig 3). The mean residual volume (RV) for both obese asthmatic children (P = .004) and nonobese asthmatic children (P = .003) was also significantly lower than in nonobese nonasthmatic children. Similarly, the RV/total lung capacity ratio was lower among both obese asthmatic children (P < .001) and nonobese asthmatic children (P = .02) as compared with nonobese nonasthmatic children. Neither sex nor ethnicity was found to be associated with the PFTs.

Correlation of PFTs With Inflammatory and Adiposity Measures

Although there was a small but significant negative correlation between BMI z score and FEV1/FVC ratio (r = −0.21, P = .02) for the entire study sample, on subgroup analysis this relationship was limited to obese nonasthmatic children (r = −0.4, P = .03). In obese asthmatic children, the FEV1/FVC ratio was negatively correlated with IP-10 (r = −0.34, P < .05) and displayed a nonsignificant trend toward correlating with IFN-γ (r = −0.25, P = .1) (Fig 4). Likewise, FEF25%-75% negatively correlated with IP-10 (r = −0.37, P = .04) and tended to correlate with IFN-γ (r = −0.34, P = .06) only in the obese asthmatic group (Fig 4). RV/total lung capacity also correlated with IFN-γ (r = 0.42, P = .02), but only in obese asthmatic children. There was no correlation between PFTs and Th2 cytokines, BMI z score, or waist to hip ratio in the obese asthmatic children.

Figure Jump LinkFigure 4. A, Correlation between FEV1/FVC and serum levels of Th1 cytokines, IFNγ, and IP-10. There was significant correlation between FEV1/FVC and serum IP-10 levels. B, Correlation between FEF25075% and serum levels of Th1 cytokines, IFNγ, and IP-10. There was significant correlation between FEF 25075% and both serum IFNγ and IP10 levels. IFNγ and IP-10 levels were log10 transformed. IP-10 = interferon-inducible protein 10. See Figure 1 and 3 legends for expansion of other abbreviations.Grahic Jump LocationGrahic Jump Location

In contrast to the well-characterized Th2 polarization associated with childhood asthma,6 obese asthmatic children exhibited Th1 polarization. Notably, the Th1 response did not differ between obese asthmatic children and obese nonasthmatic children.30 Additionally, Th1/Th2-cell ratios in the obese asthmatic children correlated with leptin and IL-6, biomarkers associated with obesity-mediated inflammation.4,5 These findings suggest that among preadolescent children, obese asthmatic children exhibit systemic Th1 polarization, which may be modulated by obesity rather than by atopic asthma.

We also found that certain pulmonary function deficits, such as decreased FRC, previously reported only among adults,31 were present in obese asthmatic children. This suggests that changes in pulmonary function observed in adulthood may begin early in childhood. Although the mean FEV1/FVC ratio was within the normal range for all four study groups, obese asthmatic children had lower FEV1/FVC ratios compared with children with asthma or obesity alone, corroborating previously published reports.19 Further, both the FEV1/FVC ratio and FEF25%-75% inversely correlated with IFN-γ and IP-10 levels, markers of Th1 inflammation, but did not correlate with Th2 biomarkers or measures of adiposity. These findings are consistent with murine studies, in which airway hyperresponsiveness was found to correlate with IL-6 levels.32 Together, these results indicate that, in obese asthmatic children, PFTs correlate with obesity-mediated systemic inflammatory patterns rather than with mechanical effects of obesity.

Our findings address a previously uninvestigated issue regarding Th-cell inflammatory patterns and their association with pulmonary function among children with obesity and asthma.1 To the best of our knowledge, our study is unique because we measured inflammatory biomarkers as well as pulmonary function, and compared pediatric cohorts with the comorbidities of obesity and asthma with cohorts with asthma or obesity alone and with healthy control subjects, thus providing the opportunity to identify the independent effects of asthma as well as obesity and of their coexistence on the systemic inflammatory profile and its association with pulmonary function.

