Impact of overweight and obesity on acute exacerbations of COPD – subgroup analysis of the Taiwan Obstructive Lung Disease cohort

Introduction

COPD is a significant health burden worldwide and, currently, the seventh leading cause of death in Taiwan.¹ The natural history of COPD is punctuated by exacerbations, defined as acute worsening of symptoms. COPD exacerbations have been shown to be associated with an accelerated decline in pulmonary function, poorer health-related quality of life (HRQL), and higher mortality rate.²

Involuntary weight loss is a common complication in COPD, and between 20% and 70% of patients with COPD have been reported to be underweight depending on the population studied.³ A low body mass index (BMI) and cachexia have been associated with negative outcomes in these patients, independent of the degree of airflow limitation.^4–7 Lin et al⁸ reported that a cross-sectional study in Taiwan indicated that lower BMI is associated with osteoporosis in patients with COPD. However, the impact of overweight and obesity on outcomes in patients with COPD remains controversial. Some studies have reported that overweight or obesity had a protective effect against mortality in patients with COPD,^6,7,9 while others have reported a worse HRQL, increased severity of dyspnea and frequency of severe exacerbations in obese patients with COPD.^10–12 To the best of our knowledge, few studies have explored the relationship between overweight or obesity and the frequency of COPD exacerbations.^12–15

Therefore, the aim of this study was to examine whether overweight and obesity are associated with the frequency of acute exacerbations in patients with COPD in Taiwan.

Patients and methods

Study design and patients

The Taiwan Obstructive Lung Disease (TOLD) study was a retrospective, observational nationwide survey of patients with COPD conducted at 12 hospitals in Taiwan (including seven medical centers and five regional hospitals) from December 2011 through November 2013. All patients enrolled in this survey were >40 years of age with a diagnosis of COPD based on the 2011 GOLD guidelines.¹⁶ The study protocol was reviewed and approved by the individual institutional review board of each center (see ‘Acknowledgment’ section), and all patients provided informed consent.

Data collection

Demographic and clinical data related to COPD were collected, including age, gender, smoking history, concomitant diseases, presence of wheezing, grade and severity of pulmonary function, reversibility of bronchodilator test, modified Medical Research Council (mMRC) dyspnea scale, COPD Assessment Test (CAT) score, exacerbation history, and maintenance pharmacological treatment. BMI was calculated as weight in kilograms divided by the square of the height in meters. BMI cutoff values were adopted as suggested by the Department of Health in Taiwan, including normal (18.5 kg/m² ≤ BMI <24 kg/m²), overweight (24 kg/m² ≤ BMI <27 kg/m²), and obese (BMI ≥27 kg/m²) categories.¹⁷ A wheezing phenotype was defined as the documentation of two or more episodes of wheezing in the medical records during the past 1 year at the time of enrollment. An exacerbation was defined as the prescription of a short course of antibiotics and/or oral steroids or an emergency department visit/hospitalization due to an acute respiratory episode recorded in the medical records during the previous 1 year. A frequent exacerbator phenotype was defined as two or more exacerbations in 1 year.² Spirometry within 6 months at enrollment was acceptable for record. Reversibility in the bronchodilator test was defined as an increase of 12% and 200 mL in forced vital capacity (FVC) or forced expiratory volume in the first second (FEV₁).

Statistical analysis

Continuous parameters were presented as mean ± SD, and categorical parameters were presented as number and percentage. Statistical differences in clinical features between the patients with a BMI <24 kg/m² and those with a BMI ≥24 kg/m² were determined using the chi-square test and Yates correction or Fisher’s exact test for categorical variables and the Student’s t-test for continuous variables where appropriate. The Wilcoxon rank-sum test was used if normal assumption was violated. One-way analysis of variance (ANOVA) or Kruskal–Wallis test was performed for analysis of more than two groups as appropriate. Multivariate logistic regression models were used to clarify the predictors of the frequent exacerbator phenotype (≥2 times/year) in the patients with COPD. All tests of significance were two sided, and a P-value of <0.05 was considered to be statistically significant. All analyses were performed using SPSS 22.0 software (IBM Corporation, Armonk, NY, USA) for Windows.

Results

A total of 1,096 patients with COPD were included in the original TOLD study, and their demographic characteristics are summarized in Table 1. Of these patients, 9.2%, 49.5%, 23.4%, and 17.9% were underweight, normal, overweight, and obese, respectively. The overweight and obese patients (n=452) accounted for 41.2% of all patients.

