Chronic obstructive pulmonary disease (COPD) remains under-recognized as a severe condition despite its global burden. This review revisits the concept of “difficult-to-treat” disease, widely applied in asthma, and explores its relevance to COPD. Through a comparative approach, we highlight key pathophysiological overlaps and differences between asthma and COPD, particularly the distinct inflammatory profiles and lack of robust biomarkers in COPD that hinder individualized treatment. A subset of COPD patients remains highly symptomatic and vulnerable to frequent exacerbations and hospitalizations despite optimal therapy—posing a clinical challenge beyond the emerging definition of “uncontrolled COPD” and reflecting a significant unmet need within the current therapeutic arsenal.

Building on lessons from severe asthma, this review proposes a multidimensional framework for defining and managing difficult-to-treat COPD, incorporating biological phenotyping, treatable traits, comorbidities, environmental exposure, and social determinants of health. We discuss the importance of confirming diagnosis, addressing modifiable factors (e.g., inhaler misuse, poor adherence), and exploring refractory symptoms such as persistent dyspnea or hypoxemia, including the role of pulmonary hypertension and extrapulmonary contributors.

The review also evaluates therapeutic strategies for this population, from pharmacological and non-pharmacological interventions to advanced options such as biologics, lung volume reduction, and transplantation. Finally, we advocate for earlier integration of palliative care and broader inclusion in clinical trials.

By refining the definition of difficult-to-treat COPD, we aim to promote more personalized, biomarker-guided care strategies that address unmet needs and improve outcomes in this high-risk population.