The therapeutic effects of dupilumab in asthma-chronic obstructive pulmonary disease overlap and pure asthma: a pilot study

Abstract

Background

The efficacy and safety of dupilumab in patients with pure asthma and asthma-COPD overlap (ACO) remain incompletely understood. This single centre pilot study aimed to evaluate the short- and long-term effects of dupilumab on symptom improvement, corticosteroid usage, and safety outcomes in patients with pure asthma and ACO.

Methods

We retrospectively analyzed 40 patients aged 12 years or older with asthma treated with dupilumab. The Asthma Control Questionnaire-5 (ACQ-5), mini-Asthma Quality of Life Questionnaire (mini-AQLQ), and modified Medical Research Council Dyspnea Scale (mMRC) were assessed at baseline, day 3, and month 3 after treatment initiation. Corticosteroid usage and safety outcomes were also evaluated.

Results

Dupilumab treatment led to significant improvements in asthma symptoms, severity of dyspnea, and quality of life as early as day 3, with sustained effectiveness observed after 3 months. Mean ACQ-5 scores decreased from 3.57±1.39 at baseline to 2.14±1.00 at day 3 and 1.11±0.91 at 3 months (both P<0.001). Mini-AQLQ scores increased from 3.84±1.30 at baseline to 5.20±0.93 at day 3 and 6.14±0.91 at 3 months (P<0.001). Dyspnea severity, assessed by mMRC, also improved at both time points. ACO patients exhibited slightly greater improvements compared with pure asthma patients, although the differences were not statistically significant. The proportion of patients requiring high-dose inhaled corticosteroids (ICS) decreased from 50% at baseline to 22.5% at 3 months. Only one patient discontinued treatment due to elevated blood eosinophil level, and no severe adverse events (AEs) were reported.

Conclusions

This study demonstrates that dupilumab is effective in alleviating symptoms in both pure asthma and ACO patients, with rapid and sustained symptom improvement observed.

Highlight box.

Key findings

• Dupilumab led to significant symptom improvement in both pure asthma and asthma-COPD overlap (ACO) groups, with rapid and durable relief.

• ACO patients showed a trend toward greater improvements in the Asthma Control Questionnaire-5, Asthma Quality of Life Questionnaire, and modified Medical Research Council Dyspnea Scale scores.

What is known and what is new?

• Dupilumab is effective in patients with moderate-to-severe asthma, particularly those with type 2 inflammation. However, ACO patients are commonly excluded from major clinical trials.

• This study adds observational data on clinical symptom changes following dupilumab treatment in patients with ACO and pure asthma in a single-centre retrospective cohort. Symptom improvement was observed in both groups, suggesting comparable or greater benefit in ACO than in pure asthma.

What is the implication, and what should change now?

• These findings support the inclusion of ACO patients in future biologic treatment guidelines and clinical studies. Dupilumab may be considered as a therapeutic option for patients with ACO, particularly when rapid symptom control is needed.

Introduction

Asthma and chronic obstructive pulmonary disease (COPD) are two major public health challenges, affecting nearly 1 in 12 people worldwide (1). Although distinct in their pathophysiology, these conditions are increasingly recognized as heterogeneous and often overlapping (2). Asthma-COPD overlap (ACO) was first raised in 2015 and used as a descriptive term to describe patients with persistent airflow limitation and clinical features of both asthma and COPD. Recent Global Initiative for Asthma (GINA) guidance has de-emphasized ACO as a discrete entity, instead promoting terminology such as “asthma + COPD” to reflect overlapping disease features and support trait-based management (3). For consistency with previously published literature and to facilitate clarity for readers, the term “asthma-COPD overlap (ACO)” is retained throughout this manuscript. ACO occurs in nearly half of patients over 50 years of age with airflow obstruction, and the prevalence increases with age (4-6). In addition to its high prevalence, patients with ACO experience more frequent respiratory exacerbations, poorer quality of life, and higher healthcare costs compared to those with either disease alone (3,7,8). Despite its clinical significance, the treatment of ACO remains poorly defined, partly because patients with ACO are frequently excluded from clinical trials targeting either COPD or asthma (2,9,10).

