Persistent and unstable eosinophil levels in the sputum and blood: impact on the clinical prognosis of patients with chronic obstructive pulmonary disease

Introduction

Chronic obstructive pulmonary disease (COPD) shifted from the third to the fourth leading cause of death in 2021 globally (1). COPD is characterized by persistent airflow limitation and is associated with chronic inflammation (2). Eosinophils are important in airway inflammation in patients with COPD (3). Approximately one third of patients with COPD have eosinophilic inflammation (4), and sputum and blood eosinophils are recognized as biomarkers of a beneficial response to inhaled corticosteroids (ICS) in patients with COPD (5,6).

Eosinophilia correlates with poor lung function and an increased acute exacerbation risk (7,8). In the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort study, higher blood eosinophil counts were associated with a more rapid decline in forced expiratory volume in one second (FEV₁) among healthy adults without a history of lung disease (9). However, studies have demonstrated that blood eosinophil levels in patients with COPD and asthma fluctuate over time, regardless of the disease stage or treatment with ICS (10,11). Furthermore, smoking has been shown to affect eosinophilic inflammation in patients with asthma (12), with some studies suggesting both suppression and induction of eosinophilic responses (13,14). In the BODE cohort study of patients with COPD, repeated blood eosinophil measurements revealed that those with persistently high eosinophilic inflammation faced an elevated acute exacerbation risk and higher hospitalization rates (15). However, the Korean Obstructive Lung Disease cohort demonstrated through serial eosinophil assessments that patients with COPD with sustained eosinophilic inflammation exhibited better survival outcomes than those with persistently low eosinophils (16).

A single eosinophil measurement is insufficient to assess prognosis and treatment efficacy in patients with COPD. Previous research has investigated the clinical relevance of variability in peripheral blood eosinophil counts; however, research on the clinical significance of sputum eosinophil variability remains limited, which is attributed to the greater difficulty in obtaining sputum eosinophils than peripheral blood eosinophils. This study aims to investigate the association of eosinophil variability over time with acute exacerbation risk and lung function decline in patients with COPD, combining sputum eosinophil and peripheral blood eosinophil measurements. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1885/rc).

Methods

Study design and patients

This study used data from a prospective longitudinal cohort registered with the Chinese Clinical Trial Registry (ChiCTR1900024643) (17). Baseline data collection was performed between July 2019 and August 2021 across three cities (Guangzhou, Shaoguan, and Heyuan) in Guangdong Province, China, with annual 3-year follow-up data up to September 2024. Participants aged 40–80 years were recruited, excluding those who had experienced myocardial infarction within the past 3 months or myocardial infarction during hospitalization within the past month. Additional exclusion criteria included (I) recent chest, abdominal, or eye surgery within the past 3 months; (II) newly diagnosed or ongoing treatment for tumors; (III) active tuberculosis or ongoing anti-tuberculosis treatment; (IV) mental disorders; (V) cognitive impairment; (VI) high paraplegia; (VII) pregnancy or lactation; (VIII) a history of retinal detachment; and (IX) asthma.

Participants were recruited in community and residents who volunteered for the study were enrolled. COPD was defined as a post-bronchodilator forced expiratory volume in one second to forced vital capacity (FEV₁/FVC) ratio below 0.70 (17). At baseline, all participants completed a questionnaire, spirometry tests (before and after bronchodilator administration), blood laboratory tests, and induced sputum tests. During the annual follow-up visits, the participants underwent spirometry and follow-up questionnaires, with blood laboratory tests and induced sputum tests additionally performed at the third year.

Ethics approval for the study was obtained from the Ethics Committee of The First Affiliated Hospital of Guangzhou Medical University (No. 2018-53). Written informed consent was obtained from all participants prior to enrolment. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Definitions

Eosinophilia was defined as a sputum eosinophil percentage ≥3% (18). Based on the sputum eosinophil percentage, the cohort was divided into three groups, as follows: persistently high sputum eosinophils (≥3%) at baseline and at the third year; unstable sputum eosinophils (fluctuating between ≥3% and <3%) at baseline and at the third year; and persistently low sputum eosinophils (<3%) at baseline and at the third year. Similarly, based on the blood eosinophil count, the cohort was divided into three groups: persistently high blood eosinophils (≥300 cells/µL) at baseline and at the third year; unstable blood eosinophils (fluctuating between ≥300 and <300 cells/µL) at baseline and at the third year; and persistently low blood eosinophils (<300 cells/µL) at baseline and at the third year. Also, the unstable eosinophils group included low-to-high (<3% or <300 cells/µL at baseline, ≥3% or ≥300 cells/µL at the third year) and high-to-low (≥3% or ≥300 cells/µL at baseline and <3% or <300 cells/µL at the third year) sputum/blood eosinophils group.

