The clinical characteristics and treatment response of patients with chronic obstructive pulmonary disease with low body mass index

Background: This study aimed to analyze the clinical characteristics and treatment response of patients with chronic obstructive pulmonary disease (COPD) with low body mass index (BMI). Methods: In this cross-sectional study, we enrolled patients with stable COPD from the database setup by the Second Xiangya Hospital of Central South University. We classified the patients into three groups based on BMI: low-BMI (<18.5 kg/m2), normal-BMI (≥18.5 and <24.0 kg/m2), and high-BMI (≥24 kg/m2) groups. We defined clinically important deterioration (CID) as a COPD Assessment Test (CAT) score increase of ≥2 and minimum clinically important difference (MCID) as a CAT score decrease of ≥2 during 6 months of follow-up. We recorded the number of exacerbations and mortality during 1 year of follow-up. Results: A total of 910 COPD patients were included with 144 (15.8%) patients in low-BMI, 475 (52.2%) in normal-BMI, and 291 (32.0%) in high-BMI groups. Patients with low BMI had worse pulmonary function, higher symptom scores, and exacerbations in the past year compared with normal- and high-BMI groups (p < 0.05). Logistic regression analysis revealed that age, Global Initiative for Chronic Obstructive Lung Disease grades 3 and 4, and hospitalizations in the past year were independent risk factors for patients with low BMI (p < 0.05). After 1 year of follow-up, patients with low BMI had higher mortality and number of hospitalizations. Patients with low BMI were more likely to attain CID and less likely to attain MCID compared with patients with high BMI (p < 0.05). In addition, patients with low BMI treated with long-acting β2-agonist (LABA)+long-acting muscarinic antagonist (LAMA) and LABA+LAMA+inhaled corticosteroid (ICS) were more likely to attain MCID than those treated with LABA+ICS and LAMA (p < 0.05). Conclusion: COPD patients with low BMI had worse pulmonary function, higher symptom scores, and higher risk of future hospitalizations and mortality and were less likely to attain MCID and more likely to attain CID. It is worth noting that patients with low BMI treated with LABA+LAMA and LABA+LAMA+ICS were more likely to attain MCID than those treated with LABA+ICS and LAMA.


Introduction
Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory disease. It has high morbidity and mortality and exerts huge burden on societies. COPD has become the third leading cause of death (GBD Chronic Respiratory Disease Collaborators, 2020). Thus, treatment and prevention are urgent.
Body mass index (BMI), calculated as the weight in kilograms divided by the square of the height in meters (kg/m 2 ), is an important indicator to evaluate nutritional status. In fact, BMI plays an important role in the pathophysiology of COPD and is an independent prognostic factor for mortality and severity of COPD (Yang et al., 2010). Putcha et al. (2022) showed that COPD patients with low BMI (<20 kg/m 2 ) had worse pulmonary function and higher risk of future severe exacerbation and mortality. In addition, low BMI (<20 kg/m 2 ) is associated with higher risk of first acute COPD admission (Hunter et al., 2016). In fact, the BMI classification standard established by the World Health Organization is not completely suitable for the Chinese population. In China, BMI <18.5 kg/m 2 is defined as underweight (Ran et al., 2007). A study from Taiwan demonstrated that overweight patients had a lower frequency of exacerbation in the past year compared with patients with normal BMI (18.5-23.9 kg/m 2 ). However, patients with low BMI (<18.5 kg/m 2 ) did not show a higher frequency of exacerbation compared with patients with normal BMI (Wei et al., 2017). Currently, the clinical characteristics and treatment response of COPD patients with low BMI have not been completely described in the Chinese population.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) documents recommend that the aim of COPD management is to reduce the symptoms and future risk of exacerbation and mortality. Currently, long-term medications including long-acting muscarinic antagonist (LAMA), long-acting β2-agonist (LABA)+inhaled corticosteroid (ICS), LABA+LAMA, and LABA+LAMA+ICS are the first choice for the treatment of patients with COPD (GOLD Executive Committee, 2023). However, it is unclear whether the treatment response differs among different inhalation therapies including LAMA, LABA+ICS, LABA+LAMA, and LABA+LAMA+ICS in COPD patients with low BMI.
Therefore, the purpose of this study was to analyze the clinical characteristics and treatment response of COPD patients with low BMI in the Chinese population and to explore the relationship between treatment response and different inhalation therapies in patients with low BMI.

