Efficacy and Safety of Dupilumab in Chronic Obstructive Pulmonary Disease with Type 2 Inflammation: A Single-Center Real-World Study

Abstract

Purpose

To evaluate the efficacy and safety of dupilumab combined with triple inhaled therapy in patients with chronic obstructive pulmonary disease (COPD) with type 2 inflammation in a real-world setting.

Patients and Methods

This retrospective cohort study included patients with COPD and a type 2 inflammatory phenotype treated at the First Affiliated Hospital of Soochow University between October 2024 and December 2025. Propensity score matching (1:1) was performed to generate a study group receiving dupilumab plus triple therapy (ICS/LABA/LAMA) (n = 34) and a control group receiving triple therapy alone (n = 34). Pulmonary function, symptom scores, inflammatory biomarkers, acute exacerbations, and adverse events were assessed over 24 weeks.

Results

After 24 weeks, improvements in pulmonary function, symptom burden, and airway inflammation were observed in patients receiving dupilumab combined with triple therapy. In the dupilumab group, FEV₁ increased by 0.20 L, CAT score decreased by 3.70 points, and FeNO levels decreased by 8 ppb. Compared with the control group, greater associated improvements were observed in FEV₁ (adjusted between-group difference: 0.12 L) and FEV₁% predicted, along with greater reductions in CAT score, mMRC score, and FeNO levels (all P < 0.05). The annualized exacerbation rate was lower in the study group than in the control group (0.49 vs. 1.21 events per person-year), with regression analyses showing results approaching statistical significance (P = 0.058). Adverse events were mainly mild injection-site reactions and did not affect treatment continuation.

Conclusion

Dupilumab combined with triple inhaled therapy was associated with improvements in lung function, symptom burden, and airway inflammation in COPD patients with type 2 inflammation, with a favorable safety profile. A potential reduction in exacerbation risk was also observed, although further prospective studies are needed for confirmation.

Introduction

Chronic obstructive pulmonary disease (COPD) is a heterogeneous pulmonary disorder characterized by persistent airflow limitation and chronic respiratory symptoms such as dyspnea, cough, and sputum production.¹ The global prevalence of COPD is estimated to be approximately 10.3%,² with nearly one-quarter of cases occurring in China.³ Traditionally, COPD has been considered a disease predominantly driven by type 1 inflammation mediated by neutrophils.⁴ However, approximately one-third of patients exhibit elevated peripheral blood eosinophil (EOS) counts, indicating the presence of type 2 inflammatory features.⁵ Elevated EOS levels are associated with exacerbation risk and corticosteroid responsiveness.⁶ Previous studies have shown that in such patients, triple inhaled therapy (ICS/LABA/LAMA) is more effective than dual bronchodilator therapy in reducing exacerbation risk.⁷ However, some patients with eosinophilic COPD continue to experience persistent inflammation and disease progression despite optimized triple therapy.

Dupilumab is a monoclonal antibody targeting the interleukin-4 receptor alpha (IL-4Rα), which inhibits both IL-4 and IL-13 signaling pathways and thereby suppresses type 2 inflammation.⁸ Randomized controlled trials have demonstrated that, in COPD patients with blood EOS ≥300 cells/μL, dupilumab was associated with lower rates of moderate-to-severe exacerbations and better lung function in randomized controlled trials.⁹ Based on these findings, the 2025 Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends considering dupilumab in patients who remain at high risk of exacerbations despite triple therapy.¹⁰ However, real-world evidence regarding dupilumab use in COPD remains limited. Therefore, this study aimed to evaluate the efficacy and safety of dupilumab in COPD patients with type 2 inflammation in a real-world setting.

Materials and Methods

Study Design and Participants

This was a retrospective cohort study. Patients with COPD with a type 2 inflammatory phenotype who initiated treatment at the Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Soochow University, between October 2024 and December 2025 were retrospectively screened. December 2025 was defined as the end of the observation period, and only patients with complete clinical follow-up data for at least 24 weeks before this time point were included in the final analysis. Patients receiving dupilumab combined with triple inhaled therapy were assigned to the study group, while patients who received triple therapy alone during the same period and met the same eligibility criteria but did not receive dupilumab were assigned to the control group. To minimize confounding, propensity score matching (PSM) was performed. A logistic regression model was used to calculate propensity scores based on age, sex, smoking status, baseline EOS, baseline annualized exacerbation rate (AER), and baseline FEV₁% predicted. Patients were matched at a 1:1 ratio using nearest-neighbor matching with a caliper of 0.05. After matching, 68 patients were included (34 in each group). The study was approved by the institutional ethics committee.