Questionnaire

The questionnaire was adapted from our previous population-based COPD epidemiological survey (19,20). The questionnaire collected demographic information, COPD risk factors, chronic respiratory symptoms, comorbidities, medication history, and exacerbations experienced in the last year. COPD-related risk factors included smoking history, passive smoke exposure, biomass exposure, occupational exposure, and family history of respiratory diseases. Chronic respiratory symptoms included dyspnea, chronic cough, chronic sputum, and wheezing.

Lung function tests

Prebronchodilator and postbronchodilator function tests were conducted using portable spirometers (Master Screen Pneumo PC spirometer; CareFusion, Yorba Linda, CA, USA) in accordance with the quality control standards outlined in the American Thoracic Society and European Respiratory Society 2005 guidelines (21,22). We used the reference values for lung function provided by the Global Lung Function Initiative equations (23).

Induced sputum

The induced sputum procedure was conducted according to previously published methods (24,25). Sputum induction was achieved through the inhalation of hypertonic saline via an ultrasonic nebulizer. Microscopic examination was used to ensure sample quality, with a requirement of <20% squamous cells. Sputum samples were subjected to mucolysis using 0.1% dithiothreitol, followed by oscillation and ice-bath filtration through 48-µm nylon mesh. Separation of sputum cells from the fluid phase was achieved by centrifugation at 3,000 rpm for 10 minutes. Supernatants were stored at −80 ℃; cell pellets were smeared. ≥400 non-squamous cells differentially were counted, including neutrophils, eosinophils, macrophages, and lymphocytes, using hematoxylin and eosin staining.

Study outcomes

The study outcomes included lung function decline and exacerbation. The participants underwent annual assessments of lung function, both before and after bronchodilator administration. The testing procedures and quality control measures remained consistent throughout the follow-up visits. If a patient experienced an exacerbation during the follow-up period, the collection of lung function data was postponed until 4 weeks after the exacerbation had resolved. If the participants could not attend the site for lung function testing, we conducted a telephone follow-up questionnaire. An exacerbation was defined as the presence or worsening of at least two of the following symptoms: cough, sputum production, purulent sputum, wheezing, or dyspnea, lasting for more than 48 hours, after excluding other potential causes such as congestive heart failure, pulmonary embolism, pneumothorax, pleural effusion, and arrhythmia. For moderate-to-severe exacerbations, the patients required outpatient, emergency, or hospital care, which often involved the use of antibiotics and/or systemic corticosteroids.

Statistical analyses

Continuous variables are presented as the mean ± standard deviation or median (interquartile range), while categorical variables are expressed as frequency (percentage). Group comparisons were performed by analysis of variance for continuous variables and the Chi-squared test for categorical variables, followed by Bonferroni correction for post hoc comparisons. Poisson regression was used to analyze the association of the number of acute exacerbation events per person-year across the three groups, with comparisons made using the persistently low group as the reference using the Bonferroni method. Mixed-effects models for repeated measures were used to identify differences in lung function among the groups across multiple visits. Adjustments were made for confounding variables, including age, sex, body mass index, smoking status, smoking index, biomass exposure, occupational exposure, family history of respiratory diseases, and ICS over 3 months during the 3-year period, frequency of exacerbation prior to last year collected at baseline for Poisson regression and baseline lung function parameter for mixed-effects models, which were associated with progression and adverse outcomes in COPD as adjusted in previous studies (7,8,26). We employed the method of multiple imputation to fill in the missing data.

All statistical analyses were performed using IBM SPSS 27.0 (IBM Corp., Armonk, NY, USA) and SAS 9.4 software (SAS, Cary, NC, USA). A two-sided α of 0.05 was considered statistically significant.