Study participants
This was a multicentric and cross-sectional study. All subjects were from the outpatient COPD database (Register number ChiCTR-POC-17010431) that includes the Second Xiangya Hospital of Central South University, Zhuzhou Central Hospital, the Hunan Prevention and Treatment Institute for Occupational Diseases, the First Attached Hospital of Shaoyang University, the Eighth Hospital in Changsha, and Longshan Hospital of Traditional Chinese Medicine (Hunan, China). The patients had been diagnosed with COPD between December 2016 and November 2021 according to the GOLD 2017 documents: the ratio of the forced expiratory volume in one second to forced vital capacity (FEV1/FVC) was <0.70 after inhaling a bronchodilator (Vogelmeier et al., 2017). Patients with asthma, lung cancer, pneumonia, bronchiectasis, tuberculosis, obstructive sleep apnea, diabetes, hormonal disorder, hypertension, and severe heart, liver, or kidney disease were excluded from this study.
This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Second Xiangya Hospital of Central South University (Hunan, China). All patients provided written informed consent.

Data collection
Data including age, sex, education level, BMI, smoke history, FEV1 % pred, FEV1/FVC, GOLD grades, GOLD groups, COPD Assessment Test (CAT) scores, modified Medical Research Council (mMRC) scores, exacerbations and hospitalizations in the past year, and inhalation therapy regimens were collected at the patients' first visit. At 6 months of follow-up, the CAT scores were recorded. The number of exacerbations, hospitalizations, and deaths was recorded during 1 year of follow-up.

Study procedures
According to the BMI (weight in kilograms divided by the square of the height in meters) at their first visit, the patients were classified into three groups (Ran et al., 2007), namely, low-BMI (<18.5 kg/m 2 ), normal-BMI (18.5-23.9 kg/m 2 ), and high-BMI (≥24 kg/m 2 ) groups. Then, the patients with low BMI were classified into the LAMA, LABA+ICS, LABA+LAMA, and LABA+LAMA+ICS subgroups based on the inhalation therapy they received at their first hospital visit.

Treatment assessment
The minimum clinically important difference (MCID) and clinically important deterioration (CID) response rates, future exacerbation, and mortality were used to evaluate the effectiveness of the therapy. CID was defined as a CAT score increase of ≥2, while MCID was defined as a CAT score decrease of ≥2 during 6 months of follow-up (Kon et al., 2014).

Variable definition
An exacerbation is COPD progression that requires antibiotics, oral corticosteroid, or hospitalization (Vogelmeier et al., 2017). According to the GOLD 2017 documents, patients with COPD assigned to group A show 0 to 1 exacerbation per year, no hospitalization, a CAT score of <10, and/or an mMRC score of 0-1. Group B shows 0-1 exacerbation per year, no hospitalization, a CAT score of ≥10, and/or an mMRC score of ≥2. Group C shows ≥2 exacerbations or ≥1 hospitalization per year, a CAT score of <10, and/or an mMRC score of 0-1. Group D shows ≥2 exacerbations or ≥1 hospitalization per year, a CAT score of ≥10, and/or an mMRC score of ≥2 (Vogelmeier et al., 2017). A current smoker has had a smoking exposure of ≥10 packyears, while an ex-smoker has had an exposure of ≥10 pack-years but had not smoked for more than 6 months (Song et al., 2021).