Inclusion criteria were as follows: (1) age ≥40 years; (2) a smoking history of ≥10 pack-years or exposure to other harmful particles; (3) diagnosis of COPD according to GOLD criteria (post-bronchodilator FEV₁/FVC <0.70);¹¹ (4) blood eosinophil count ≥300 cells/μL within 4 weeks prior to treatment initiation; (5) persistent symptoms despite at least 3 months of triple inhaled therapy (CAT score ≥10 or mMRC score ≥2); (6) ≥2 moderate or ≥1 severe exacerbations in the previous year;¹¹ (7) availability of complete clinical data for at least 24 weeks. Exclusion criteria were as follows: (1) presence of other pulmonary diseases (eg, asthma, interstitial lung disease, or bronchiectasis) or systemic conditions associated with eosinophilia (eg, parasitic infection); (2) acute exacerbation of COPD or use of systemic corticosteroids within 4 weeks prior to enrollment; (3) prior treatment with biologic agents; (4) severe comorbidities (eg, cardiovascular, hepatic, renal diseases, or malignancy); (5) known hypersensitivity to dupilumab.

Procedures

Patients in the study group received dupilumab 300 mg subcutaneously every 2 weeks in addition to standard triple inhaled therapy (ICS/LABA/LAMA). Patients in the control group continued triple inhaled therapy alone. Commonly used ICS/LABA/LAMA regimens were administered according to routine clinical practice. Patients underwent outpatient follow-up approximately every 4 weeks, and concomitant medications and adverse events were assessed every 4 weeks based on routine outpatient follow-up records and prescription refill documentation.

Study Endpoints

The study endpoints included: (1) Baseline characteristics, including sex, age, body mass index (BMI), disease duration, smoking status, and type 2 comorbidities (eg, atopic dermatitis, chronic rhinosinusitis with nasal polyps, and urticaria); (2) Clinical outcomes assessed at baseline and after 24 weeks including peripheral blood eosinophil counts, fractional exhaled nitric oxide (FeNO), alveolar nitric oxide concentration (CaNO), COPD Assessment Test (CAT) score, and modified Medical Research Council (mMRC) dyspnea score;¹¹ (3) Pulmonary function parameters before bronchodilator use (pre-bronchodilator, pre-BD) were assessed at baseline and follow-up, including forced expiratory volume in 1 second (FEV₁), percentage of predicted FEV₁ (FEV₁% predicted), percentage of predicted forced vital capacity (FVC% predicted), FEV₁/FVC ratio, and forced expiratory flow at 25–75% of vital capacity (FEF_25–75% predicted); (4) Acute exacerbations of COPD and treatment-related adverse events were recorded during the one year prior to enrollment and throughout the treatment period.

Statistical Analysis

Statistical analyses were performed using SPSS version 27.0. Baseline characteristics were summarized using descriptive statistics and compared using the chi-square test, independent-samples t test, or Mann–Whitney U-test, as appropriate. Between-group comparisons were adjusted for baseline values using regression models. Continuous outcomes were reported as adjusted mean differences or geometric mean ratios (GMRs) with 95% confidence intervals (CIs), as appropriate. The annualized exacerbation rate (AER) was analyzed using negative binomial regression with adjustment for follow-up duration. Binary outcomes were analyzed using logistic regression, with results reported as adjusted odds ratios (aORs) and 95% CIs. A two-sided P value < 0.05 was considered statistically significant.

Results

Baseline Characteristics

A total of 68 patients with COPD and type 2 inflammatory phenotype were included in this study, with 34 patients in the treatment group and 34 in the control group. The mean age was 66.82 years in the treatment group and 67.56 years in the control group. There were no significant differences between the two groups in age, sex, BMI, disease duration, smoking status, GOLD stage, baseline AER, lung function, symptom scores, or inflammatory markers (P > 0.05), indicating good comparability between groups (Table 1).

Table 1.