Results

Study recruitment and follow-up

According to study flowchart (Figure 1), 825 participants were from the ECOPD study and 434 were from the screening procedure but did not participate in the ECOPD study. After excluding 26 patients with asthma, 2 who did not undergo blood laboratory tests, and 503 without COPD, 728 patients with COPD were included in this study. Using 3% as the cutoff for sputum eosinophilia, the patients were classified into two groups: the low sputum eosinophils group (n=458) and the high sputum eosinophils group (n=270). Using 300 cells/µL as the cutoff for blood eosinophilia, patients were classified into two groups: low blood eosinophils group (n=557) and high blood eosinophils group (n=171). At the 3-year follow-up, 373 patients underwent induced sputum tests and 420 underwent blood laboratory tests, and we also classified patients into the low sputum/blood eosinophils group and the high sputum/blood eosinophils group.

Figure 1 Flow diagram. To avoid potential interference from asthma patients, we excluded individuals with asthma from our study and we defined COPD as FEV₁/FVC <0.70. We collected sputum/blood eosinophil count at baseline and at 3-year follow-up. COPD, chronic obstructive pulmonary disease; ECOPD, Early Chronic Obstructive Pulmonary Disease; FEV₁/FVC, ratio of forced expiratory volume in one second to forced vital capacity.

Persistently low sputum eosinophils group (n=183) had a sputum eosinophil count <3% at baseline, which persisted at the third year. The unstable sputum eosinophils group (n=122) had an intermittently variable sputum eosinophil count (fluctuating between ≥3% and <3%) at baseline and at the third year. The persistently high sputum eosinophils group (n=68) had a sputum eosinophil count ≥3% at baseline, which persisted at the third year. Similarly, there were three subgroups based on the blood eosinophil counts, including the persistently low blood eosinophils group (n=279), the unstable blood eosinophils group (n=80), and the persistently high eosinophils group (n=61) (Figure 2).

Figure 2 Sankey diagram. There were 183 COPD patients had low sputum eosinophils at baseline and the third year follow-up and 122 patients had variable sputum eosinophils, 68 patients had high sputum eosinophils at baseline and the third year follow-up. Similarly, There were 279 COPD patients had low blood eosinophils at baseline and the third year follow-up and 80 patients had variable blood eosinophils, 61 patients had high blood eosinophils at baseline and the third year follow-up. COPD, chronic obstructive pulmonary disease

Patients’ baseline characteristics

As shown in Table 1, the persistently high sputum eosinophils group (mean age 63.5±7.8 years, 95.6% male) had a higher proportion of patients with dyspnea, higher modified Medical Research Council (mMRC) score, and poorer baseline lung function than the persistently low sputum eosinophils group. The unstable sputum eosinophils group (mean age 65.3±6.8 years, 93.4% male) demonstrated a higher COPD Assessment Test (CAT) score and poorer baseline lung function than the persistently low sputum eosinophils group. There were no statistically significant differences among the three groups in smoking status, smoking index, occupational exposure, biomass exposure, and family history of respiratory diseases.

As shown in Table S1, the persistently high blood eosinophils group had a lower percentage predicted FEV₁ than the persistently low blood eosinophils group. The unstable blood eosinophils group demonstrated a higher CAT score than the persistently low blood eosinophils group.

Exacerbation

The persistently high sputum eosinophils group experienced more exacerbations than the persistently low sputum eosinophils group, with a total exacerbation rate of 0.88 vs. 0.52 per patient-year [adjusted relative risk (RR) 1.47, 95% confidence interval (CI): 1.21–1.80, P<0.001] and a moderate-to-severe exacerbation rate of 0.55 vs. 0.31 per patient-year (adjusted RR 1.62, 95% CI: 1.25–2.10, P<0.001). Moreover, the unstable sputum eosinophils group experienced more exacerbations than the persistently low sputum eosinophils group, with a total exacerbation rate of 0.79 vs. 0.52 per patient-year (adjusted RR 1.47, 95% CI: 1.24–1.75, P<0.001) and a moderate-to-severe exacerbation rate of 0.42 vs. 0.31 per patient-year (adjusted RR 1.29, 95% CI: 1.02–1.63, P=0.03). Similarly, the persistently high blood eosinophils group experienced more exacerbations than the persistently low blood eosinophils group, with a total exacerbation rate of 0.82 vs. 0.61 per patient-year (adjusted RR 1.27, 95% CI: 1.05–1.54, P=0.02). The unstable blood eosinophils group experienced more exacerbations than the persistently low blood eosinophils group, with a total exacerbation rate of 0.78 vs. 0.61 per patient-year (adjusted RR 1.27, 95% CI: 1.07–1.51, P=0.008) and a moderate-to-severe exacerbation rate of 0.46 vs. 0.36 per patient-year (adjusted RR 1.29, 95% CI: 1.03–1.62, P=0.03). However, there was no significant difference between the persistently high blood eosinophils group and the persistently low blood eosinophils group in moderate-to-severe exacerbation, with a rate of 0.46 vs. 0.36 per patient-year (adjusted RR 1.18, 95% CI: 0.91–1.52, P=0.21) (Figure 3).