Statistical analysis
SPSS Statistics Version 26.0 (IBM, Armonk, NY, USA) and Free Statistics software version 1.7.1 (Beijing, China) were used for statistical analysis of the data. Continuous variables are expressed as the mean ± standard deviation or median and interquartile range (IQR). Continuous variables with a normal distribution and homogeneity of variance were analyzed with the analysis of variance; otherwise, non-parametric tests were used. The chi-squared test or Fisher's exact test was used to analyze categorical variables. Propensity score matching (PSM) was conducted by using package R 2.15.3 (http://www.R-project. org). Adjusted odds ratio (aOR) and adjusted 95% confidence interval Frontiers in Pharmacology frontiersin.org 05 (a95% CI) were calculated by using logistic regression. A value of p < 0. 05 was considered to be statistically significant.

Results
Clinical characteristics of the patients A total of 910 patients with COPD were enrolled in this study (Figure 1). The mean age was 64.7 ± 8.3 years, and the majority were male (86.8%). The patients were assigned to low-BMI (15.8%), normal-BMI (52.2%), and high-BMI (32.0%) groups (Table 1).
As shown in Table 2, the COPD patients with low BMI had lower FEV1 %pred and FEV1/FVC and higher CAT scores, mMRC scores, number of exacerbations and hospitalizations in the past year compared with patients with normal BMI and high BMI (p < 0.05). In addition, the low-BMI group had a higher proportion of patients in GOLD grade 4, group D, exacerbations in the past year (≥2 times per year), and hospitalizations in the past year (≥1 time per year) and a lower proportion of GOLD grades 1-2 (p < 0.05).

Treatment response in different BMI groups after propensity score matching
After PSM, there were 96 (25.8%) patients in the low-BMI group, 183 (49.2%) patients in the normal-BMI group, and 93 (25.0%) patients in the high-BMI group. The baseline clinical characteristics showed no significant differences (Table 4).
As shown in Table 5, patients in the low-BMI group were less likely to attain MCID (53.9% vs. 69.6% and p < 0.05) and more likely to attain CID (27.0% vs. 12.0% and p < 0.05) compared with the high-BMI group. In addition, the future risk of hospitalizations and mortality in the low-BMI group was higher than in the normal-and high-BMI groups (p < 0.05).

Treatment response among different inhalation therapies in patients with low BMI
Considering the poor treatment response of patients with low BMI, we further explored which inhalation drug would be better for patients with low BMI. A total of 137 patients with low BMI were classified into the LAMA (n = 33, 24.1%), LABA+ICS (n = 11, 8.0%), LABA+LAMA (n = 29, 21.2%), and LABA+LAMA+ICS (n = 64, 46.7%) subgroups after adjusting for sex, age, education level, smoke history, FEV1 %pred, CAT and mMRC scores, and exacerbations in the past year. Patients with low BMI treated with LABA+LAMA and LABA+LAMA+ICS were more likely to attain MCID than those treated with LAMA and LABA+ICS (p < 0.05). However, there were no significant differences in CID, future exacerbations, and mortality among the different inhalation therapies (Table 6; Table 7; Table 8).