Recent literatures suggest that T helper 2 (Th2)-mediated inflammation is an important mechanism underlying disease pathophysiology in ACO (11-13). Th2-mediated inflammation refers to an immune response primarily regulated by Th2 CD4⁺ T cell subpopulation or group 2 innate lymphoid cells (ILC2s), and is characterized by the production of prototypical cytokines such as interleukin (IL)-4, IL-5 and IL-13, as well as eosinophilia (14,15). IL-4 and IL-13 mediates effects on mucus hypersecretion, subepithelial fibrosis, and airway smooth muscle dysfunction, causing persistent airflow limitation and airway remodeling (12,16). IL-13 was also remarked as a central inflammatory node in ACO, positioned between asthma and COPD (17). Recently, many therapies targeting Th2-mediated inflammation have shown significant progress in the treatment of asthma and selected COPD populations (18,19). However, the role of IL-4/IL-13 blockade in patients with overlapping asthma and COPD features remains insufficiently characterised.

Dupilumab was selected for evaluation in ACO patient because it targets the shared IL-4 receptor alpha subunit, thereby simultaneously inhibiting IL-4 and IL-13 driven inflammatory pathways (20). This broader mechanism of action may better cover the heterogeneous patterns in ACO than biologics targeting a single mediator. Several clinical trials have proved the efficacy of dupilumab in reducing acute exacerbations, alleviating symptoms, and improving lung function in patients with asthma, and more recently in selected patients with COPD characterised by type 2 inflammation (21-23). Recent phase-3 data from the BOREAS and NOTUS programme indicate that dupilumab reduced exacerbations and improved lung function in patients with COPD selected for type-2 inflammatory biomarkers (24,25). Comparative observational data (the PRISM study) have previously evaluated lung function responses to biologic therapies, including dupilumab, in cohorts with ACO versus pure asthma (26). However, it remains unclear whether patients with ACO also symptomatically benefit from dupilumab treatment.

In this study, we explored short- and long-term clinical outcomes following dupilumab treatment in patients with pure asthma or ACO in a single centre retrospective cohort. This design allows exploratory evaluation in ACO patients, a population that is frequently under-represented or excluded from prospective randomised clinical trials. The day 3 assessment was included to descriptively capture early symptom changes observed in routine clinical practice rather than to establish definitive treatment efficacy. The 3-month follow-up time point was selected because prior clinical studies have shown that improvements in lung function and symptom control with dupilumab are most pronounced within the first 3 months of treatment, with responses tending to plateau thereafter (27). Therefore, the 3-month evaluation was intended to reflect the early, clinically meaningful phase of treatment response. The inclusion criteria were defined to reflect routine clinical decision-making. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2051/rc).

Methods

Study design and population

This single-center retrospective study aimed to evaluate the therapeutic efficacy and safety of dupilumab in patients with pure asthma and ACO. A total of 40 patients who received dupilumab therapy were enrolled from outpatient clinics in Zhongshan Hospital, Shanghai, China between October 2023 and September 2024. Follow-up was done 3 months after the enrollment. The diagnosis of asthma is based on the GINA guidelines (28). While proposed ACO definitions vary, most share several core components: a history of asthma or bronchodilator reversibility, persistent airflow obstruction, and age ≥40 years (13,29). In this study, ACO was defined as physician-diagnosed asthma in patients aged 40 years or older with a post-bronchodilator forced expiratory volume in one second to forced vital capacity (FEV₁/FVC) ratio <0.7 and Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 2 or higher airflow limitation (FEV₁ <80% predicted) (12).

Patients were eligible if they were aged 12 years or older, had a physician-confirmed diagnosis of asthma, and received at least one dose of dupilumab during the study period. Exclusion criteria included: (I) incomplete follow-up data at either day 3 or month 3; (II) active malignancy, autoimmune disease, or other severe comorbidities that could confound interpretation of treatment response. Patients with missing key baseline clinical variables [e.g., Asthma Control Questionnaire-5 (ACQ-5), mini-Asthma Quality of Life Questionnaire (mini-AQLQ), or modified Medical Research Council Dyspnea Scale (mMRC) scores] were also excluded. No imputation methods were applied. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Zhongshan Hospital Affiliated to Fudan University (No. B2025-048R) and individual consent for this retrospective analysis was waived.