Because obese asthmatic children did not demonstrate the typical allergic response, one potential explanation for asthma among the obese may be the activation of an alternative inflammatory pathway, such as one mediated by Th1 polarization. This likelihood has been proposed recently.1 Although nonatopic or intrinsic asthma, defined by the lack of association with atopy, is a well-defined entity among adults, it is less frequently reported among children. The complexity of classifying asthma as atopic and nonatopic has also been highlighted, because cellular response in an asthma phenotype depends on the asthma trigger and may or may not be Th2-cell mediated.13 These studies identify the need for a better understanding of the alternative inflammatory pathways associated with the asthma phenotype, which is different from classic “atopic” asthma.

At this time, based on our findings, we speculate that inflammatory mechanisms in obese asthmatic children may mimic those found in association with nonatopic asthma among adults. To support our hypothesis, there are reports of a lack of association between obesity-associated asthma and atopic measures such as IgE levels and skin prick testing in large population-based studies in both the United States11,12 and Europe.10 In turn, the association between leptin levels and Th1 polarization in our study provides a potential biologic mechanism for previously reported1012 links between obesity and nonatopic asthma. Moreover, the association between obesity-mediated Th1 polarization and PFTs provides a likely pathway for the recently reported association between metabolic abnormalities and higher asthma prevalence.33

Although several studies have shown a positive association between leptin levels and asthma prevalence in obese individuals,1 the mechanistic link between leptin and asthma remains unclear. Mai et al34 demonstrated higher serum leptin levels among overweight asthmatic children that correlated with serum IFN-γ levels, suggesting that IFN-γ may play a role in the pathogenesis of obesity-associated asthma. Our findings support this hypothesis by demonstrating a higher percentage of Th1 cells and a higher Th1/Th2-cell ratio in obese asthmatic children, even in response to dust-mite, an antigen typically associated with a Th2 response29,35 in asthmatic children. Additionally, the inverse correlation between Th1 biomarkers, IFN-γ, and IP-10, and PFTs primarily among obese asthmatic children, further supports the role of IFN-γ in the pathogenesis of obesity-associated asthma. This association also identifies a potential mechanistic pathway for the higher asthma morbidity among the obese.36

There may be several reasons for the lack of association between PFTs and measures of adiposity among obese asthmatic children in our study sample. The association between FEV1/FVC ratio and BMI z score in our entire sample is consistent with a previous population-based study.18 However, studies that have investigated the individual association of the FEV1/FVC ratio with BMI in obese asthmatic children compared with subjects with either asthma or obesity have demonstrated a similar lack of association.37 Other pediatric studies that demonstrated a correlation between PFTs and adiposity included adolescents, raising the question as to whether change in body fat distribution occurring during adolescence may have played a role38 and may provide an explanation for the discordance between pediatric and adult findings. The lack of correlation may also be due to the pulmonary function being within the normal range in our study subjects. This finding may be due to the selection of well-controlled asthmatic children as defined by the lack of an exacerbation in the 3 months preceding recruitment. Further, controller medication use may have also contributed to the observed normal PFTs. Finally, lack of statistical power may also explain these differences.

Additionally, we did not identify differences in asthma symptom frequency between obese and nonobese asthmatic children in our study. Prior literature suggests that substantial weight gain must occur over time to manifest as increased airway hyperresponsiveness.32 Young age, and hence relatively shorter duration of obesity, may explain the lack of difference in symptom perception in the asthmatic children in our study. The lack of difference may also be due to a small sample size; epidemiologic studies with larger study populations have demonstrated increased symptoms among children in an age group similar to that of our study.39 However, irrespective of perceived symptoms, we demonstrated that pulmonary function deficits, specifically decreased FRC, were already present among preadolescent obese asthmatic children.