Baseline Clinical Characteristics of the Study Population

Variable	Treatment Group (n = 34)	Control Group (n = 34)	P value
Age (years), mean ± SD	66.82 ± 9.53	67.56 ± 8.93	0.712
Male sex, n (%)	25 (73.5)	29 (85.3)	0.369
BMI (kg/m2), mean ± SD	24.03 ± 3.53	24.30 ± 3.71	0.765
Type 2 comorbidities, n (%)	18 (52.9)	12 (35.3)	0.249
Disease duration ≥5 years, n (%)	18 (52.9)	13 (38.2)	0.275
Baseline AER (events/person-year)	2 (2, 3)	2 (2, 3)	0.910
Smoking status (never/former/current), n (%)	13/13/8 (38.2, 38.2, 23.5)	11/11/12 (32.4, 32.4, 35.3)	0.432
GOLD stage (II/III/IV), n (%)	16/14/4 (47.1, 41.1, 11.8)	16/13/5 (47.1, 38.2, 14.7)	0.924
Pulmonary function, mean ± SD
FEV1 (L)	1.32 ± 0.56	1.33 ± 0.44	0.849
FEV1% predicted (%)	52.39 ± 18.66	52.84 ± 15.78	0.916
FEV1/FVC (%)	47.44 ± 12.26	47.91 ± 11.38	0.762
FVC% predicted (%)	85.56 ± 19.23	84.61 ± 17.23	0.736
FEF25-75% predicted (%)	16.18 ± 9.56	16.29 ± 9.01	0.822
EOS (×106/L), Median (IQR)	355 (318, 453)	385 (345, 480)	0.377
FeNO (ppb), Median (IQR)	27 (19, 52)	25 (18, 37)	0.110
CaNO (ppb), Median (IQR)	3.4 (2.3, 5.1)	2.8 (2.3, 4.4)	0.170
CAT score, mean ± SD	13.41 ± 2.62	13.35 ± 1.81	0.789
mMRC score, mean ± SD	3.06 ± 0.81	2.85 ± 0.70	0.268

Abbreviations: BMI, body mass index; AER, annualized exacerbation rate; GOLD, Global Initiative for Chronic Obstructive Lung Disease; FEV₁, forced expiratory volume in 1 second; FEV₁% predicted, percentage of predicted FEV₁; FVC, forced vital capacity; FEF_25–75%, forced expiratory flow at 25–75% of vital capacity; EOS, blood eosinophil count; FeNO, fractional exhaled nitric oxide; CaNO, alveolar nitric oxide concentration; CAT, COPD Assessment Test; mMRC, modified Medical Research Council dyspnea scale.

Changes in Lung Function

After 24 weeks, lung function parameters were higher than baseline levels in both groups. In the treatment group, FEV₁ increased from 1.32 L to 1.52 L (mean change: +0.20 L, P < 0.05), and FEV₁% predicted increased from 52.39% to 61.31% (P < 0.05). FVC% predicted and FEF_25–75% predicted also showed significant improvements. Increases in FEV₁ and FEV₁% predicted were also observed in the control group. After adjustment for baseline values using analysis of covariance (ANCOVA), a larger increase in FEV₁ was observed in the treatment group compared with the control group (adjusted mean difference: 0.12 L; 95% CI: 0.03–0.21; P = 0.007), as well as a greater improvement in FEV₁% predicted (4.89%, P = 0.013). Improvements in FVC% predicted were also greater in the treatment group. No statistically significant differences were observed between groups for the remaining parameters (Table 2).

Table 2.

Changes in Pulmonary Function Parameters From Baseline to 24 weeks

Variable	Treatment Group (n = 34)	Control Group (n = 34)	Adjusted Mean Difference (95% CI)	P value
FEV1 (L)	1.52 ± 0.63*	1.41 ± 0.49*	0.12 (0.03, 0.21)	0.007
FEV1% predicted (%)	61.31 ± 21.74*	56.92 ± 18.16*	4.89 (1.09, 8.70)	0.013
FEV1/ FVC (%)	50.79 ± 14.24*	50.10 ± 12.21*	1.16 (−1.44, 3.75)	0.377
FVC% predicted (%)	94.67 ± 18.73*	87.59 ± 13.82	6.38 (0.74, 12.01)	0.027
FEF25-75% predicted (%)	21.77 ± 10.42*	18.42 ± 10.11*	3.48 (−0.99, 7.95)	0.125

Notes: Data are presented as mean ± SD. * or bold indicate P < 0.05. * denotes comparison within the same group from baseline; bold denotes between-group comparison after adjustment.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FEV₁% predicted, percentage of predicted FEV₁; FVC, forced vital capacity; FEF_25–75%, forced expiratory flow at 25–75% of vital capacity.

Changes in Symptoms and Quality of Life

After 24 weeks, CAT and mMRC scores were significantly lower than baseline values in both groups. In the treatment group, CAT and mMRC scores decreased by 3.70 and 0.85 points, respectively (P < 0.05). In the control group, CAT and mMRC scores decreased by 2.27 and 0.35 points, respectively (P < 0.05). After adjustment for baseline values, improvements in symptoms were significantly greater in the treatment group than in the control group. The adjusted mean difference in CAT score was −1.42 points (95% CI: −2.34 to −0.50; P = 0.003), and the between-group difference in mMRC score was −0.46 points (95% CI: −0.77 to −0.15; P = 0.005) (Table 3).