Data collection

Baseline demographic and clinical data were extracted from medical records, including age, sex, body mass index (BMI), duration of asthma, number of exacerbations in the past year, comorbidities, and baseline lung function parameters. Therapeutic responses were assessed using validated clinical measures, including the ACQ-5 (30,31), the mini-AQLQ (32), and the mMRC (33). These responses were recorded at baseline, 3 days and 3 months post-treatment. Sputum characteristics (color, thickness, and volume) and the use of inhaled corticosteroids (ICS) and oral corticosteroids (OCS) was also monitored at these time points. The ICS and OCS dosage level are based on the GINA guidelines (28). Safety outcomes were assessed by recording adverse events (AEs), including their frequencies, severity, and any treatment discontinuations. The questionnaire was administered by trained interviewers who were blinded to the participants’ disease status. To address potential sources of bias, all eligible patients who met the inclusion criteria during the study period were consecutively enrolled to minimize selection bias, and standardized assessment tools (ACQ-5, mini-AQLQ, mMRC) were used consistently across time points to reduce measurement bias.

Intervention

Patients received subcutaneous dupilumab, starting with a loading dose of 600 mg, followed by 300 mg every 2 weeks. All patients continued their baseline asthma therapies, including ICS and long-acting beta-agonists (LABA), with adjustments made based on clinical judgment during follow-up visits. No additional biologic therapies were allowed during the study period.

Statistical analysis

Continuous variables were presented as mean ± standard deviation (SD), while categorical variables were reported as frequencies and percentages. Paired t-tests and McNemar tests were used to compare changes in outcomes over time. The Mann-Whitney U test and Wilcoxon test were employed to compare outcomes between the pure asthma and ACO groups. No interaction terms were tested, as the sample size was insufficient to support multivariable modeling. Statistical significance was defined as a two-sided P value <0.05. Exact P values are reported where available; values below the reporting threshold are presented as P<0.001. The study size was determined by the total number of eligible patients who initiated dupilumab treatment and had sufficient follow-up data during the defined study period (October 2023 to September 2024); no formal sample size calculation was performed, as this was an exploratory, retrospective study. A post-hoc power analysis was performed for the between-group comparisons of change scores using Cohen’s d and the pwr package in R. All analyses were performed using R version 4.4.1.

Results

Patients’ general information

A total of 48 patients with asthma or ACO were screened for eligibility between October 2023 and September 2024. Of these, 5 patients were excluded due to incomplete baseline clinical data and 3 were lost to follow-up before 3-month assessment. All included patients received at least one dose of dupilumab and completed symptom assessments at both 3 days and 3 months’ time points. The number of participants with missing data was recorded for each outcome variable. Specifically, blood eosinophil counts were missing in 12 patients at baseline; immunoglobulin E (IgE) was missing in 15 patients at baseline; Atopy history scores were missing in 12 patients at baseline. All participants were followed for a fixed duration of 3 months after initiating dupilumab treatment. The average follow-up time was 2.87 months per patient.

A total of 40 asthma patients were enrolled, including 26 with pure asthma and 14 with ACO. The mean age of the overall cohort was 47.6±16.42 years, with asthma patients being significantly younger than those with ACO (40.65±14.90 vs. 60.50±10.27 years, P<0.001). Female patients accounted for 45.0% of the total cohort. The mean duration of asthma was significantly longer in the ACO group compared to the asthma group (14.07±12.23 vs. 5.46±6.63 years, P=0.006). The number of exacerbations in the past year was slightly higher in the ACO group (1.50±1.51 vs. 0.88±0.52, P=0.065), although the difference was not statistically significant. ACO patients had higher baseline ICS doses, with 42.9% of ACO patients requiring high-dose ICS compared to 30.8% of pure asthma patients. ACO patients also exhibited poorer baseline lung function. The average baseline ACQ-5 scores for the pure asthma and ACO groups were 3.31 and 4.06, respectively, indicating that neither group was well controlled, with ACO patients being slightly worse. Similarly, the baseline mini-AQLQ and the mMRC scores also reflected poorer conditions in the ACO group (Table 1).