Although the inflammatory pattern in obese asthmatic children did not differ from that in obese nonasthmatic children in our study, several factors can be hypothesized for the occurrence of asthma in some, but not all, obese children. The pattern of fat distribution may play a role, because central adiposity has been associated with asthma in children.40 Similarly, the extent and rapidity of weight gain may play a role, because a threshold effect has been reported with weight gain and onset of airway reactivity in murine models.32 Further, in keeping with the occurrence of atopy in the general population in the absence of atopic symptoms,41 it can be hypothesized that obesity may occur in the absence of its associated morbidities. Moreover, although not investigated thus far, in keeping with multifactorial diseases including diabetes and cancer, one can also speculate a role of gene-environment interaction. A genetic predisposition toward an asthma phenotype or epigenetic changes42 may set the stage for asthma in some, but not all, obese children. These aspects need further investigation to improve the understanding of obesity-associated asthma.

Our study has certain limitations. The cytokine and cell measures were quantified at a systemic level and may not be reflective of organ-specific inflammatory responses. However, the lack of airway inflammation previously reported in obese asthmatic children43 suggests that systemic, rather than local, inflammation may be determining the clinical phenotype. Another potential limiting factor is that the asthma diagnosis was based on physician assessment rather than objective documentation of airway reactivity by using tests such as the methacholine challenge. However, because the degree of Th2 polarization observed in our nonobese asthmatic children was comparable to those previously reported among urban children, it adds validity to the physician-based clinical diagnosis. Medication use may also alter the inflammatory responses. However, the proportions of subjects in both the obese and nonobese asthma groups prescribed inhaled steroids or leukotriene antagonists were similar (Table 2); thus, medication use is unlikely to explain the observed differences in the inflammatory or pulmonary function profile. Finally, although our study was cross sectional, we demonstrate that alterations in systemic inflammation and pulmonary function occur as early as the preadolescent years and are linked to obesity-associated asthma, thus identifying a need for future longitudinal evaluation.

In summary, the pulmonary function deficits reported previously in obese asthmatic adults were present in our pediatric population. Systemic inflammation in obese asthmatic children was characterized by Th1 polarization, which inversely correlated with PFTs. As recently proposed,1 our study suggests that pediatric obesity-associated asthma is indeed a distinct entity from asthma in the nonobese, and is characterized by Th1 polarization that is different from the well-characterized Th2 pattern associated with asthma in nonobese children. These findings identify the need for different treatment strategies in the management of obese compared with nonobese asthmatic children. Moreover, the direct association of obesity-mediated inflammation with pulmonary function suggests that interventions addressing the onset and progression of obesity may have the most substantial impact on decreasing the morbidity occurring with obesity-associated asthma.

Author contributions: Dr Rastogi was the principal investigator, had full access to the data, and vouches for the integrity of the data analysis.

Dr Rastogi: contributed to conducting of the experiments and development of the manuscript.

Dr Canfield: contributed to the development of the assays and preparation of the manuscript.

Ms Andrade: contributed to subject recruitment, completion of questionnaires, data entry, and preparation of the manuscript.

Dr Isasi: contributed to the concept of the study and critical review of the manuscript.

Dr Hall: contributed to the statistical analysis and critical review of the manuscript.

Dr Rubinstein: contributed to the concept of the study and critical review of the manuscript.

Dr Arens: contributed to the concept of the study and critical review of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in the design and conduct of study, data collection, analysis or interpretation, or in manuscript preparation and review.

Other contributions: The authors acknowledge Betsy Herold, MD, for her critical review and editing of the manuscript.

Additional information: The e-Appendix can be found in the Online Supplement at http://chestjournal.chestpubs.org/content/141/4/895/suppl/DC1.

FEF25%-75%

forced expiratory flow 25% to 75%

FRC

functional residual capacity

IFN-γ

interferon-γ

IP-10

interferon-inducible protein 10

PFT

pulmonary function test

PMA

phorbol 12-myristate 13-acetate

RV

residual volume

Th

T helper

TNF-α

tumor necrosis factor-α

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Visness CM, London SJ, Daniels JL, et al. Association of childhood obesity with atopic and nonatopic asthma: results from the National Health and Nutrition Examination Survey 1999-2006. J Asthma. 2010;477:822-829 [CrossRef] [PubMed]
 
Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol. 2010;117:577-584 [CrossRef] [PubMed]
 
Busse WW, Lemanske RF Jr. Asthma. N Engl J Med. 2001;3445:350-362 [CrossRef] [PubMed]
 