Table 1 Demographic characteristics of the study population by BMI category (n=1,096) Note: Bronchodilator responder was defined as an increase of 12% and 200 mL in the FEV1 or FVC after bronchodilator drug treatment. Abbreviations: AE, acute exacerbation; BMI, body mass index; CAT, COPD Assessment Test; GOLD, Global Initiative for Chronic Obstructive Lung Disease; mMRC, modified Medical Research Council; SD, standard deviation.

Figure 1 shows the patients with few (0–1 time/year) exacerbations had a significantly higher BMI than those with the frequent exacerbator phenotype (P=0.019). In addition, the patients with a BMI ≥24 had fewer COPD exacerbations than those with a BMI <24, and the lowest rate of exacerbations was observed in the overweight patients, but the differences were not statistically significant (Figure 2). The patients with a higher BMI had a significantly higher rate of comorbidities (Table 2), of which cardiovascular disease, hypertension, diabetes mellitus, ischemic heart disease, and dyslipidemia were the most common.

Figure 1 Frequency of COPD exacerbations in the previous year (overall, P=0.019). Abbreviation: BMI, body mass index.

Figure 2 Frequency of COPD exacerbations by BMI category (overall, P=0.062). Abbreviation: BMI, body mass index.

Table 2 Comorbidities of the study participants Abbreviation: BMI, body mass index.

The results of multivariate logistic regression analysis for the frequent exacerbator phenotype are summarized in Table 3. The wheezing phenotype and a higher mMRC score were positively associated with the frequent exacerbator phenotype, with odds ratios (ORs) of 4.52 (95% confidence interval [CI] 2.84–7.20, P<0.001) and 1.36 (95% CI 1.07–1.73, P=0.011), respectively. In contrast, the overweight and obese patients were inversely related to the frequent exacerbator phenotype (OR 0.49 [95% CI 0.28–0.87], P=0.015, and 0.49 [95% CI 0.26–0.94], P=0.033, respectively).

Table 3 Multivariate logistic regression analysis of the frequent exacerbator phenotype (AE ≥2/year) Abbreviations: AE, acute exacerbation; BMI, body mass index; CAT, COPD Assessment Test; CI, confidence interval; mMRC, modified Medical Research Council; OR, odds ratio.

Discussion

In this study, we retrospectively investigated the relationship between BMI and the frequency of COPD exacerbations in Taiwan. We found that overweight and obese patients with COPD were not uncommon in Taiwan and that these patients were associated with a lower frequent exacerbator phenotype. Moreover, the wheezing phenotype and a higher mMRC score were also related to this phenotype. These findings indicate that a high BMI is a predictor for a better outcome in terms of acute exacerbations in patients with COPD.

The prediction and prevention of COPD exacerbations are important goals in the management of COPD. BMI is an easily accessible parameter for patient assessment and risk stratification. It is well known that underweight increases the risk of mortality in patients with COPD. However, the impact of increased body weight on the outcomes of COPD was not conclusive. Cao et al⁷ conducted a meta-analysis of 22 studies with 21,150 participants and concluded that overweight and obese COPD patients were associated with a lower risk of mortality (risk ratio [RR] 0.47, 95% CI 0.33–0.68, and RR 0.59, 95% CI 0.38–0.91, respectively) than those with a normal BMI. On the other hand, a multicenter prospective cohort study conducted by Lambert et al¹² found that obesity was associated with worse COPD-related outcomes, including HRQL, dyspnea (mMRC score) during a 6-minute walk test, and severe exacerbations of COPD.

The results of our study are similar to a cross-sectional study reported by Cecere et al,¹⁸ which showed a trend toward a lower frequency of COPD exacerbations in overweight or obese patients compared to normal-weight patients. Another study conducted by Jacob et al¹⁴ also showed a lower incidence of hospitalized patient-treated exacerbations in overweight COPD patients. Other studies, however, have reported different results, such as the study of Lambert et al that reported that obesity was associated with severe exacerbations of COPD.¹² The possible explanations for the contradictory results may include differences in ethnicity, obesity levels, comorbidities, and exacerbation types. Ethnic differences may affect the role of obesity due to body fat distribution.¹⁹ In addition, the current study compared overweight/obese patients to normal-weight patients, rather than obese patients to normal/overweight patients in Lambert et al’s study. Furthermore, different cutoff points of obese level may have interfered with the outcomes in these studies. Finally, obesity was only associated with severe but not moderate exacerbations in Lambert et al’s study. However, we did not have data on the severity of the exacerbations. A large prospective cohort study conducted by Colak et al¹⁵ showed that only genetically determined, but not observationally determined, high BMI was associated with an increased risk of recurrent exacerbations and pneumonias in individuals with COPD.