Discussion
BMI is used as an indicator to assess the nutritional status of patients and is related to the prognosis of the diseases including COPD (Girón et al., 2009;Lainscak et al., 2011;Chen et al., 2018). Therefore, to prevent and treat COPD patients more effectively, it is necessary to explore the relationship between BMI and COPD. We found that the proportion of low-BMI patients accounted for 15.8%, which was higher than that in previous studies. This might be associated with the socioeconomic conditions in the previous year in China. In addition, Putcha et al. (2022) found that baseline FEV1 % pred and FEV1/FVC were lower in patients with low BMI. In the present study, we also found that patients with low BMI had worse pulmonary function. Unlike the study of Wei et al. (2017), in our study, patients with low BMI had higher number of exacerbations and hospitalizations in the past year. This difference might be because we excluded comorbidities including cardiovascular disease, hypertension, diabetes, and dyslipidemia from this study. Indeed, overweight has been linked to a better prognosis in patients with various chronic diseases, especially cardiovascular diseases, a phenomenon that has been termed the obesity paradox (Lavie et al., 2009). Furthermore, several independent risk factors for COPD patients with low BMI were identified including age, GOPD grades, and the number of hospitalizations in the past year.
Symptoms including cough, phlegm, chest tightness, dyspnea, and sleep impairment confer huge burdens to patients (Miravitlles and Ribera, 2017). In this study, CAT scores served as an indicator to assess whether the symptoms improved or deteriorated during the 6 months of follow-up. In fact, previous systematic reviews have confirmed the reliability and validity of CAT scores and have concluded that the tool is responsive to interventions. Furthermore, the correlation between CAT and St George's Respiratory Questionnaire (SGRQ) scores is typically quite high, which has also been demonstrated (Gupta et al., 2014). Two or more patient-reported outcome measures such as CAT, SGRQ, and Evaluating Respiratory Symptoms are more suitable for randomized controlled trials. A single CAT score for assessing symptoms is more operable in real-world clinical practice and has been used in previous studies (Buhl et al., 2018;Cheng et al., 2021;Lin et al., 2023). In addition, exacerbation and mortality are important events of deterioration in patients with COPD (Flattet et al., 2017;Dong et al., 2020). Reducing the symptoms and risk of exacerbation and mortality are the main goals in the treatment of COPD patients. In the present study, patients with low BMI had a higher future risk of hospitalizations and mortality during 1 year of follow-up. The CAT score is responsive to short-term changes in patients with COPD, including MCID and CID, indicating whether the symptoms have improved and deteriorated (Kon et al., 2014). Our study is the first to demonstrate that COPD patients with low BMI had a lower MCID response rate and a higher CID response rate compared with high-BMI patients. Overall, the patients with low BMI had worse treatment response.
Inhalation drugs are the main treatment used to reduce symptoms and risk of exacerbation and mortality and to improve the health status of patients with COPD. Currently, LAMA, LABA+LAMA, LABA+ICS, and LABA+LAMA+ICS are the most used treatment regimens (Nici et al., 2020;Song et al., 2021). We have previously found that patient with low BMI had a poor treatment response, but which inhalation drug would be better for low-BMI patients was uncertain. Our study is the first to show that patients with low BMI treated with LABA+LAMA and LABA+LAMA+ICS are more likely to attain MCID than those treated with LABA+ICS and LAMA. However, there were no significant differences in future exacerbations and mortality among different inhalation therapies in patients with low BMI. This finding is different from the ETHOS/KRONOS study (Ferguson et al., 2018;Singh et al., 2022), perhaps because our core focus was COPD patients with low BMI patients. Taken together, our findings indicate that it might be more appropriate to provide LABA+LAMA or LABA+LAMA+ICS as the initial inhalation therapy for COPD patients with low BMI. This study has limitations. As recommended by the GOLD documents, non-pharmacological treatment including pulmonary rehabilitation, vaccination, and oxygen therapy is another method to reduce the symptoms and future risk of exacerbations for stable COPD patients and was not accounted for in this study. In fact, we have previously found that relatively few patients with COPD were receiving nonpharmacological treatment (Zeng et al., 2020). So, we do not believe that non-pharmacological treatment would have had a significant impact on the results of this study. In addition, this was a real-world and cross-sectional study. We included as many patients as possible who had completed the 1-year follow-up to obtain the data on exacerbation, mortality, and CAT scores. Therefore, we did not use power analysis to determine the sample size.

Conclusion
COPD patients with low BMI had worse pulmonary function and higher symptom scores and number of exacerbations in the past year. Several independent risk factors for patients with low BMI were identified including age, GOLD grades, and hospitalizations in the past year. In addition, patients with low BMI had a higher risk of future hospitalizations and mortality and were less likely to attain MCID and more likely to attain CID. It was worth noting that patients with low BMI treated with LABA+LAMA and LABA+LAMA+ICS were more likely to attain MCID than those treated with LABA+ICS and LAMA.

Data availability statement
The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation.

Ethics statement
The studies involving human participants were reviewed and approved by the Second Xiangya Hospital of Central South University. The patients/participants provided their written informed consent to participate in this study.