Marcon A, Corsico A, Cazzoletti L, et al; Therapy and Health Economics Group of the European Community Respiratory Health Survey Therapy and Health Economics Group of the European Community Respiratory Health Survey Body mass index, weight gain, and other determinants of lung function decline in adult asthma. J Allergy Clin Immunol. 2009;1235:1069-1074-1074 e1-e4. [CrossRef] [PubMed]
 
Santamaria F, Montella S, Greco L, et al. Obesity duration is associated to pulmonary function impairment in obese subjects. Obesity. 2011;198:1623-1628 [CrossRef] [PubMed]
 
Aaron SD, Fergusson D, Dent R, Chen Y, Vandemheen KL, Dales RE. Effect of weight reduction on respiratory function and airway reactivity in obese women. Chest. 2004;1256:2046-2052 [CrossRef] [PubMed]
 
Spathopoulos D, Paraskakis E, Trypsianis G, et al. The effect of obesity on pulmonary lung function of school aged children in Greece. Pediatr Pulmonol. 2009;443:273-280 [CrossRef] [PubMed]
 
Tantisira KG, Litonjua AA, Weiss ST, Fuhlbrigge AL. Childhood Asthma Management Program Research Group Childhood Asthma Management Program Research Group Association of body mass with pulmonary function in the Childhood Asthma Management Program (CAMP). Thorax. 2003;5812:1036-1041 [CrossRef] [PubMed]
 
Schwarz AG, McVeigh KH, Matte T, et al. Childhood Asthma in New York City. 2008; New York, NY NYC Vital Signs:1-4
 
Egger JR, Bartley KF, Benson L, et al. Childhood Obesity is a Serious Concern in New York City: Higher Levels of Fitness Associated with Better Academic Performance. 2008; New York City NYC Vital Signs:1-4
 
 Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. 2007; Bethesda, MD National Institute of Health, National Heart, Lung, and Blood Institute
 
Miller MR, Crapo R, Hankinson J, et al. ATS/ERS Task Force. General considerations for lung function testing. Eur Respir J. 2005;261:153-161 [CrossRef] [PubMed]
 
Foster B, Prussin C, Liu F, Whitmire JK, Whitton JL. Detection of intracellular cytokines by flow cytometry. Curr Protoc Immunol. 2007; Chapter 6:Unit 6.24.
 
Jung T, Schauer U, Heusser C, Neumann C, Rieger C. Detection of intracellular cytokines by flow cytometry. J Immunol Methods. 1993;1591-2:197-207 [CrossRef] [PubMed]
 
Mayer S, Laumer M, Mackensen A, Andreesen R, Krause SW. Analysis of the immune response against tetanus toxoid: enumeration of specific T helper cells by the Elispot assay. Immunobiology. 2002;2053:282-289 [CrossRef] [PubMed]
 
Movérare R, Elfman L, Stålenheim G, Björnsson E. Study of the Th1/Th2 balance, including IL-10 production, in cultures of peripheral blood mononuclear cells from birch-pollen-allergic patients. Allergy. 2000;552:171-175 [CrossRef] [PubMed]
 
Wang J, Visness CM, Calatroni A, Gergen PJ, Mitchell HE, Sampson HA. Effect of environmental allergen sensitization on asthma morbidity in inner-city asthmatic children. Clin Exp Allergy. 2009;399:1381-1389 [CrossRef] [PubMed]
 
Rastogi D, Reddy M, Neugebauer R. Comparison of patterns of allergen sensitization among inner-city Hispanic and African American children with asthma. Ann Allergy Asthma Immunol. 2006;975:636-642 [CrossRef] [PubMed]
 
Pacifico L, Di Renzo L, Anania C, et al. Increased T-helper interferon-gamma-secreting cells in obese children. Eur J Endocrinol. 2006;1545:691-697 [CrossRef] [PubMed]
 
Watson RA, Pride NB, Thomas EL, et al. Reduction of total lung capacity in obese men: comparison of total intrathoracic and gas volumes. J Appl Physiol. 2010;1086:1605-1612 [CrossRef] [PubMed]
 