Table 3.

Changes in Symptom Scores and Inflammatory Biomarkers From Baseline to 24 weeks

Variable	Treatment Group (n = 34)	Control Group (n = 34)	Effect Estimate (95% CI)	P value
EOS (×106/L), Median (IQR)	370 (205, 453)	355 (158, 535)*	1.10 (0.80, 1.52)	0.534
FeNO (ppb), Median (IQR)	19 (15, 29)*	21 (17, 31)	0.77 (0.63, 0.94)	0.009
CaNO (ppb), Median (IQR)	2.9 (2.0, 4.3)*	2.8 (2.2, 3.8)	0.88 (0.70, 1.10)	0.252
CAT score, mean ± SD	9.71 ± 3.46*	11.08 ± 2.92*	−1.42 (−2.34, −0.50)	0.003
mMRC score, mean ± SD	2.21 ± 0.88*	2.50 ± 0.86*	−0.46 (−0.77, −0.15)	0.005

Notes: Data are presented as mean ± SD. * or bold indicate P < 0.05. * denotes comparison within the same group from baseline; bold denotes between-group comparison after adjustment. Effect estimates are presented as adjusted mean differences for normally distributed variables and GMRs for skewed variables.

Abbreviations: EOS, blood eosinophil count; FeNO, fractional exhaled nitric oxide; CaNO, alveolar nitric oxide concentration; CAT, COPD Assessment Test; mMRC, modified Medical Research Council dyspnea scale.

Changes in Airway Inflammatory Markers

After 24 weeks of treatment, the median FeNO level in the treatment group decreased from 27.0 ppb to 19.0 ppb (P < 0.05), with an adjusted geometric mean ratio (GMR) of 0.77 (P = 0.009), corresponding to an approximately 23% lower FeNO level compared with the control group. The median CaNO level in the treatment group decreased from 3.4 to 2.9 ppb (P < 0.05). However, no significant between-group differences were observed in changes in CaNO or EOS counts (P > 0.05) (Table 3).

Acute Exacerbations

Due to variability in follow-up duration among patients, the observation period was defined from treatment initiation to study endpoint or loss to follow-up. The number of exacerbation events was recorded, and the AER was calculated. The AER was numerically lower in the treatment group than in the control group (0.49 vs. 1.21 events per person-year). Although negative binomial regression analysis did not demonstrate a statistically significant difference, there was a trend toward a lower exacerbation rate in the treatment group (IRR = 0.40, 95% CI: 0.16–1.03; P = 0.058). Within 24 weeks, 6 patients (17.6%) in the treatment group experienced at least one exacerbation, compared with 12 patients (35.3%) in the control group. Logistic regression analysis similarly showed numerically lower odds of exacerbation in the treatment group, although the difference did not reach statistical significance (aOR = 0.28, 95% CI: 0.07–1.05; P = 0.059) (Table 4).

Table 4.

Comparison of Acute Exacerbation Outcomes Between the Two Groups

Variable	Treatment Group (n = 34)	Control Group (n = 34)	Effect Estimate (95% CI)	P value
AER (events per person-year)	0.49	1.21	IRR 0.40 (0.16, 1.03)	0.058
≥1 exacerbation within 24 weeks, n (%)	6 (17.6)	12 (35.3)	aOR 0.28 (0.07, 1.05)	0.059

Notes: Effect estimates are expressed as incidence rate ratios (IRRs) and adjusted odds ratios (aORs).

Abbreviations: AER, annualized exacerbation rate; IRR, incidence rate ratio; aOR, adjusted odds ratio.

Safety

During the treatment period, 5 patients (14.7%) in the treatment group experienced injection-site reactions. Among them, 3 patients presented with local erythema or pain, which occurred mainly after the first dose and resolved spontaneously within 48 hours; the other 2 patients (5.9%) developed injection-site rash with pruritus, which was relieved after oral loratadine administration. One patient experienced transient arthralgia, which also resolved within 48 hours. None of these adverse events affected subsequent treatment. No treatment-related adverse events were reported in the control group.

Discussion

In this retrospective real-world study, dupilumab combined with triple therapy was associated with greater improvements in lung function, symptom burden, and airway inflammation than triple therapy alone, without serious adverse events.