The mechanisms underlying the protection of a higher BMI against COPD exacerbations in this study are unclear. Overweight and obesity have been linked to a better prognosis in patients suffering from various chronic diseases, especially cardiovascular disease, which has been termed the obesity paradox.^20–23 The mechanism responsible for this phenomenon is still unclear.²⁴ Circulating adipokines such as leptin and adiponectin may regulate metabolic and inflammatory systems, which play important roles in obese patients.²⁵ It is well known that most obese individuals have higher levels of serum leptin and lower levels of serum adiponectin compared to non-obese individuals, indicating chronic inflammation in obese patients.²⁶ Krommidas et al²⁷ reported a higher leptin/adiponectin ratio during COPD exacerbations and a lower ratio during the resolution period. However, the significance of the association between adipokines and COPD is still controversial. Wolk et al²⁸ reported that patients with a low BMI with a high leptin/adiponectin ratio and patients with a high BMI with a low leptin/adiponectin ratio were associated with better cardiovascular outcomes, indicating the complexity of the underlying pathophysiology. In addition, cardiorespiratory fitness and physical activity may also have positive effects on reducing deconditioning and play an important role in the obesity paradox.²⁹ In addition, the effects of overweight and obesity on exacerbations may be different in patients with asthma and COPD. A multicenter study of patients presented to the emergency department with asthma exacerbation showed that obese adults were at a higher risk of hospitalization compared with normal-weight adults.³⁰ This may reflect a difference in the perception of dyspnea, or it may reflect an underlying difference in asthma severity between the two groups. In a recent study by Denlinger et al,³¹ patients with exacerbation-prone asthma (>3/year) had a higher BMI than patients with few or no exacerbations.

There are several limitations to this study. First, the data were collected retrospectively, and only 12 hospitals in Taiwan were involved in the recruitment of patients in the TOLD cohort, which may lead to selection bias. However, the selection of the study sites (including medical centers and regional hospitals) and good geographic representation minimized this limitation. Second, a relatively small number of subjects with extreme and morbid obesity in the study population were involved, which may preclude the generalization of our findings to these patients. Third, BMI was used as a sole measurement of obesity in this study. The type of obesity and fat distribution, as well as the amount of visceral fat, were not assessed. Further prospective study is necessary to clarify various anthropometric parameters and their clinical relevance in COPD patients.

Conclusion

Our findings suggest that a higher BMI is a predictor of a better outcome in terms of acute exacerbations in Taiwanese patients with COPD. The lowest frequency of COPD exacerbations was observed in the overweight patients. These findings cannot be extended to patients with extreme or morbid obesity because of the small number of such patients included in this study cohort.

Acknowledgments

The TOLD study received financial support from Novartis Pharmaceuticals Corporation. Data management and statistical analysis were supported by the CRO service division of Formosa Biomedical Technology Corporation. The principal investigators of the TOLD study group included Ming-Shian Lin (Division of Pulmonary and Critical Care Medicine, Chia-Yi Christian Hospital, Chiayi, Taiwan), Shih-Lung Cheng (Division of Thoracic Medicine, Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan and Department of Chemical Engineering and Materials Science, Yuan-Ze University, Taoyuan, Taiwan), Wu-Huei Hsu (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University and China Medical University Hospital, Taichung, Taiwan), Yao-Kuang Wu (Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Tzu Chi Hospital, Taipei, Taiwan), Ning-Hung Chen (Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan), Chao-Hsien Lee (Division of Pulmonary and Critical Care Medicine, Mackay Memorial Hospital, Taipei, Taiwan), Jeng-Yuan Hsu (Division of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan), and Chi-Wei Tao (Department of Internal Medicine, Cheng-Hsin General Hospital, Taipei, Taiwan).

Disclosure

The authors report no conflicts of interest in this work.

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