Shore SA. Obesity and asthma: lessons from animal models. J Appl Physiol. 2007;1022:516-528 [CrossRef] [PubMed]
 
Cottrell L, Neal WA, Ice C, Perez MK, Piedimonte G. Metabolic abnormalities in children with asthma. Am J Respir Crit Care Med. 2011;1834:441-448 [CrossRef] [PubMed]
 
Mai XM, Böttcher MF, Leijon I. Leptin and asthma in overweight children at 12 years of age. Pediatr Allergy Immunol. 2004;156:523-530 [CrossRef] [PubMed]
 
Yabuhara A, Macaubas C, Prescott SL, et al. TH2-polarized immunological memory to inhalant allergens in atopics is established during infancy and early childhood. Clin Exp Allergy. 1997;2711:1261-1269 [CrossRef] [PubMed]
 
Luder E, Melnik TA, DiMaio M. Association of being overweight with greater asthma symptoms in inner city black and Hispanic children. J Pediatr. 1998;1324:699-703 [CrossRef] [PubMed]
 
Consilvio NP, Di Pillo S, Verini M, et al. The reciprocal influences of asthma and obesity on lung function testing, AHR, and airway inflammation in prepubertal children. Pediatr Pulmonol. 2010;4511:1103-1110 [CrossRef] [PubMed]
 
Chen Y, Rennie D, Cormier Y, Dosman JA. Waist circumference associated with pulmonary function in children. Pediatr Pulmonol. 2009;443:216-221 [CrossRef] [PubMed]
 
Figueroa-Muñoz JI, Chinn S, Rona RJ. Association between obesity and asthma in 4-11 year old children in the UK. Thorax. 2001;562:133-137 [CrossRef] [PubMed]
 
Musaad SM, Patterson T, Ericksen M, et al. Comparison of anthropometric measures of obesity in childhood allergic asthma: central obesity is most relevant. J Allergy Clin Immunol. 2009;1236:1321-1327-, e12 [CrossRef] [PubMed]
 
Arbes SJ Jr, Gergen PJ, Vaughn B, Zeldin DC. Asthma cases attributable to atopy: results from the Third National Health and Nutrition Examination Survey. J Allergy Clin Immunol. 2007;1205:1139-1145 [CrossRef] [PubMed]
 
Miller RL, Ho SM. Environmental epigenetics and asthma: current concepts and call for studies. Am J Respir Crit Care Med. 2008;1776:567-573 [CrossRef] [PubMed]
 
