Published ahead of print on February 8, 2008, doi:10.1164/rccm.200711-1738OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200711-1738OC
Dynamic Hyperinflation with BronchoconstrictionDifferences between Obese and Nonobese Women with Asthma1 Respiratory Research Unit, Department of Medical and Surgical Sciences, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand Correspondence and requests for reprints should be addressed to Professor D. Robin Taylor, M.D., Otago Respiratory Research Unit, Dunedin School of Medicine, University of Otago, P.O. Box 913, Dunedin, New Zealand. E-mail: robin.taylor{at}stonebow.otago.ac.nz
Rationale: Symptoms and respiratory function tests may be difficult to assess and interpret in obese patients with asthma, particularly if the asthma is severe. It is unclear whether the dynamic changes that occur during bronchoconstriction differ between obese versus nonobese patients with asthma. Objectives: To explore whether the changes in airway caliber and lung volumes that occur with acute bronchoconstriction are different in obese and nonobese patients with asthma and whether any differences contribute to the quality and intensity of symptoms. Methods: Thirty female patients with asthma were studied. Spirometry, lung volume measurements, and dyspnea scores were obtained before and immediately after bronchoconstriction induced by methacholine, aiming to provoke a reduction in FEV1 of 30%. Measurements and Main Results: Body mass index was independently associated with changes in lung volume after adjustment for baseline airway caliber and hyperresponsiveness. Increases in functional residual capacity and decreases in inspiratory capacity were significantly greater in obese participants (P < 0.001 and P = 0.003, respectively). Conclusions: Changes in respiratory function, notably dynamic hyperinflation, are greater in obese individuals with bronchoconstriction. This may potentially alter the perception and assessment of asthma severity in obese patients with asthma.
Key Words: asthma • hyperinflation • methacholine challenge • obesity
Obesity is known to affect the respiratory system. An important mechanism is via mass loading of the thorax, resulting in a reduction in chest wall compliance and changes in airway resistance (1–3). In individuals without underlying respiratory disease, this can cause reductions in static lung volumes, notably FRC and total lung capacity (TLC). In more severe obesity, there may also be a reduction in FVC with an FEV1/FVC ratio that designates a "restrictive" defect (4–6). Over the last decade, a number of epidemiologic studies have reported an association between obesity and asthma (7), which appears to be stronger in women (8–10). In practice, the coexistence of obesity and asthma makes it increasingly challenging for the clinician to interpret symptoms and simultaneous changes in respiratory function. Cross-sectional studies have shown that, in some patients with asthma, a restrictive spirometric pattern may occur, often but not exclusively associated with obesity (11). Moreover, it has been shown that the effects of obesity and asthma on respiratory function may operate in opposing directions, with "pseudo-normalization" of lung volume measurements in individuals with asthma who are also obese (12). This may be attributable to the effect of adiposity on chest wall recoil. These observations raise the question as to whether dynamic changes in respiratory function are different in obese patients with asthma. Obese patients with asthma may respond differently to inhaled corticosteroids and have symptoms that are more difficult to control (13–15). Given that dyspnea is associated with dynamic hyperinflation after bronchoconstriction (16), and that different pulmonary dynamics operate in obese individuals (2, 4), it is possible that a similar bronchoconstrictor stimulus may give different functional abnormalities in obese patients. To date, no studies have been performed to explore whether the changes in airway caliber and lung volumes that occur with acute bronchoconstriction differ between obese and nonobese patients with asthma, or whether such differences have an impact on asthma symptoms. In this prospective study, we hypothesized that the pattern of changes in respiratory function associated with bronchospasm would differ between these groups. Our aim was to explore this issue by simulating an acute asthma episode using inhaled methacholine to bring about a reduction in the FEV1 of 30%, in a group of subjects with asthma with a range of body mass indexes (BMIs).
For the complete study methods, see the online supplement. Thirty women between 20 and 60 years of age with a diagnosis of asthma were recruited and selected in order to provide a range of BMIs. Each participant's asthma was diagnosed according to international guidelines (17) and each had significant responsiveness to methacholine at screening, defined as a provocative dose causing a 20% reduction in FEV1 (PD20) of less than 8 µmol (steroid naive) or less than 12 µmol (if taking inhaled corticosteroids). Exclusion criteria included the following: current smokers, ex-smokers with a greater than 10–pack-year history of smoking, those receiving oral corticosteroids, and those who had had a respiratory tract infection in the previous 6 weeks. For safety reasons, those with an FEV1 of less than 60% predicted or less than 1.5 L were excluded. All subjects gave written, informed consent, and the study was approved by the Lower South Regional Ethics Committee (Dunedin, New Zealand).