Figure 3 The frequency of exacerbations in persistently low sputum/blood, unstable sputum/blood and persistently high sputum/blood eosinophils group. Data are shown as the mean (95% CI). The frequency of exacerbations was evaluated for the relative risk using a Poisson regression model over the 3-year follow-up period. The total events occurrences served as the response variable, while the natural log-transformed follow-up duration was considered as an offset variable. The model was adjusted for confounding factors including age, sex, body mass index, smoking status, smoking index, biomass exposure, occupational exposure, family history of respiratory diseases, ICS medication over 3 months during 3-year period and number of exacerbations during the year prior to baseline. CI, confidence interval; ICS, inhaled corticosteroids; RR, relative risk.

The low-to-high sputum eosinophils group had a higher total exacerbation risk (0.96 vs. 0.52 per patient-year, adjusted RR 1.80, 95% CI: 1.47–2.20, P<0.001) and a higher risk of moderate-to-severe exacerbations (0.46 vs. 0.31 per patient-year, adjusted RR 1.41, 95% CI: 1.06–1.88, P=0.02) than the persistently low sputum eosinophils group (Table S2). The high-to-low blood eosinophils group had a higher total exacerbation risk (0.90 vs. 0.61 per patient-year, adjusted RR 1.39, 95% CI: 1.11–1.73, P=0.004) and a higher risk of moderate-to-severe exacerbations (0.57 vs. 0.36 per patient-year, adjusted RR 1.46, 95% CI: 1.10–1.94, P=0.009) (Table S3).

Lung function decline

There was no significant difference in the annual decline in prebronchodilator FEV₁ between the persistently high sputum eosinophils group [26 mL/year (95% CI: 8–43)] and the persistently low sputum eosinophils group [30 mL/year (95% CI: 20–41)], with an adjusted mean difference of −6 mL/year (95% CI: −26 to 16) (P=0.61). Similar findings were observed for post-bronchodilator FEV₁, percentage predicted prebronchodilator FEV₁, and percentage predicted post-bronchodilator FEV₁. Similar findings were observed between the unstable sputum eosinophils group and the persistently low sputum eosinophils group. Moreover, similar results were observed for the blood eosinophils groups (Figure 4).

Figure 4 Lung function decline in persistently low sputum/blood, unstable sputum/blood and persistently high sputum/blood eosinophils group throughout the study. Data are shown as the mean (95% CI). Mixed-effects models were used to identify differences in lung function among groups across multiple visits. The model was adjusted for confounding factors including age, sex, body mass index, smoking status, smoking index, biomass exposure, occupational exposure, family history of respiratory diseases, ICS medication over 3 months during 3-year period and baseline spirometric values (pre or post-bronchodilator FEV₁ or FEV₁% predicted). CI, confidence interval; FEV₁, forced expiratory volume in 1 second; ICS, inhaled corticosteroids.

Discussion

This longitudinal follow-up study is the first prospective cohort study to investigate the effects of dynamic changes in blood or sputum eosinophil counts over time on the clinical outcomes of COPD. Over the 3-year follow-up period, the proportion of patients with COPD with persistently high eosinophils was 14.5% based on sputum analysis and 13.4% based on blood analysis. Persistently high sputum (≥3%) or blood (≥300 cells/µL) eosinophil levels and unstable sputum/blood eosinophil levels were associated with an increased exacerbation risk, but not with lung function decline.