Table 1. Baseline demographic and clinical characteristics of patients with pure asthma and ACO.

Characteristics	Overall (N=40)	Pure asthma (N=26)	ACO (N=14)	P value
Age (years)	47.60±16.42	40.65±14.90	60.50±10.27	<0.001
Female sex	18 (45.0)	13 (50.0)	5 (35.7)	0.59
Body mass index (kg/m2)	23.38±4.66	23.05±3.53	23.96±6.32	0.57
Duration of asthma (years)	8.47±9.77	5.46±6.63	14.07±12.23	0.006
No. of exacerbations in the past year	1.10±1.01	0.88±0.52	1.50±1.51	0.07
Comorbidities
Allergic rhinitis	22 (55.0)	17 (65.4)	5 (35.7)	0.14
Chronic rhinitis sinusitis	15 (37.5)	10 (38.5)	5 (35.7)	>0.99
Atopic dermatitis	4 (10.0)	2 (7.7)	2 (14.3)	0.91
Eczema	5 (12.5)	5 (19.2)	0 (0.0)	0.21
Sleep apnea syndrome	4 (10.0)	3 (11.5)	1 (7.1)	>0.99
Smoking				0.30
Still smoking	5 (12.5)	3 (11.5)	2 (14.3)
Smoked	4 (10.0)	1 (3.8)	3 (21.4)
Second handed	5 (12.5)	3 (11.5)	2 (14.3)
Non-smoker	26 (65.0)	19 (73.1)	7 (50.0)
Atopy	14 (51.9)	11 (55.0)	3 (42.9)	0.91
Family history	9 (22.5)	5 (19.2)	4 (28.6)	0.78
Patients on OCS	12 (30.0)	5 (19.2)	7 (50.0)	0.10
Baseline ICS				0.22
Low dose	7 (17.5)	5 (19.2)	2 (14.3)
Medium dose	13 (32.5)	6 (23.1)	7 (50.0)
High dose	20 (50.0)	15 (57.7)	5 (35.7)
Previous biologics	9 (22.5)	6 (23.1)	3 (21.4)	>0.99
Baseline BEC (×109 cells/L)	0.39±0.63	0.33±0.19	0.41±0.70	0.90
Baseline FEV1%	76.78±30.24	94.93±15.57	40.47±15.39	<0.001
Baseline FEV1 (L)	2.38±1.08	2.99±0.69	1.21±0.62	<0.001
Baseline FEV1chg%	6.60±7.74	4.29±7.42	11.23±6.40	0.02
Baseline IgE (>60 KU/L)	483.28±659.86	545.60±710.34	372.50±581.88	0.54
Baseline ACQ-5	3.57±1.39	3.31±1.22	4.06±1.59	0.10
Baseline mini-AQLQ	3.84±1.30	4.10±1.20	3.36±1.38	0.09
Baseline mMRC	2.58±1.28	2.23±1.21	3.21±1.19	0.02

Data are presented as mean ± standard deviation or n (%). ACO, asthma-COPD overlap; ACQ-5, Asthma Control Questionnaire-5; BEC, blood eosinophil counts; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; IgE, immunoglobulin E; mini-AQLQ, mini-Asthma Quality of Life Questionnaire; mMRC, modified Medical Research Council Dyspnea Scale; OCS, oral corticosteroid.

Evaluation of therapeutic efficacy

The administration of dupilumab resulted in significant improvements in clinical outcomes over both short- and long-term periods. The ACQ-5 scores showed a marked improvement from baseline (3.57±1.39) to 3 days (2.14±1.00, P<0.001) and 3 months (1.11±0.91, P<0.001) after treatment initiation. Similarly, the mini-AQLQ scores increased from 3.84±1.30 at baseline to 5.20±0.93 at 3 days and 6.14±0.91 at 3 months (P<0.001) after treatment initiation. All categories in life quality, including symptoms, activity limitation, emotional function and environment exposure, showed statistically significant improvements (P<0.001 at both time points, data not shown). Additionally, the mMRC scores showed significant improvements in both 3 days and 3 months, indicating dupilumab’s efficacy in alleviating dyspnea (Figure 1).