Study Procedures
Methacholine Challenge
Lung Volumes
Dyspnea Scores
Statistical Analysis The relationships between changes in lung volume and BMI after methacholine challenge were explored using multiple linear regression analysis. BMI, as the independent variable, was adjusted for baseline FEV1 and PD20 of methacholine (as surrogates for asthma severity) and the baseline value of the lung volume of interest (to account for baseline differences). Analyses were adjusted for each covariate separately, then in a stepwise manner adding each covariate in descending order of the magnitude of variance. Multiple linear regression analysis was also used to explore the effect of the change in lung volumes on symptoms postmethacholine, with adjustments for baseline percent-predicted FEV1 and BMI. Analyses were performed using Stata version 9.1 (Stata Corporation, College Station, TX).
All patients who were entered completed the study procedures. Demographic details of the study participants, stratified by BMI tertile, are shown in Table 1. There was an increase in the dose of inhaled corticosteroids (expressed as beclomethasone dipropionate equivalent) across the BMI tertiles but this was not statistically significant. The percentage reduction in FEV1 during methacholine challenge and the PD20 methacholine was similar in each tertile.
Change in Respiratory Function after Bronchoconstriction The spirometric measurements obtained before and after methacholine challenge are reported in Table 2, together with the mean changes. The only statistically significant difference was a decrease in post-methacholine VC with increasing BMI (P = 0.017).
The lung volume measurements are reported in Table 3 and Figures 1 and 2. At baseline, FRC was higher, and inspiratory capacity (IC) was lower with increasing BMI, although neither was significant. However, these trends were both highly significant after bronchoconstriction with methacholine (P = 0.002 and P = 0.001, respectively). In absolute terms, the mean increase in FRC was 0.50, 0.70, and 0.80 L, and reduction in IC was 0.45, 0.65, and 0.75 L, for each of the ascending BMI tertiles, respectively. Expiratory reserve volume was also higher with increasing BMI both before and after methacholine challenge, but the changes with bronchoconstriction were not related to BMI.
Multiple linear regression analysis demonstrated that the change in FRC with bronchoconstriction was highly significant when using BMI as a continuous independent variable, and this relationship remained after adjusting for all covariates (see Table 4 and Table E1 of the online supplement). The PD20 methacholine explained most of the variance. The change in IC was only significant after adjustment, with baseline IC providing the greatest source of variance in the association. No relationships were found between BMI and changes in TLC and RV.
Interpretation of Spirometry: Obstruction versus Restriction Using international criteria (22), and after stratifying by the conventional cut point for obesity (BMI  30), 14 of 17 nonobese participants demonstrated an obstructive spirometric pattern at baseline, whereas, among the obese participants, only 6 of 13 demonstrated airway obstruction (P = 0.04 for the difference in proportions). This was despite comparable baseline FEV1 and PD20 values in both groups (P = 0.94 and P = 0.32 for differences, respectively). After the methacholine challenge, all participants demonstrated an obstructive spirometric pattern. No subject had restrictive spirometry before or after methacholine.