A previous study reported a blood eosinophil stability rate of 75% using a cutoff value of 340 cells/µL (27). Another showed that eosinophil stability ranged between 70% and 85% in patients hospitalized for acute exacerbation of COPD before and after hospitalization using cutoff values of 200 and 300 cells/µL for eosinophil count and 2% and 3% for eosinophil percentage, respectively (28). The few studies that have focused on eosinophils in patients with COPD over time have observed significant instability. In the present study, sputum or blood eosinophil stability was similar to previous research, further corroborating the patterns of eosinophil variability. Eosinophils are influenced by various factors. RNA expression analysis of the sputum or nasal epithelium, along with leukocyte activation markers in the blood/sputum and bacterial/viral load, may help to clarify the origins and fluctuations in eosinophils (29). Indeed, given the significant variability in blood eosinophil levels during follow-up, a single eosinophil measurement is proven unreliable for assessing the prognosis and outcomes of patients with COPD.

Eosinophils have been detected in the airways, tissues, and peripheral circulation of patients with COPD during both stable periods and exacerbations. T helper 2 inflammation, particularly focused on eosinophils, has been associated with the frequency of COPD exacerbations (30). Induced sputum and blood eosinophil levels have been shown to guide ICS therapy and reduce the frequency of acute exacerbations (31,32). The ECLIPSE study found no significant differences in exacerbation frequency based solely on blood eosinophil counts, whereas the SPIROMICS study indicated that sputum eosinophilia is a good predictor of exacerbations in patients with mild-to-moderate COPD (33,34). In the present study, persistently high and unstable sputum eosinophils were related to higher total exacerbation and moderate-to-severe exacerbation risks in patients with COPD, while having persistently high blood eosinophils was not related to the risk of moderate-to-severe exacerbation, and exacerbations increased in the low-to-high sputum eosinophils group, whereas exacerbations increased in the high-to-low blood eosinophils group, we reasoned that blood eosinophils served as a surrogate marker of systemic inflammation while sputum eosinophils could directly reflect airway inflammation. These findings suggest that the blood eosinophil count should not be considered alone when evaluating the frequency of acute exacerbations; sputum eosinophil measurements may be a better biomarker of COPD exacerbation.

ICS together with long-acting bronchodilators, including long-acting β2-adrenoreceptor agonists (LABA) and long-acting muscarinic antagonists (LAMA), were advised for decreasing the risk of exacerbations and improved lung function and health status, while recent studies suggest potential mortality of COPD benefits with triple ICS/LABA/LAMA therapy (35) and compared to LAMA, ICS/LABA, or LAMA/LABA, triple therapy decreased the risk of exacerbations and improved lung function and health status, with a favorable benefit-to-harm ratio (36). Several randomized clinical trials have investigated the efficacy of anti-IL-5 (mepolizumab) and IL-4Rα (dupilumab), in eosinophilic COPD (37). Mepolizumab could safely reduce exacerbations in eosinophilic COPD (38). Phase-III trials METREX and METREO have demonstrated that mepolizumab (100 or 300 mg subcutaneously every 4 weeks for 52 weeks) reduced the annual exacerbation rate by 14–20% in COPD with an eosinophilic phenotype (≥150 eosinophils/µL at screening); similar RCTs were under way with benralizumab (anti-IL-5Rα) and dupilumab (anti-IL-4Rα) (39). Moreover, blood eosinophils ≥150 cells/µL predicted response to biologics in COPD, which found that persistent eosinophilia correlates with higher exacerbation risk and these patients would be ideal candidates for anti-IL-5 therapy, which could reduce annual exacerbation rates by 20–30% (40). In our study, we considered that persistently high blood/sputum eosinophils group, might benefit from ICS/LABA/LAMA triple therapy and anti-IL-5 antibodies to reduce annual exacerbation rates. For unstable group, regular monitoring and flexible treatment adjustment were required, and for persistently low group, primarily with bronchodilators was enough, as ICS benefits appear limited in this population.

In the Copenhagen General Population Study, a longitudinal cohort with a 10-year follow-up period demonstrated that for every 100 cells/µL increase in blood eosinophil count, the annual rate of FEV₁ decline accelerated by 1 mL (95% CI: 0.6–1.4, P<0.001). Notably, the patients with COPD in that cohort exhibited a baseline annual FEV₁ decline of 37 mL/year (41). LeMaster et al. demonstrated that the correlation between the blood eosinophil level and the rate of lung function decline was not statistically significant (42). This finding aligns with previous research documenting that during a 2-year follow-up period, patients with COPD with elevated blood eosinophil levels did not exhibit accelerated annual FEV₁ decline compared with those with lower eosinophil levels (7). The CanCOLD study (43) demonstrated accelerated annual lung function decline over 3 years in both non-COPD and COPD populations with elevated blood eosinophil counts. Our study also had a 3-year follow-up period, but we found that elevated eosinophil levels, whether in the blood or sputum, showed no significant association with lung function decline, which might because our cohort was community-recruited rather than from hospital-based populations and risk factors of COPD in China differed from Western populations, including higher biomass fuel exposure (e.g., crop residues) and significantly lower smoking prevalence among women-factors that might also contribute to the observed discrepancy in results. These epidemiological differences may modulate eosinophil-pathology relationships.

