In this study of inner-city adolescents with asthma, we have provided an extensive analysis of the relationship between obesity and asthma morbidity using a prospective, well-characterized and closely-monitored cohort. Our major finding is that, as in the case between asthma prevalence and obesity,19, 20
gender has substantial influence on the relationship of adiposity to asthma morbidity. In female adolescents only, increased BMI and body fat were associated with worse asthma control, more asthma exacerbations, and lower FEV1
/FVC. In males, we report another novel finding, a protective role of serum adiponectin on the same parameters, independent of adiposity. Notably, these effects were observed despite good adherence to guideline-based management.37
Our study is also the first to provide information on the relationship between adiposity measures other than BMI and asthma morbidity and to examine the relationship of serum adipokines to asthma control and measures of airway inflammation.
Adiponectin is produced exclusively by adipocytes; however, circulating levels decrease with increasing adiposity.25
This protein has anti-inflammatory properties.41–43
It acts on macrophages and monocytes to inhibit production of pro-inflammatory cytokines and to augment IL-10 and IL-1 receptor antagonist expression.44
Despite higher serum levels of adiponectin in females, the protective effect was seen in males only. The sex-specific effect of adiponectin was not explained by the ratio of leptin to adiponectin, which is significantly different in males and females. A possible explanation may be that adiponectin receptors are down regulated with increased adiposity in adolescent females. In a study evaluating asthma prevalence, adiponectin was found to be protective against current asthma prevalence in pre-menopausal women independent of BMI.27
The reported protective effects of adiponectin in human studies are consistent with mouse studies where exogenous administration of adiponectin resulted in an almost complete suppression of allergen-induced airway hyper-reactivity, airway inflammation, and TH
2 cytokine expression in the lung.45
In contrast, leptin was associated with poorer asthma control, but an independent effect could not be demonstrated because of the high correlation between adiposity measures and leptin. The role of adiponectin in asthma warrants further study and may have implications for therapy.
Adipocytes and macrophages that infiltrate adipose tissue are important sources of inflammatory cytokines.46
It has been hypothesized that high levels of pro-inflammatory molecules released from adipose tissue into the systemic circulation could contribute to airway inflammation and increase asthma severity.47
However, Sutherland et al. found that although systemic and airway inflammation were present in obesity and asthma, there was no evidence of interaction between the two.48
In our study, the markers of systemic inflammation generally increased with increasing BMI or percent body fat in both genders with females having higher levels than males. However, the markers did not correlate with asthma morbidity. In the absence of bronchial lavage to directly measure cytokines, we cannot determine the association of adiposity with these markers of airway inflammation. However, we demonstrated no correlation of adiposity and serum leptin with FENO
. This supports the possibility that adipokines may be related to asthma by a mechanism unrelated to inflammation.
The relationship between obesity and asthma severity as classified in published asthma guidelines is controversial. Obesity was associated with severity as classified by Global Initiative for Asthma guidelines among adults in the National Asthma Survey in the USA,17
but not in the European Community Respiratory Health Survey49
or a Canadian sample of asthmatics.11
The impact of increasing body weight on asthma control or response to therapy is not consistently reported in the literature. Elevated BMI has been associated with increased symptoms or health care use for asthma attacks among 3 to 5 year olds in Head Start,50
inner-city children 4 to 9 years old,9
and adults in the National Asthma Survey.17
In the Childhood Asthma Management Program cohort there was no correlation between BMI and markers of asthma control. However, these children were pre-pubertal, and median BMI was much lower than in our study.51
A cross-sectional study of urban adults with asthma found no differences in asthma control as measured by 4 validated asthma control questionnaires with changes in BMI.52
In a recent study comparing obese and non-obese adult asthmatics presenting to emergency rooms, the severity of the asthma exacerbations were found to be similar.12
Responsiveness to asthma treatment shows a similar ambiguity. Secondary analyses performed on participants 18 years of age and older from 5 clinical trials found obese asthmatics (BMI >=40) have a lower response to inhaled corticosteroids (ICS) or ICS combined with a long acting beta agonist.53
In a study of 18 to 50 year olds seeking treatment in an ER, heavier patients (BMI >=25) had more residual wheezing and a higher hospitalization rate.54
A review of the hospitalization course for asthmatics 2 to 18 years of age admitted to an ICU found obese (BMI >=95th
%) had longer treatment and hospital stays despite similar severity at presentation.55
In contrast, for inner-city asthmatics 2 to 18 years of age participating in the Breathmobile project, obesity (BMI >=95th
%) had no impact on the ability to achieve or maintain asthma control.56
Failure to adequately measure or standardize therapy limits the interpretability of these studies. The design of the ACE study included guidelines-based standardized treatment for all participants and therefore addressed these limitations of previous studies.