Figure 1.

ACQ-5, mini-AQLQ, and mMRC changes from baseline to day 3 and month 3 following treatment. ACQ-5, Asthma Control Questionnaire-5; mini-AQLQ, mini-Asthma Quality of Life Questionnaire; mMRC, modified Medical Research Council Dyspnea Scale; SD, standard deviation.

Furthermore, the proportion of patients requiring ICS and OCS significantly changed following treatment. At baseline, 50% of patients required high-dose ICS. After 3 months, the proportion of patients requiring high-dose ICS decreased substantially to 22.5%. OCS use declined more significantly, with fewer patients requiring systemic corticosteroids after 3 days and a further reduction at 3 months, reflecting improved disease control (Table 2). These findings suggest that dupilumab not only enhances symptom control and quality of life but also reduces the need for corticosteroid therapy in both short- and long-term settings.

Table 2. Changes in ICS dose and OCS usage at baseline, day 3, and month 3.

Treatment	Baseline	3 days	P value†	3 months	P value‡
ICS			0.57		0.02
Low	7 (17.5)	4 (10.0)		9 (22.5)
Medium	13 (32.5)	17 (42.5)		22 (55.0)
High	20 (50.0)	19 (47.5)		9 (22.5)
OCS	12 (30.0)	3 (7.5)	0.02	2 (5.0)	0.02

Data are presented as n (%). ^†, baseline vs. 3 days; ^‡, baseline vs. 3 months. ICS, inhaled corticosteroid; OCS, oral corticosteroid.

Sputum characteristics were recorded descriptively based on routine clinical documentation and patient reports. The color, thickness, and volume demonstrated notable improvements over time following dupilumab treatment. Before treatment, most patients reported thick sputum, with significant proportions describing yellow coloration and substantial volume. Three days post-treatment, sputum characteristics began to improve, with a noticeable shift toward thinner and less voluminous sputum. By 3 months, these changes were even more pronounced, with a higher proportion of patients reporting white, thin, and less sputum (Figure 2). These changes suggested that dupilumab had a beneficial effect on reducing airway mucosal inflammation.

Figure 2.

Changes in sputum characteristics following treatment.

Comparison of pure asthma and ACO

Both pure asthma and ACO patients demonstrated improvements in asthma control, quality of life, and dyspnea at 3 days and 3 months post-treatment. Notably, the ACO patients showed slightly greater reductions in the ACQ-5 scores (−1.76±1.22 at day 3 and −2.57±1.72 after 3 months) and the mMRC scores (−1.43±0.94 at day 3 and −2.36±1.28 after 3 months), as well as increases in the mini-AQLQ scores (1.62±1.10 at day 3 and 2.36±1.62 after 3 months). These outcomes were numerically more favorable compared to the pure asthma patients (ACQ-5: −1.25±0.83 at day three and −2.39±1.30 after 3 months; mMRC: −1.00±0.80 at day 3 and −1.88±1.34 after 3 months; mini-AQLQ: 1.21±0.84 at day 3 and 2.26±1.25 after 3 months) (Figure 3). Although the differences were not statistically significant, the consistency of trends across all clinical measures suggests a potentially more pronounced treatment response in the ACO subgroup. To explore the potential confounding effect of age, stratified analyses were performed using an age cut-point of 55 years. Among patients aged <55 years (asthma, n=21; ACO, n=4) and those aged ≥55 years (asthma, n=5; ACO, n=10), mean changes in ACQ-5, mini-AQLQ, and mMRC at day 3 and at month 3 were numerically similar between diagnostic groups, and no within-stratum comparisons reached statistical significance (all P>0.18). These findings suggested that age alone did not materially alter the observed pattern (Figure 4). Also, ICS and OCS requirements, as well as improvements in sputum characteristics, were comparable between the two groups, suggesting the broad therapeutic benefit of dupilumab across distinct airway disease phenotypes.

