Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is characterized by the presence of multiple clinical features of both asthma and COPD (1). This term was formally established in the 2015 joint report by the Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) (2). However, the term “syndrome” implied a single disease entity, which was later recognized as an oversimplification of the complex and heterogeneous nature of these overlapping conditions (3). In 2017, the American Thoracic Society (ATS) and the National Heart, Lung, and Blood Institute (NHLBI) have further refined ACOS as ACO to emphasize that it is not a single disease but a cluster of phenotypes driven by distinct underlying mechanisms (3). These documents highlighted a pragmatic diagnostic framework for ACO, defined by a history of asthma, significant smoking exposure, and persistent airflow obstruction, while acknowledging the need for individualized assessment.

Key clinical manifestations of ACO include persistent airflow obstruction, mixed inflammatory patterns, and concurrent symptoms of both disorders (4). The pathophysiology of ACO involves an interplay between neutrophilic inflammation and Th2-driven eosinophilic inflammation, with elevated Th2 cytokines (e.g., IL-4, IL-5, IL-13) promoting IgE production, eosinophil recruitment, and airway hyperresponsiveness (5–7). This Th2-inflammation contrasts with the neutrophilic inflammation typical of COPD, yet overlaps with the Th2 signature of asthma, contributing to diagnostic and therapeutic complexity.

Although a standardized diagnostic framework for ACO is currently lacking, core diagnostic criteria typically integrate key features of both conditions. The diagnostic approach often differs based on whether the patient is initially assessed from an asthma or a COPD perspective. For patients with a primary diagnosis of COPD, features suggestive of ACO include a documented history of asthma, particularly with onset before age 40, a significant bronchodilator (BD) response evidenced by an increase in forced expiratory volume in one second (FEV₁) of at least 15%, or the presence of airway hyper-responsiveness. Conversely, in patients with diagnosed asthma, the diagnosis of ACO usually requires a significant smoking history of at least 10 pack-years together with persistent airflow limitation demonstrated by a post-BD FEV₁ / forced vital capacity (FVC) ratio below 0.7 (8–10).

The reported prevalence of ACO varies widely, likely due to differences in diagnostic criteria (9). Previous studies indicate that the combined prevalence of ACO in the general population, asthma patients, and COPD patients is 2.0, 26.5, and 29.6% respectively (11). Moreover, ACO patients experience a higher disease burden, reduced health-related quality of life, and more frequent and severe exacerbations compared to those with isolated COPD or asthma (8, 12, 13). Management of ACO typically follows a stepwise or escalating regimen based on symptom progression and clinical worsening, similar to asthma or COPD, with pharmacological interventions primarily involving inhaled glucocorticoids (ICS) and bronchodilators (14). Nevertheless, a significant proportion of patients with ACO and severe asthma exhibit poor or absent response to glucocorticoid therapy, a condition often referred to as steroid resistance (15, 16). This resistance considerably limits the efficacy of conventional anti-inflammatory regimens, underscoring the need for alternative therapeutic strategies. In this context, biologics that target specific inflammatory pathways have gained increasing importance as potential treatment options for this challenging patient subgroup (17).

Omallizumab, an anti-IgE monoclonal antibody, has been approved for the treatment of allergic asthma in patients sensitized to perennial allergens and IgE levels between 30 and 700 kU/L (18). Previous studies have shown that omalizumab reduces acute asthma exacerbations, improves Asthma Control Test (ACT) scores, and decreases neutrophil counts (19). A long-term retrospective analysis further indicated that 12 months of omalizumab treatment significantly improved lung function and reduced airway inflammation in patients with severe asthma (20).

However, most omalizumab efficacy studies have focused on populations, with limited investigations in ACO cohorts (21, 22). Emerging evidence suggests that Th2-inflammatory biomarkers may predict the responses to biologics like omalizumab (23, 24), though their utility in ACO remains debated due to confounding neutrophilic inflammation. This retrospective cohort study aimed to evaluate the therapeutic efficacy of omalizumab in non-ACO asthma and ACO patients, while offering new insights into clinical management of ACO.

In this retrospective cohort study, we primarily aimed to compare treatment responses to omalizumab over 20 weeks between asthma patients with and without ACO. To account for diagnostic heterogeneity, our study incorporated two distinct ACO criteria, with the analysis of their impact constituting an exploratory aim. The differential treatment responses observed between ACO and non-ACO patients highlight the clinical challenge of applying asthma-related biological therapies to ACO, particularly when Th2-driven inflammation coexists with non-Th2 inflammatory pathways.

The clinical profile of ACO patients provides a tangible reflection of this pathophysiological complexity. The baseline characteristics of ACO patients, characterized by poorer lung function and a higher proportion of smokers compared to those with non-ACO asthma, provide a crucial context for interpreting the differential responses to omalizumab observed in our study. These pre-existing differences suggest that the distinct pathophysiology of ACO may underlie its modified response to Th2-targeted therapy.