Lung function is a key indicator for the diagnosis, severity assessment, and treatment evaluation of COPD.¹⁰ In this study, both groups showed improvements in FEV₁, FEV₁% predicted, and FVC% predicted after 24 weeks of treatment, with greater improvements observed in the treatment group. The between-group difference in FEV₁ reached 0.12 L. Previous Phase III trials (BOREAS and NOTUS) reported a between-group difference in FEV₁ of approximately 83 mL at 12 weeks, sustained up to 52 weeks.⁹ These findings were generally consistent with previous randomized controlled trials. Although FEV₁/FVC improved more in the treatment group, the between-group difference was not statistically significant, possibly due to concurrent improvements in FVC and the limited reversibility of structural airway remodeling in COPD over a short period.

Regarding small airway function, FEF_25–75% predicted showed an improving trend in the treatment group, although the between-group difference did not reach statistical significance. Small airways are considered a major site of early pathological changes in COPD and are associated with airway remodeling and mucus plugging.^12,13 Previous studies have reported improvements in mucus plugging and distal airway ventilation with dupilumab treatment.¹⁴ In this study, CaNO also showed a decreasing trend, although further validation in larger studies is needed.

A significant reduction in FeNO was observed in the treatment group, indicating that dupilumab treatment was associated with reduced type 2 airway inflammatory activity. Similar findings have been reported in previous phase III trials.⁹ In contrast, peripheral blood eosinophil levels did not show a significant decrease, and transient increases were observed in some patients. This phenomenon has also been reported in previous studies and is not indicative of worsening inflammation. It may be related to reduced expression of VCAM-1 following IL-4/IL-13 blockade, which may reflect decreased migration of eosinophils from the circulation into tissues; this effect is typically transient and normalizes over time.¹⁵

In addition to improvements in objective physiological measures, dupilumab treatment was associated with greater reductions in CAT and mMRC scores, suggesting favorable changes in symptom burden and patient-reported outcomes (PROs). Although the magnitude of CAT score improvement should be interpreted cautiously in relation to the established minimal clinically important difference (MCID) of 2 points for COPD, symptom scores were consistently lower in the treatment group.¹⁰ Previous studies and systematic reviews have similarly reported associations between biologic therapies and better symptom control and health-related quality of life in type 2 inflammatory COPD.^9,16

Regarding acute exacerbations, both the annualized exacerbation rate and the proportion of patients experiencing exacerbations within 24 weeks were numerically lower in the treatment group compared with the control group. Although these differences did not reach statistical significance, regression analyses consistently showed lower exacerbation rates in the treatment group. The lack of statistical significance may be related to the small sample size and short follow-up duration. Previous randomized controlled trials and real-world studies have also reported a potential reduction in exacerbation risk with dupilumab.¹⁷ Nevertheless, a trend toward lower exacerbation rates was observed and warrants further investigation in larger prospective studies.

At present, real-world studies on dupilumab in COPD remain limited in sample size, often involving only a small number of patients.¹⁸ Although some large population-based studies exist, they primarily focus on long-term outcomes such as exacerbation risk and mortality, with limited comprehensive evaluation of multidimensional outcomes, including lung function, symptom scores, and airway inflammation.¹⁷ In addition, some studies did not clearly exclude patients with a prior diagnosis of asthma or lacked parallel control groups, potentially affecting the interpretation of results.^19,20

This study has several strengths, including the use of propensity score matching to reduce confounding bias, strict exclusion of patients with asthma, and comprehensive assessment of lung function, symptom burden, inflammatory markers, and exacerbation outcomes. However, several limitations should be acknowledged. The single-center retrospective design may introduce selection bias. The 24-week follow-up period was insufficient to assess long-term outcomes and safety. In addition, dynamic monitoring of key inflammatory cytokines such as IL-4 and IL-13 was not performed, limiting mechanistic insights.

Conclusion

Dupilumab combined with triple therapy was associated with improvements in lung function, symptom burden, and airway inflammation in patients with type 2 inflammatory COPD. A trend toward lower exacerbation rates was also observed. These findings suggest potential clinical utility of dupilumab in this patient population, although larger prospective studies are still needed for further confirmation.

Funding Statement

This work was supported by the Open Project of the National Key Laboratory of Radiological Medicine and Radiation Protection (Grant No. GZK12024027).

Data Sharing Statement

Data supporting the findings of this study are available from the corresponding author upon reasonable request.

Ethics Approval and Informed Consent

This retrospective real-world study was approved by the Ethics Committee of the First Affiliated Hospital of Soochow University (Approval No.: (2025) LunShenPi No. 696; Ethics Acceptance No.: 2025696). The study was conducted in accordance with the principles of the Declaration of Helsinki. As this was a non-interventional retrospective study using only de-identified existing clinical data, the requirement for written informed consent from individual participants was waived by the ethics committee.

Author Contributions

All authors reviewed and approved the final version of the manuscript All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.