Figure 3.

ACQ5, mini-AQLQ and mMRC changes between asthma and ACO, from baseline to 3 days and 3 months after treatment. ACO, asthma-COPD overlap; ACQ-5, Asthma Control Questionnaire-5; COPD, chronic obstructive pulmonary disease; mini-AQLQ, mini-Asthma Quality of Life Questionnaire; mMRC, modified Medical Research Council Dyspnea Scale; SD, standard deviation.

Figure 4.

Mean ± SD changes in ACQ-5, mini-AQLQ, and mMRC from baseline to day 3 and month 3 in patients with asthma and ACO, stratified by age (<55 and ≥55 years). ACO, asthma-COPD overlap; ACQ-5, Asthma Control Questionnaire-5; COPD, chronic obstructive pulmonary disease; mini-AQLQ, mini-Asthma Quality of Life Questionnaire; mMRC, modified Medical Research Council Dyspnea Scale; SD, standard deviation.

Safety outcomes

Dupilumab demonstrated a favorable safety profile across the study population, with treatment-related AEs occurring in 35.0% of participants. The AE incidence was similar between the pure asthma (30.8%) and ACO (42.9%) groups. A single discontinuation (2.5%) occurred in the asthma cohort due to eosinophilia. Upper respiratory tract infections constituted the most prevalent AE (12.5% overall), followed by allergic rhinitis, sinusitis, dryness of eyes and mouth, headache, injection-site reactions, myalgia, and fatigue. The safety profile comparison between the pure asthma and ACO patients revealed no clinically meaningful differences in the AE types or frequencies (Table 3).

Table 3. Summary of adverse events observed during the study period.

Adverse events	Overall (N=40)	Pure asthma (N=26)	ACO (N=14)
Any adverse events	14 (35.0)	8 (30.8)	6 (42.9)
Any adverse events leading to permanent discontinuation of the intervention	1 (2.5)	1 (2.5)	0 (0.0)
Elevated EOS	1 (2.5)	0 (0.0)	1 (7.1)
Rhinitis allergic	3 (7.5)	3 (11.5)	0 (0.0)
Upper respiratory tract infection	5 (12.5)	3 (11.5)	2 (14.3)
Sinusitis	2 (5.0)	1 (3.8)	1 (7.1)
Urinary tract infection	0 (0.0)	0 (0.0)	0 (0.0)
Headache	1 (2.5)	1 (3.8)	0 (0.0)
Injection-site reaction	1 (2.5)	1 (3.8)	0 (0.0)
Conjunctivitis	0 (0.0)	0 (0.0)	0 (0.0)
Dryness of the eyes and mouth	2 (5.0)	0 (0.0)	2 (14.3)
Myalgia	1 (2.5)	0 (0.0)	1 (7.1)
Fatigue	1 (2.5)	0 (0.0)	1 (7.1)

Data are presented as n (%). ACO, asthma-COPD overlap; COPD, chronic obstructive pulmonary disease; EOS, eosinophils.

Discussion

This retrospective observational study evaluated short- and long-term clinical outcomes following dupilumab treatment in patients with pure asthma and ACO in a single-centre cohort. The PRISM study recently conducted by Shim et al. compared lung function and exacerbation outcomes after dupilumab treatment between patients with ACO and those with pure asthma. Our findings further extend these observations by focusing on patient-reported clinical symptoms. In our cohort, the consistent therapeutic responses suggested that the presence of COPD features does not appear to attenuate symptom improvement associated with dupilumab, in line with the previous lung function outcomes by Shim et al. (26). Although the ACO group demonstrated numerically greater improvement in certain outcomes, these differences were not statistically significant. Given the limited sample size, these results should be interpreted cautiously, and no definitive conclusions regarding comparative treatment response can be drawn.