Santamaria F, Montella S, De Stefano S, et al. Asthma, atopy, and airway inflammation in obese children. J Allergy Clin Immunol. 2007;1204:965-967 [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. A, Comparison of CD4+ Th-cell responses to PMA/ionomycin. The bar represents the mean values. Mean IFNγ+ CD4+ Th cells were significantly higher in the obese asthmatic children than in the nonobese asthmatic children and nonobese nonasthmatic children. Mean IL-4+ CD4+ cells were lower in the obese asthmatic children and nonobese nonasthmatic children than in the nonobese asthmatic children. The mean IFNγ/IL-4 ratio was higher among the obese asthmatic children than among the nonobese asthmatic children. B, Comparison of CD4+ Th-cell responses to tetanus toxoid. Mean IFNγ+ CD4+ Th cells were significantly higher in the obese asthmatic children, obese nonasthmatic children, and nonobese nonasthmatic children than in the nonobese asthmatic children. Mean IL-4+ CD4+ cells were lower in the obese asthmatic children than in the nonobese asthmatic children. The mean IFNγ/IL-4 ratio was higher among the obese asthmatic children and obese nonasthmatic children than among the nonobese asthmatic children. C, Comparison of CD4+ Th-cell responses to Dermatophagoides farinae stimulation. Mean IFNγ+ CD4+ Th cells were significantly higher in the nonobese nonasthmatic children than in the nonobese asthmatic children. Mean IL-4+ CD4+ cells were lower in the obese asthmatic children than in the nonobese asthmatic children. The mean IFNγ/IL-4 ratio was higher among the obese asthmatic children than among the nonobese asthmatic children. *P < .05; **P < .01. The bar represents the mean values. IFNγ = interferon-γ; NOA = nonobese asthmatic children; NONA = nonobese nonasthmatic children; OA = obese asthmatic children; ONA = obese nonasthmatic children; Th = T helper.Grahic Jump Location
Figure Jump LinkFigure 2. Correlation between measures of Th1/Th2-cell ratio in response to PMA/ionomycin stimulation and serum. A, Leptin levels. B, IL-6 levels. *Leptin and IL-6 levels were log10 transformed. PMA = phorbol 12-myristate 13-acetate. See Figure 1 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 3. Comparison of pulmonary function tests. A, Spirometry indices. B, Lung volume indices among the four study groups. *P < .05; **P < .01; #P < .001. FEF25-75% = forced expiratory flow 25% to 75%; FRC = functional residual capacity; RV = residual volume; TLC = total lung capacity.Grahic Jump Location
Figure Jump LinkFigure 4. A, Correlation between FEV1/FVC and serum levels of Th1 cytokines, IFNγ, and IP-10. There was significant correlation between FEV1/FVC and serum IP-10 levels. B, Correlation between FEF25075% and serum levels of Th1 cytokines, IFNγ, and IP-10. There was significant correlation between FEF 25075% and both serum IFNγ and IP10 levels. IFNγ and IP-10 levels were log10 transformed. IP-10 = interferon-inducible protein 10. See Figure 1 and 3 legends for expansion of other abbreviations.Grahic Jump LocationGrahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Comparison of Demographics and Anthropometrics Among the Four Study Groups

Data are presented as mean ± SD.

Table Graphic Jump Location
Table 2 —Comparison of Asthma Characteristics Between the Two Asthma Groups

Data are presented as No. (%) or mean (95% CI).

a 

The groups were compared using the χ test for the categorical variables and Student t test for the continuous variables. There were no differences in symptom frequency or medication use between the two asthmatic study groups.

Table Graphic Jump Location
Table 3 —Comparison of Leptin, Th1, and Th2 Cytokine Levels Among the Four Study Groups

Data are presented as mean ± SD. P values indicate comparisons of cytokine values between study groups. All cytokines were log10 transformed. Cytokine levels were compared among the study groups using analysis of variance followed by Bonferroni post hoc analysis in those cytokine comparisons in which analysis of variance was statistically significant. Similar letters in each row of the table denote significant differences in the cytokine values between those two study groups. TNF-α and IL-6 were significantly higher among obese asthmatic children than nonobese nonasthmatic control subjects. IL-4 and IL-13 levels were significantly higher among nonobese asthmatic children than nonobese nonasthmatic children. Further, IL-13 levels among nonobese asthmatic children were higher than those in obese asthmatic children. In keeping with the BMI z score, leptin levels in the obese groups were significantly higher than in their nonobese counterparts. IFN-γ = interferon-γ; IP-10 = interferon-inducible protein 10; Th = T helper; TNF-α = tumor necrosis factor-α.

a 

P < .05.

b 

P < .001.

c 

P < .01.

References

Dixon AE, Holguin F, Sood A, et al; American Thoracic Society Ad Hoc Subcommittee on Obesity and Lung Disease American Thoracic Society Ad Hoc Subcommittee on Obesity and Lung Disease An official American Thoracic Society Workshop report: obesity and asthma. Proc Am Thorac Soc. 2010;75:325-335 [CrossRef] [PubMed]
 
McGinley B, Punjabi NM. Obesity, metabolic abnormalities, and asthma: establishing causal links. Am J Respir Crit Care Med. 2011;1834:424-425 [CrossRef] [PubMed]
 
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Cho SH, Stanciu LA, Holgate ST, Johnston SL. Increased interleukin-4, interleukin-5, and interferon-γ in airway CD4+and CD8+T cells in atopic asthma. Am J Respir Crit Care Med. 2005;1713:224-230 [CrossRef] [PubMed]
 
