Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by persistent respiratory symptoms and airflow limitations,1 leading to increased morbidity and mortality.2 The use of biomarkers in COPD can help stratify patients, enhancing management and improving prognoses.3 The Global Initiative for Chronic Obstructive Lung Disease (GOLD) report recommends using high blood eosinophil count (BEC) as a criterion to identify individuals who are most likely to benefit from inhaled corticosteroid treatment,4 making this a useful biomarker for guiding therapeutic decisions.5–7

In recent years, there has been an increase in research on the clinical characteristics and outcomes of patients with high BEC, yet the findings have been inconsistent. The Evaluation Of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort demonstrated that patients with high BEC had better baseline health status, including higher forced expiratory volume in 1 second (FEV1), and lower St. George's Respiratory Questionnaire and modified Medical Research Council (mMRC) scores.8 Analysis of data from a Copenhagen general population study indicated an elevated risk of exacerbations in patients with high BEC, aligning with results from other population-based studies.9–11 Furthermore, a Canadian study found a correlation between high BEC and an increased risk of lung function decline and undetected structural airway abnormalities.12 The variability in these results may be attributed to differences in the characteristics of the study population. However, to our knowledge, there have been no studies examining the clinical characteristics and outcomes of patients with high BEC within Chinese communities. Factors such as obesity, smoking status, use of biomass fuels, and exposure to particulate matter differ significantly in the Chinese population compared with other countries.13–16 These differences suggest that the clinical characteristics and outcomes of COPD patients with high BEC in China may differ from those in other regions. Therefore, investigating these characteristics and outcomes in Chinese communities is crucial to develop a sound theoretical foundation for the precise and effective management of COPD.

In light of this, we conducted an analysis using data from a prospective, observational cohort study in a Chinese community population. Our aim was to explore the clinical characteristics and 2-year outcomes of patients with high BEC, in comparison with those with low BEC.

Fig. 1 presents a flowchart of the study. Initially, 2055 subjects completed a respiratory epidemiology questionnaire and underwent spirometry. Of these, 33 had unavailable BEC, leaving 2022 subjects with BEC results. Subsequently, 1125 subjects with normal spirometry were excluded, resulting in 897 patients with spirometry-defined COPD included in the final analysis. Among these patients, 692 (77.1%) had a BEC of less than 300cells/μL, while 205 (22.9%) exhibited a BEC of 300cells/μL or more.

Fig. 1.

Study flowchart.

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Decline in Lung Function and Risk of Acute Exacerbation

In this cross-sectional analysis of 897 patients, 771 (86.0%) – 591 with high BEC and 180 with low BEC – completed a follow-up questionnaire interview. A subset of 679 patients (75.7%), comprising 523 with high BEC and 156 with low BEC, underwent lung function testing (Fig. 1). Table 3 shows the association between BEC and annual decline in lung function. The comparison between patients with high and low BEC revealed no significant differences in the annual decline of pre-bronchodilator FEV1 (30±8mL vs. 29±4mL, unadjusted P=0.937, adjusted P=0.899), pre-bronchodilator FVC (31±17mL vs. 27±9mL, unadjusted P=0.887, adjusted P=0.746), and pre-bronchodilator FEV1/FVC ratio (0.4±0.2% vs. 0.5±0.1%, P=0.982, adjusted P=0.488). Similar non-significant differences were noted in post-bronchodilator measurements: FEV1 (31±8mL vs. 35±4mL, P=0.633, adjusted P=0.527), FVC (48±15mL vs. 49±8mL, P=0.950, adjusted P=0.726), and FEV1/FVC ratio (0.2±0.2% vs. 0.2±0.1%, P=0.950, adjusted P=0.365). However, Fig. 2 shows a significant association between BEC and the risk of exacerbations. The high BEC group exhibited a higher risk of acute exacerbations (relative risk: 1.28, 95% confidence interval: 1.09–1.49; adjusted P=0.002) and moderate–severe acute exacerbations (relative risk: 1.29, 95% confidence interval: 1.07–1.56; adjusted P=0.009) compared with the low BEC group (Fig. 2). This was further corroborated by subgroup analysis that excluded the patients with a history of corticosteroid use and asthma (Table S2 and Fig. S1).