Age is a key determinant in studies of ACO. Epidemiological studies consistently show that patients with ACO are older than those with pure asthma (3,34). Current hypotheses propose that cumulative exposures such as smoking, air pollution, and chronic airway inflammation in patients with asthma may progressively lead to airway remodeling and fixed airflow limitation (34). Age and longer disease duration are likely to increase cumulative exposure to these risk factors. In our cohort, patients with ACO were likewise older than those with pure asthma, consistent with epidemiological findings. However, age-stratified analyses did not demonstrate a clear differential effect of age on treatment response between the two groups. Further longitudinal studies are needed to clarify the respective roles of age and disease duration in the development of ACO.

Our study also suggests that dupilumab may be associated with early symptomatic improvement in patients with severe asthma and ACO. Improvements in ACQ-5 and mMRC scores were observed in both asthma and ACO patients within 3 days after treatment initiation, indicating a potential rapid onset of symptom relief, particularly for dyspnea. Additionally, improvements in sputum characteristics over time were also observed, reflecting a reduction in airway inflammation, a key pathological feature of both asthma and ACO (12,35,36). However, these short-term findings must be interpreted with caution, as the day 3 assessments were obtained retrospectively and are subject to substantial recall and information bias.

Compared to previous studies, which reported a mean reduction in ACQ-5 of 1.00 to 1.50 points over 3 months in asthma patients treated with dupilumab (22,37), our study observed a greater reduction of 2.39 points in the pure asthma group. This discrepancy may be attributed to the more severe clinical condition of patients in our study, as reflected by a higher baseline ACQ-5 score of 3.31, compared to the 2.1–2.7 range reported in prior clinical trials. A similar trend was observed in mini-AQLQ scores, further supporting that patients in this study had more severe disease than those enrolled in controlled trials. As this was a single-centre study conducted in a tertiary referral setting, the study population likely represents individuals with more severe or treatment-refractory disease. These results provide exploratory evidence regarding dupilumab use in patients with severe asthma. However, the tertiary care setting may introduce selection bias and limit the generalisability of the findings.

The definition of ACO remains controversial. While some consensus statements consider a ≥10 pack-year smoking history essential for diagnosis (10), our study adopted a more inclusive, clinically relevant approach by not requiring a smoking history. It reflects the observed prevalence of non-smoking ACO in Asian populations, where environmental exposures such as biomass fuel are common (38). Although this broader definition may introduce heterogeneity, it enhances the relevance and applicability of our findings to diverse patient populations.

This study has several limitations. First, baseline pulmonary function tests and fractional exhaled nitric oxide (FeNO) measurements were not available for all patients, due to acute presentation and in some cases, severely compromised respiratory status. This may introduce potential measurement bias if data were disproportionately missing from patients with severer disease. Second, although all eligible patients during the study period were included, the relatively small sample size limited the statistical power to detect clinically meaningful differences between groups. Based on the established minimum clinically important difference of 0.5 points in ACQ5, approximately 147 patients per group would be required to achieve 80% power. Post-hoc power analysis showed small to moderate effect sizes (d=0.07–0.52) with low achieved power (for example, ACQ-5 at day 3: d=0.52, power ≈0.33), indicating that the study was underpowered differences. Accordingly, this study should be regarded as a pilot, hypothesis-generating investigation. The absence of statistically significant differences between groups should not be interpreted as evidence of equivalence. Additionally, given the high baseline symptom burden and the retrospective design, some of the observed improvement may reflect natural symptom fluctuation and regression to the mean rather than a treatment-specific effect. Future larger, prospective and randomized controlled trials are needed to further explore dupilumab’s efficacy and safety in severe asthma and ACO patients.

Conclusions

In conclusion, this retrospective observational study observed improvements in asthma control, quality of life, and patient-reported sputum characteristics while reducing corticosteroid dependency after dupilumab treatment in both pure asthma and ACO patients. The favorable safety profile was also observed in our cohort. However, given the observational design, absence of a control group, and small, imbalanced sample size, these findings should be interpreted with caution. Larger, prospective, and controlled studies are required to further explore the effect of biological therapies on patients with asthma and ACO.

Supplementary

The article’s supplementary files as

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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Zhongshan Hospital Affiliated to Fudan University (No. B2025-048R) and individual consent for this retrospective analysis was waived.

Data Sharing Statement

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DOI: 10.21037/jtd-2025-aw-2051