As an anti-IgE monoclonal antibody, omalizumab inhibits IgE from binding to its receptor on mast cells and basophils, thereby preventing their activation, reducing the release of cytokines such as IL-5, and suppressing eosinophil recruitment and activation (25). This mechanism underpins its targeted anti-inflammatory effect in Th2-high driven disease. A recent long-term retrospective study defined reductions in FeNO and EOS counts as integral components of a “complete response” to biologics in severe asthma (20). Our observations are in alignment with this definition, demonstrating a significant decrease in both biomarkers following omalizumab treatment, which reflects the core biological mechanism of omalizumab in targeting Th2 inflammation (26). Furthermore, our subgroup analysis based on baseline peripheral blood EOS counts provided deeper insights, revealing that the magnitude of eosinophilic inflammation was a pivotal determinant of the treatment response to anti-IgE therapy. Specifically, patients with baseline blood EOS counts ≥150 cells/μL demonstrated a significantly stronger treatment response to omalizumab compared to those with values below this threshold. This suggests that assessing eosinophilic inflammation may hold greater predictive value for omalizumab responsiveness than the broad syndromic classification of ACO alone, underscoring a personalized, biomarker-driven approach. Consequently, our findings add to the body of evidence supporting the role of EOS and FeNO as potential biomarkers for identifying patients likely to benefit from omalizumab treatment (27–32). However, the predictive value of FeNO and EOS as standalone biomarkers remains limited (25, 33). Therefore, identifying more robust biomarkers to predict omalizumab efficacy remains an ongoing priority. This endeavor has expanded to include candidates such as serum periostin, a downstream marker of IL-13 activity (34), dynamic changes in total IgE levels early in treatment (35), and markers of eosinophilic inflammation in the upper airways (36).

In addition to exploring new candidates, our findings call for a re-evaluation of classic biomarkers, particularly total IgE, in the context of treatment. Our study observed a significant increase in serum total IgE levels in non-ACO asthma patients after omalizumab initiation, a finding that contrasts with certain previous reports (37). This apparent discrepancy can be explained by its mechanism: omalizumab binds to free IgE, forming large, stable complexes that are detected in standard assays, leading to a transient elevation in measured total IgE during early treatment—even as bioactive free IgE declines substantially (30, 37, 38). Thus, the observed rise in total IgE does not indicate treatment failure but rather reflects expected pharmacological activity. Consequently, serum total IgE proves to be a suboptimal short-term efficacy biomarker for omalizumab (39, 40).

Beyond the monitoring of biomarkers, the evaluation of therapeutic response should prioritize tangible clinical improvements, such as symptom control and reduced exacerbation frequency. In our study, both ACO and non-ACO groups showed improved symptom control and reduced exacerbations. However, longitudinal improvement in biomarkers and lung function was observed only in the non-ACO group, a finding consistent with the Australian Xolair Registry report that omalizumab improved quality of life but not lung function in ACO patients (41). This underscores that for ACO patients, the primary treatment goal may not be to reverse lung function decline but to maintain disease stability and reduce the burden of life, an objective supported by a decrease in exacerbation rates and hormone use. This is corroborated by a post hoc analysis of the PROSPERO trial, which found both groups experienced improvements in ACT scores and exacerbation rates (42). Therefore, although omalizumab demonstrates lower efficacy in ACO than in non-ACO patients, it remains a viable therapeutic option for symptom management in this population (43, 44).

The observed heterogeneity in treatment response underscores the importance of how ACO is defined. Our exploratory analysis using two distinct diagnostic criteria provided further insight. The significant differences in longitudinal changes of FeNO, IgE and pre-BD FEV₁%pred between groups under criterion A, but not under criterion B, suggest that these criteria may select for patient populations with differing underlying inflammatory endotypes. Criterion A, with its emphasis on clinical history, might better identify an “asthma-dominant” ACO phenotype, characterized by a stronger Th2 component, which is consequently more responsive to Th2-targeted therapy like omalizumab. In contrast, criterion B, which incorporates fixed airflow limitation and smoking history, might capture a “COPD-dominant” ACO phenotype where non-Th2 inflammatory pathways such as neutrophilic inflammation play a more dominant role, explaining the attenuated response. This supports the concept of ACO as an umbrella term for mixed inflammation (45), encompassing subtypes like smoking asthmatics (SA) and COPD with eosinophilia (COPD-e) (46). Consequently, the Th2 inflammatory endotype and its associated biomarkers (e.g., EOS, FeNO) are more informative predictors of omalizumab responsiveness than the broad syndromic classification of ACO itself (47). Therefore, in clinical practice, evaluating a patient’s individual inflammatory burden may hold greater value for biologic selection than the specific ACO definition used.

This study provides a multidimensional comparison of omalizumab efficacy in ACO versus non-ACO asthma, stratified by two diagnostic criteria. However, several limitations should be considered. Firstly, the retrospective design, limited sample size, and short follow-up duration constrain the generalizability and assessment of long-term outcomes. Secondly, the use of the fixed-ratio (FEV₁/FVC < 0.70) for ACO-B classification, while clinically pragmatic, may less accurately define airflow limitation compared to the lower limit of normal (LLN). Finally, the absence of functional validation (e.g., bronchoscopic biopsies) limits causal inferences from biomarker correlations. Consequently, future research requires larger longitudinal cohorts to validate diagnostic criteria and confirm response durability, incorporate free IgE measurements to clarify the significance of post-treatment total IgE elevation, and employ direct tissue sampling to mechanistically link Th2 inflammation reduction to clinical improvement.

Our study clearly indicates that the presence of a Th2-high inflammatory endotype—not the specific ACO diagnostic label—is the key predictor of omalizumab response. While all patient groups experienced clinical benefits from omalizumab, including reduced exacerbations and improved symptom control, the degree of improvement in biomarkers and lung function was most pronounced in non-ACO asthma patients and those identified by the COPD history-based ACO criterion, which effectively selects for a stronger Th2 phenotype. Prioritizing direct assessment of Th2 inflammation, rather than relying on the ACO definition, provides a better guide for selecting biologic therapy.