Table 3.

Association Between Blood Eosinophil Counts and Annual Lung Function Decline in Patients With Chronic Obstructive Pulmonary Disease During the Study Follow-up Period.

Parameter	BEC <300cells/μL	BEC ≥300cells/μL	Unadjusted		Adjusted*
	n=523	n=156	Difference (95% CI)	P Value	Difference (95% CI)	P Value
Pre-bronchodilator spirometry
FEV1, mL	29±4	30±8	1 (−17 to 18)	0.937	−1 (−19 to 16)	0.899
FVC, mL	27±9	31±17	3 (−33 to 38)	0.887	6 (−30 to 42)	0.746
FEV1/FVC, %	0.5±0.1	0.4±0.2	0.0 (−0.5 to 0.5)	0.982	−0.2 (−0.7 to 0.3)	0.488

Parameter	BEC <300cells/μL	BEC ≥300cells/μL	Unadjusted		Adjusted*
	n=522	n=156	Difference (95% CI)	P Value	Difference (95% CI)	P Value
Post-bronchodilator spirometry
FEV1, mL	35±4	31±8	−4 (−22 to 13)	0.633	−6 (−23 to 12)	0.527
FVC, mL	49±8	48±15	−1 (−33 to 31)	0.950	6 (−27 to 39)	0.726
FEV1/FVC, %	0.2±0.1	0.2±0.2	0.0 (−0.5 to 0.5)	0.950	−0.2(−0.7 to 0.3)	0.365

Abbreviations: BEC, blood eosinophil count; CI, confidence interval; FEV1, forced expiratory volume in one second; FVC, forced vital capacity.

*

Multivariable linear regression models adjusted for age, sex, body mass index, smoking status, smoking index, passive smoking, biomass exposure, occupational history of dusts/gases/fumes, family history of respiratory diseases, history of asthma, and history of corticosteroid use.

Fig. 2.

Risk of exacerbations in subjects with blood eosinophil counts ≥300cells/μL in patients with chronic obstructive pulmonary disease during the study follow-up period.

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Our study revealed that 22.9% of COPD patients exhibited high BEC. This group had poorer health status, evidenced by increased chronic respiratory symptoms and more severe SAD. Over a 2-year follow-up period, patients with high BEC showed a greater risk of exacerbations compared with those with low BEC, even after adjusting for potential confounding factors. However, no significant difference was found in the rate of annual lung function decline between the two groups. These findings persisted in patients with no history of corticosteroid use or asthma.

Our findings coincide with previous studies showing that patients with high blood eosinophils generally have more chronic respiratory symptoms,26,27 even after excluding those with a history of corticosteroid use or a history of asthma. A plausible explanation for these results is that airway eosinophils and their secreted cytokines may increase airway hyperresponsiveness,27,28 a phenomenon closely associated with respiratory symptoms. Moreover, BEC can serve as a reliable surrogate marker for airway eosinophilic inflammation.8,29,30 Consequently, the high BEC group exhibited more chronic respiratory symptoms. However, in the ECLIPSE cohort,8 patients with persistent eosinophilia had lower scores on the St. George's Respiratory Questionnaire and the mMRC, suggesting variations may be due to differences in study populations. As COPD is characterized by persistent respiratory symptoms that can reduce quality of life and increase mortality,31,32 BEC are a highly valuable adjunctive tool for identifying symptomatic patients.

A notable observation emerging from our study was that patients with high BEC experienced more severe small airway dysfunction, despite no significant increase in the rate of emphysema. This observation is in line with findings from the CanCOLD study, which indicated that patients with elevated eosinophil counts exhibit increased airway remodeling.12 Furthermore, a recent German study identified sputum eosinophil count as an independent predictor for small airway dysfunction.33 These findings collectively suggest a strong association between high eosinophil counts and underlying small airway abnormalities. Our study further demonstrated this relationship from three distinct perspectives and maintains its validity in a subgroup analysis, providing a solid foundation for future experimental studies.