Reported differences between males and females in the effect of body size on asthma have been called into question due to methodological and statistical concerns about the studies.57, 58
Our findings demonstrate that in females, asthma control, asthma exacerbations and FEV1
/FVC are adversely affected by increasing BMI and percent body fat. The increased morbidity and subsequent treatment found in obese females was not associated with increased atopy or FENO
.. Our results are consistent with studies in adults.48, 59
This raises two potential explanations, namely, that increased asthma morbidity is a result of a mechanism other than atopy and inflammation, or that there is a difference in the perception of asthma symptoms among obese females.
Other studies have suggested a difference in perception and reporting of symptoms among obese asthmatics to account for the increased asthma severity. Asthmatic children ages 8 to 12 years who were obese or overweight as defined by BMI reported greater limitation of physical activity than their normal weight peers, yet they had similar maximum aerobic power and levels of habitual activity.60
Despite similar levels of severity, obese asthmatics reported lower quality of life scores.11
Secondary analyses from clinical trial participants found obese asthmatics report a lower response to placebo.61
Further supporting the possibility of perception differences, bronchial reactivity to methacholine has been found to be equivalent51, 62
among obese asthmatics when compared to lower weight subjects. These studies do not find that this difference in perception is limited to females, and therefore they do not provide an explanation for the gender differences found in this study.
Among children and adolescents, previous studies have reported that an increase in BMI is accompanied by a higher FEV1
and FVC but a lower FEV1
/FVC in both non-asthmatics64, 65
This effect may reflect the failure of airway size to increase proportionately to lung volume. The impact of increasing body size on pulmonary function seen in this study is consistent with the previous literature.
The question that arises from previous studies that examined the relationship between asthma and obesity is whether BMI, the most commonly used index of adiposity, is an adequate measure. A similar BMI represents a differing level of percent body fat depending on the gender, race, or sexual maturity of the child\adolescent.66
Our study provides a unique opportunity to examine the relationship between BMI and DEXA measurements of overweight and body fat. The measures were highly correlated in both males and females. While BMI alone has limitations in assessing the true degree of adiposity of an individual child,29
more sophisticated measures provided little additional value in studies relating adiposity to asthma outcomes in African-American and Hispanic adolescents.
The strength of this study is that it combines multiple measures of adiposity with adipokines and prospectively evaluates asthma outcome. By limiting our study to adolescents, it addresses the criticism that conflicting gender effects found in obesity studies do not take into account overlapping periods of development.58
The effects of BMI in females and adiponectin in males on asthma control were seen despite optimal guideline-based management.
Our study has a number of limitations. We measured circulating, but not airway, measures of adipokines and cytokines. It is possible that levels in bronchoalveolar lavage would give additional information on the relationship between asthma morbidity and adiposity. Secondly, the improved control of asthma over the 42-week study period would tend to minimize the differences between obese and non-obese asthmatics. Finally, despite the design of the ACE study, with its uniform comprehensive follow-up, data collection, and standardized treatment, it does not eliminate the possibility that perceptional differences in symptom reporting influenced our results.
In summary, our data support a gender-specific role for adipokines produced by adipose tissue in asthma morbidity as measured by symptoms, pulmonary function, and exacerbations but not reflected in other indicators of airway inflammation. Asthma outcome is adversely affected by adiposity in females but not males; whereas for males, but not for females, adiponectin has a protective effect independent of adiposity.
The implications of this study are highlighted by the high prevalence of those at risk for overweight in this inner-city population of predominantly black and Hispanic adolescents. Future therapeutic approaches for asthma are more likely to succeed if gender and body size are taken into account. Further investigations into the roles of adipokines in asthma morbidity may have particular relevance to the high risk inner city populations.