Huang SL, Shiao G, Chou P. Association between body mass index and allergy in teenage girls in Taiwan. Clin Exp Allergy. 1999;293:323-329 [CrossRef] [PubMed]
 
Guler N, Kirerleri E, Ones U, Tamay Z, Salmayenli N, Darendeliler F. Leptin: does it have any role in childhood asthma? J Allergy Clin Immunol. 2004;1142:254-259 [CrossRef] [PubMed]
 
Nagel G, Koenig W, Rapp K, Wabitsch M, Zoellner I, Weiland SK. Associations of adipokines with asthma, rhinoconjunctivitis, and eczema in German schoolchildren. Pediatr Allergy Immunol. 2009;201:81-88 [CrossRef] [PubMed]
 
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;5611:835-838 [CrossRef] [PubMed]
 
Visness CM, London SJ, Daniels JL, et al. Association of childhood obesity with atopic and nonatopic asthma: results from the National Health and Nutrition Examination Survey 1999-2006. J Asthma. 2010;477:822-829 [CrossRef] [PubMed]
 
Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol. 2010;117:577-584 [CrossRef] [PubMed]
 
Busse WW, Lemanske RF Jr. Asthma. N Engl J Med. 2001;3445:350-362 [CrossRef] [PubMed]
 
Marcon A, Corsico A, Cazzoletti L, et al; Therapy and Health Economics Group of the European Community Respiratory Health Survey Therapy and Health Economics Group of the European Community Respiratory Health Survey Body mass index, weight gain, and other determinants of lung function decline in adult asthma. J Allergy Clin Immunol. 2009;1235:1069-1074-1074 e1-e4. [CrossRef] [PubMed]
 
Santamaria F, Montella S, Greco L, et al. Obesity duration is associated to pulmonary function impairment in obese subjects. Obesity. 2011;198:1623-1628 [CrossRef] [PubMed]
 
Aaron SD, Fergusson D, Dent R, Chen Y, Vandemheen KL, Dales RE. Effect of weight reduction on respiratory function and airway reactivity in obese women. Chest. 2004;1256:2046-2052 [CrossRef] [PubMed]
 
Spathopoulos D, Paraskakis E, Trypsianis G, et al. The effect of obesity on pulmonary lung function of school aged children in Greece. Pediatr Pulmonol. 2009;443:273-280 [CrossRef] [PubMed]
 
Tantisira KG, Litonjua AA, Weiss ST, Fuhlbrigge AL. Childhood Asthma Management Program Research Group Childhood Asthma Management Program Research Group Association of body mass with pulmonary function in the Childhood Asthma Management Program (CAMP). Thorax. 2003;5812:1036-1041 [CrossRef] [PubMed]
 
Schwarz AG, McVeigh KH, Matte T, et al. Childhood Asthma in New York City. 2008; New York, NY NYC Vital Signs:1-4
 
Egger JR, Bartley KF, Benson L, et al. Childhood Obesity is a Serious Concern in New York City: Higher Levels of Fitness Associated with Better Academic Performance. 2008; New York City NYC Vital Signs:1-4
 
 Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. 2007; Bethesda, MD National Institute of Health, National Heart, Lung, and Blood Institute
 
Miller MR, Crapo R, Hankinson J, et al. ATS/ERS Task Force. General considerations for lung function testing. Eur Respir J. 2005;261:153-161 [CrossRef] [PubMed]
 
Foster B, Prussin C, Liu F, Whitmire JK, Whitton JL. Detection of intracellular cytokines by flow cytometry. Curr Protoc Immunol. 2007; Chapter 6:Unit 6.24.
 
