This prospective observational pilot study evaluated whether peripheral blood neutrophil expression of programmed death ligand-1 (PD-L1, measured as CD15⁺CD274⁺ neutrophils) is associated with acute exacerbation of COPD (AECOPD) and correlates with the neutrophil-to-lymphocyte ratio (NLR). The authors report higher proportions of CD15⁺CD274⁺ neutrophils in COPD compared with healthy controls and the highest levels in patients experiencing AECOPD.
Between June 1 and December 30, 2024, the analysis included 41 patients with confirmed COPD (27 stable COPD, 14 AECOPD) and 9 healthy controls; all participants self-reported as Asian Han Chinese. Inclusion required age ≥ 40 years and COPD defined by clinical symptoms and post-bronchodilator airflow obstruction (post-bronchodilator FEV1/FVC < 70%). AECOPD was defined as worsening respiratory symptoms over <14 days; enrolled AECOPD cases were moderate and treated outpatient. Exclusion criteria included other severe pulmonary diseases, end-stage organ dysfunction, active malignancy, prior immune checkpoint inhibitor therapy, prolonged systemic immunosuppression (>14 days), and pregnancy or lactation. The study protocol and verbal consent procedures were approved by the Ethics Committee of Beijing Chao-Yang Hospital (2024-KE-414-1).
Whole blood was processed to separate granulocytes and mononuclear cells. Granulocyte pellets were washed and resuspended at 3 × 10^5 cells per 100 μL for staining. After blocking with 1% bovine serum albumin, cells were stained with FITC-conjugated anti-human CD15 and PE-conjugated anti-human CD274 (PD-L1) antibodies and analyzed by flow cytometry. Gating excluded debris and doublets, and the percentage of CD15⁺CD274⁺ neutrophils was quantified. Magnetic sorting and prompt processing maintained cell viability above 90%.
Group comparisons used Chi-square for categorical variables, Shapiro–Wilk to assess normality, Student’s t-test for normally distributed continuous variables, and Mann–Whitney U test for non-normal data. Pearson correlation assessed relationships between CD15⁺CD274⁺ percentage and predicted FEV1%; partial correlation (controlling for neutrophil count) evaluated CD15⁺CD274⁺ versus NLR. Receiver-operating characteristic (ROC) analyses reported AUCs, optimal cutoffs, sensitivity, specificity, predictive values, and diagnostic accuracy. Multivariate logistic regression with forward stepwise selection tested independent associations with AECOPD. Two-tailed analyses used P < 0.05 as significance.
Compared with healthy controls, patients with COPD had a significantly higher percentage of CD15⁺CD274⁺ neutrophils. Within the COPD cohort, the AECOPD group demonstrated a higher percentage of CD15⁺CD274⁺ neutrophils than the stable-COPD group. Baseline comparisons also showed AECOPD patients were older, had a higher incidence of respiratory failure, lower FEV1% and FEV1/FVC, higher C-reactive protein (CRP), and lower hemoglobin, platelet and lymphocyte counts versus stable COPD. Leukocyte and eosinophil counts did not differ between AECOPD and stable COPD.
Across the combined AECOPD and stable-COPD participants, the percentage of CD15⁺CD274⁺ neutrophils correlated positively with NLR (Pearson r = 0.315, P = 0.045) and inversely with percent predicted FEV1 (r = −0.329, P = 0.036). The authors also note that as the CD15⁺CD274⁺ percentage increased, NLR tended to rise and FEV1% tended to fall.
ROC analysis showed the AUC for CD15⁺CD274⁺ neutrophil percentage predicting AECOPD was 0.894 (95% CI 0.8–0.989), exceeding the AUCs reported for age, CRP, NLR, hemoglobin and platelets in this cohort. An optimal cutoff of CD15⁺CD274⁺ > 3.273 was reported. In multivariate logistic regression including CD15⁺CD274⁺ percentage, platelets, hemoglobin, NLR, CRP and age, the CD15⁺CD274⁺ neutrophil percentage was independently associated with AECOPD (OR 1.386; 95% CI 1.016–1.891; P = 0.039).
The authors place these findings in the broader context of innate–adaptive immune imbalance in COPD. They note prior evidence of neutrophil activation in COPD and impaired lymphocyte function, and they reference PD-1/PD-L1 as an inhibitory immune checkpoint that can suppress adaptive immunity. The observed association between elevated neutrophil PD-L1 expression and higher NLR and lower FEV1% suggests a potential role for PD-L1–expressing neutrophils in the immune dysregulation accompanying COPD exacerbations. The study reports that PD-L1 upregulation on neutrophils has been observed in other inflammatory states such as sepsis, where it may promote lymphocyte apoptosis.
The authors characterize this analysis as a pilot study with a limited sample size and note that prior data were insufficient to power a primary endpoint calculation. The cohort is single-center, ethnically homogeneous, and limited to moderate, outpatient-managed AECOPD. The authors call for larger, multi-center studies with mechanistic validation to determine the clinical utility of neutrophil PD-L1 measurement as a biomarker for exacerbation risk. They also report that all relevant data will be made available upon study completion and that no competing interests were declared.