This study has some strengths. This is the first study in China to offer novel insights into eosinophil fluctuations based on sputum measurements to evaluate airway inflammation in COPD. Few studies have explored this area, particularly cohort studies utilizing induced sputum, given the extensive time and financial resources required, which limit the feasibility of this method in the community setting. Moreover, most existing cohort studies have relied on blood eosinophil counts, while our study evaluated the clinical prognosis of patients with eosinophilia based on sputum or blood eosinophil measurements in patients with COPD, and the sample size was reasonably large.

There are several limitations in this study that should be acknowledged. First, a limitation of the present study is that asthma status was ascertained solely by self-report, without spirometric or medical-record validation. Consequently, some misclassification of asthma cases and non-cases may have occurred, which could lead to misdiagnosis and missed diagnosis. Future investigations should incorporate objective measures such as bronchodilator reversibility testing or physician-verified diagnoses to increase diagnostic accuracy. Second, some participants were either unwilling to undergo sputum induction or were unable to expectorate during Visit 3, leading to loss of follow-up data. Third, as the majority of the study participants were recruited from rural areas with generally lower educational attainment, most of them used ICS inconsistently. We would asked them whether they used ICS, how they used it and for long at annual follow up. We used ICS medication over 3 months to quantify ICS exposure to avoid selection bias which affected the key clinical outcomes. Finally, there were only two time points to collect sputum and blood eosinophils, which might potentially cause misclassification of the true long-term eosinophilic phenotype because eosinophil levels variability were influenced by factors such as infection, smoking status, seasonality, and ICS use.

Conclusions

Patients with COPD demonstrated variability in sputum and blood eosinophil levels. Persistently high eosinophil levels and unstable eosinophil levels based on sputum or blood measurements did not confer annual lung function decline among patients with COPD, but they were associated with a higher risk of COPD exacerbation. This study has unveiled the prognostic value of eosinophil fluctuations in patients with COPD, providing important insights for clinical practice.

Acknowledgments

We thanked all the participants who participated in the study. We would like to express our appreciation to Shan Xiao, Youlan Zheng, Huajing Yang, Peiyu Huang, Bijia Lin, Shaodan Wei, Xiaopeng Ling, Heshen Tian, Zihui Wang (State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University), Jianhui Huang and Xiangwen Luo (Lianping County People’s Hospital) for their effort in collecting and verifying the data.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1885/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1885/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1885/prf

Funding: This work was supported by Foundation of Guangzhou National Laboratory (grant numbers SRPG22-018 and SRPG22-016), the Clinical and Epidemiological Research Project of State Key Laboratory of Respiratory Disease (grant number SKLRD-L-202402), and Major Clinical Research Project of Guangzhou Medical University’s Scientific Research Capability Improvement Plan (grant number GMUCR2024-01012), the National Natural Science Foundation of China (82570065), Zhongnanshan Medical Foundation of Guangdong Province (grant number ZNSXS-20250019), and Noncommunicable Chronic Diseases-National Science and Technology Major Project (grant number 2024ZD0528400).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1885/coif). All authors report that this work was supported by Foundation of Guangzhou National Laboratory (Nos. SRPG22-018 and SRPG22-016), the Clinical and Epidemiological Research Project of State Key Laboratory of Respiratory Disease (No. SKLRD-L-202402), and Major Clinical Research Project of Guangzhou Medical University’s Scientific Research Capability Improvement Plan (No. GMUCR2024-01012), Zhongnanshan Medical Foundation of Guangdong Province (No. ZNSXS-20250019), and Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2024ZD0528400). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Ethics approval for the study was obtained from the Ethics Committee of The First Affiliated Hospital of Guangzhou Medical University (No. 2018-53). Written informed consent was obtained from all participants prior to enrolment. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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