Jung T, Schauer U, Heusser C, Neumann C, Rieger C. Detection of intracellular cytokines by flow cytometry. J Immunol Methods. 1993;1591-2:197-207 [CrossRef] [PubMed]
 
Mayer S, Laumer M, Mackensen A, Andreesen R, Krause SW. Analysis of the immune response against tetanus toxoid: enumeration of specific T helper cells by the Elispot assay. Immunobiology. 2002;2053:282-289 [CrossRef] [PubMed]
 
Movérare R, Elfman L, Stålenheim G, Björnsson E. Study of the Th1/Th2 balance, including IL-10 production, in cultures of peripheral blood mononuclear cells from birch-pollen-allergic patients. Allergy. 2000;552:171-175 [CrossRef] [PubMed]
 
Wang J, Visness CM, Calatroni A, Gergen PJ, Mitchell HE, Sampson HA. Effect of environmental allergen sensitization on asthma morbidity in inner-city asthmatic children. Clin Exp Allergy. 2009;399:1381-1389 [CrossRef] [PubMed]
 
Rastogi D, Reddy M, Neugebauer R. Comparison of patterns of allergen sensitization among inner-city Hispanic and African American children with asthma. Ann Allergy Asthma Immunol. 2006;975:636-642 [CrossRef] [PubMed]
 
Pacifico L, Di Renzo L, Anania C, et al. Increased T-helper interferon-gamma-secreting cells in obese children. Eur J Endocrinol. 2006;1545:691-697 [CrossRef] [PubMed]
 
Watson RA, Pride NB, Thomas EL, et al. Reduction of total lung capacity in obese men: comparison of total intrathoracic and gas volumes. J Appl Physiol. 2010;1086:1605-1612 [CrossRef] [PubMed]
 
Shore SA. Obesity and asthma: lessons from animal models. J Appl Physiol. 2007;1022:516-528 [CrossRef] [PubMed]
 
Cottrell L, Neal WA, Ice C, Perez MK, Piedimonte G. Metabolic abnormalities in children with asthma. Am J Respir Crit Care Med. 2011;1834:441-448 [CrossRef] [PubMed]
 
Mai XM, Böttcher MF, Leijon I. Leptin and asthma in overweight children at 12 years of age. Pediatr Allergy Immunol. 2004;156:523-530 [CrossRef] [PubMed]
 
Yabuhara A, Macaubas C, Prescott SL, et al. TH2-polarized immunological memory to inhalant allergens in atopics is established during infancy and early childhood. Clin Exp Allergy. 1997;2711:1261-1269 [CrossRef] [PubMed]
 
Luder E, Melnik TA, DiMaio M. Association of being overweight with greater asthma symptoms in inner city black and Hispanic children. J Pediatr. 1998;1324:699-703 [CrossRef] [PubMed]
 
Consilvio NP, Di Pillo S, Verini M, et al. The reciprocal influences of asthma and obesity on lung function testing, AHR, and airway inflammation in prepubertal children. Pediatr Pulmonol. 2010;4511:1103-1110 [CrossRef] [PubMed]
 
Chen Y, Rennie D, Cormier Y, Dosman JA. Waist circumference associated with pulmonary function in children. Pediatr Pulmonol. 2009;443:216-221 [CrossRef] [PubMed]
 
Figueroa-Muñoz JI, Chinn S, Rona RJ. Association between obesity and asthma in 4-11 year old children in the UK. Thorax. 2001;562:133-137 [CrossRef] [PubMed]
 
Musaad SM, Patterson T, Ericksen M, et al. Comparison of anthropometric measures of obesity in childhood allergic asthma: central obesity is most relevant. J Allergy Clin Immunol. 2009;1236:1321-1327-, e12 [CrossRef] [PubMed]
 
Arbes SJ Jr, Gergen PJ, Vaughn B, Zeldin DC. Asthma cases attributable to atopy: results from the Third National Health and Nutrition Examination Survey. J Allergy Clin Immunol. 2007;1205:1139-1145 [CrossRef] [PubMed]
 
Miller RL, Ho SM. Environmental epigenetics and asthma: current concepts and call for studies. Am J Respir Crit Care Med. 2008;1776:567-573 [CrossRef] [PubMed]
 
Santamaria F, Montella S, De Stefano S, et al. Asthma, atopy, and airway inflammation in obese children. J Allergy Clin Immunol. 2007;1204:965-967 [CrossRef] [PubMed]
 
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