Change in Dyspnea Score after Bronchoconstriction
In this study, we have explored whether the response to bronchoconstriction differs in obese and nonobese women with asthma. Our results demonstrate that the dynamic changes that occur during acute bronchoconstriction are significantly influenced by BMI. First, VC, IC, and FRC were all significantly different in obese versus nonobese study participants after methacholine challenge. These differences were not apparent before bronchoconstriction. Second, the increase in FRC and decrease in IC were significantly greater in relation to BMI after adjusting for airway hyperresponsiveness (PD20), the severity of airflow obstruction (FEV1), and lung volume measurements, indicating the effect of BMI was an independent one. Taken together, these results suggest that dynamic changes in respiratory function in response to bronchoprovocation differ significantly in obese individuals. Our data offer a possible mechanism for differences in the perceived severity of asthma in obese patients. A number of researchers have reported that obese patients with asthma may respond differently to inhaled medication (13, 14) and that the severity of asthma is greater (15). These disparities may be related to our finding that, for a similar reduction in airflow, an individual's weight contributes significantly to the development of dynamic hyperinflation. With bronchoconstriction, obese individuals are at a greater mechanical disadvantage due to the presence of enhanced gas trapping, reflected in the increases in FRC, together with reductions in IC. These factors are known to contribute significantly to dyspnea (23). The mechanisms of dynamic hyperinflation in asthma are not well understood. During bronchoconstriction, there is an increase in the sustained postinspiratory activity of the inspiratory muscles, effectively acting as a brake on expiration, which serves to maintain tidal flow and ventilation (23). Why this occurs to a greater degree in obese individuals is not clear. Perhaps the deposition of adipose tissue and the resultant reduction in chest wall compliance (1) alter the response properties of the inspiratory muscles to changes in airway caliber during acute bronchoconstriction. If the baseline FRC was lower in obese patients with asthma, as it is in obese individuals without asthma, the greater change in FRC might be explained by pseudo-normalization of FRC to an equivalent of their nonobese counterparts. However, we found that, rather than having a lower FRC at baseline, the individuals with asthma who were obese had higher levels of FRC than in the nonobese group, and yet still recorded a greater increase in FRC with bronchoconstriction (Table 3). We cannot offer a pathophysiologic explanation for this observation. In the study by Lougheed and colleagues, the various components of dyspnea were shown to be related to dynamic hyperinflation after bronchoconstriction (16). In the present study, the changes in symptoms after methacholine were not significantly different between BMI groups and this may be because the number of subjects in our study was insufficient to explore this issue adequately. Perhaps in a larger population of obese patients with asthma, a clearer picture of the symptomatic consequences of dynamic hyperinflation would have emerged. Apart from the issue of study size, there are a number of important differences between the study by Lougheed and coworkers (n = 116) and the present one (n = 30). To quantify the sensation of dyspnea, Lougheed and colleagues used categorical variables (i.e., the presence or absence of chest tightness), whereas in our study, we recorded only changes in sensation using a visual analog scale. In addition, the magnitude of methacholine-induced bronchoconstriction was greater in the Lougheed study (46% reduction in FEV1). Further investigations are required to identify the extent to which the differences in the magnitude of dynamic hyperinflation with bronchoconstriction observed in obese patients may account for the differences in the perceived severity of their asthma. We studied women only because the effects of obesity on respiratory function differ between the sexes (8–10). Even in the absence of obesity, lung volumes and the mass of respiratory musculature are reduced in women. Although population studies suggest that female subjects have greater dyspnea for a given reduction in FEV1 (24), Lougheed and colleagues failed to identify any sex-related differences in symptoms with methacholine-induced bronchoconstriction (16). Thus, although our study results were obtained in women only, their application may potentially be extended to include men. A further aspect of the present study relates to the use and interpretation of spirometry. The proportion of obese patients who demonstrated abnormal spirometry (n = 22) was significantly less than among nonobese patients (P = 0.04), despite similar degrees of airflow obstruction and airway hyperresponsiveness (P = not significant for the differences between baseline FEV1 and PD20). This suggests that abnormal airway function is less likely to be identified using spirometry in obese individuals. Furthermore, in the absence of lung volume measurements, the important BMI-related differences in the response to bronchoconstriction would not have been clearly identified. Thus, spirometry may have limitations when used to evaluate symptoms in obese patients with asthma, with the potential for misinterpretation. In summary, we have demonstrated significant differences in the changes in respiratory function that occur with bronchoconstriction in relation to obesity. Our results provide new evidence that dynamic hyperinflation is likely to be greater in obese individuals. This may help to explain why asthma severity is perceived to be greater in patients with a high BMI.
The authors thank Drs. Jeffrey Fredberg and Stephanie Shore for their comments on the findings of this study. The authors record with deep sadness that Chris McLachlan, Senior Respiratory Physiologist in the Pulmonary Function Laboratory of Dunedin Hospital, who reviewed the lung volume measurements, died shortly after the acceptance of this manuscript. They are grateful to Associate Professor Peter Herbison for statistical advice.
Supported by the Frances G. Cotter Scholarship awarded by the Dunedin School of Medicine, University of Otago (to T.J.T.S.). This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200711-1738OC on February 8, 2008 Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form November 26, 2007; accepted in final form February 5, 2008
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