The relationship between BEC and the rate of lung function decline has been the focus of research, but results remain inconsistent. Although patients with high BEC initially had worse lung function, our study did not find any association between BEC and decline in lung function, in line with a previous study.8 In contrast, a large Korean cohort study found that high BEC was associated with the development of COPD.34 Coincidentally, the CanCOLD study identified a BEC of ≥300cells/μL as an independent risk factor for accelerated lung function decline.12 It is worth noting that our study included a higher proportion of males, ever-smokers and individuals with a lower body mass index, so the differences in study populations might account for these controversial results. Another potential explanation for the absence of a positive correlation in our study could be the heterogeneity of COPD. Eosinophilic inflammation is not a central feature in COPD, and other factors besides BEC may play a more significant part in lung function decline in our cohort35 that comprised mainly patients with low GOLD grade. The limited follow-up period and the one-time BEC measurement may also have contributed to the lack of correlation. Prior research has demonstrated significant fluctuations in BEC,8,36 with Schumann et al. noting considerable variability in COPD patients’ BEC over time.

In our study population, patients with elevated BEC were at a higher risk of both acute exacerbation and moderate-to-severe acute exacerbation, consistent with findings reported in previous studies.10,37 Although some groups used different BEC thresholds, their results generally supported our findings.9,11 Given that BEC is a reliable surrogate marker for airway eosinophilic inflammation and considering the evidence that eosinophilic airway inflammation contributes to COPD exacerbations not exclusively triggered by bacteria or viruses – approximately 30% of all COPD exacerbations are eosinophilic in nature30 – this observation further corroborates the link between high BEC and exacerbation risk. COPD exacerbations are known to adversely impact quality of life, lung function, and prognosis, often leading to a gradual decline.38,39 Therefore, high BEC warrants careful attention and monitoring. Some recent clinical trials focusing on COPD patients with high BEC revealed that treatment with monoclonal antibodies targeting interleukin 5 (IL-5) or its receptor-α (IL-5Rα) or IL-4Rα reduced the frequency of acute exacerbations compared with a placebo group.40–42 This finding opens new avenues for the development of more effective COPD treatment strategies.

The primary strength of this study is that it is the first population-based cohort study to investigate the clinical characteristics and long-term prognoses of patients with high BEC in China. Nevertheless, the study has several limitations. First, it analyzes lung function data over a subsequent two-year period, which is a relatively short follow-up period. This limited duration may potentially lead to a false-negative association between high BEC and the lung function decline rate. Second, BEC was measured only once. Previous studies have shown considerable variability in BEC,8,36 raising concerns about its reliability for predicting outcomes. However, other studies provide evidence that eosinophilic inflammation is a consistent phenotype in COPD.43,44 Third, there is a possibility that exacerbations remained unreported due to recall bias, potentially impacting the study results. Fourth, the small proportion of patients with severe to very severe COPD in our study might cause a bias. Fifth, despite its large number of patients, our cohort may not fully represent the entire Chinese population. Our findings should therefore be validated in other populations to improve the generalizability of our results. Lastly, the exclusion of data on parasitic infections, a known cause of high BEC, is a notable omission. However, the distribution of BEC in our study population was 170cells/μL (IQR: 100–280), in line with figures from regions with low parasitic infection rates.9

This study demonstrated that patients with high BEC experience poorer health status, more severe small airway dysfunction, and a significantly higher risk of exacerbation. These findings emphasize the need for heightened attention to COPD patients with high BEC in clinical practice. Future research should focus on elucidating the pathological mechanisms behind poorer prognoses among patients with high BEC.

The study was approved by the Ethics Committee of The First Affiliated Hospital of Guangzhou Medical University (No. 2018-53).

The written informed consent was obtained from all participants.

This work was supported by the Foundation of Guangzhou National Laboratory (SRPG22-016 and SRPG22-018) and the Clinical and Epidemiological Research Project of State Key Laboratory of Respiratory Disease (SKLRD-L-202402). The Plan on Enhancing Scientific Research in Guangzhou Medical University (GMUCR2024-01012).

X.W., F.W., Y.Z., and P.R. had full access to all of the data in the study and X.W. take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design – P.R., Y.Z., X.W., Z.D., and F.W. Acquisition, analysis or interpretation of data – all authors. Statistical analysis – X.W. and F.W. Drafting of the manuscript – X.W., F.W., Z.D., Y.Z., and P.R. Study guarantor – X.W. Critical revision of the manuscript – all authors.

None declared.