The Heterogeneity of COPD: A Comprehensive Review of Clinical Phenotypes

Abstract

Current understanding of the epidemiology and pathogenesis of chronic obstructive pulmonary disease (COPD) is limited by difficulties in defining and classifying the different phenotypes that make up this complex group of disorders. COPD is a multi-factorial and heterogeneous disease and not every patient responds to all available drugs. In order to approach this heterogeneity, an attempt to group patients with similar characteristics that could be associated to a differential clinical outcome has been done by using the term clinical phenotype. Such in-depth phenotyping can pave the way for personalized treatment regimens, ensuring that the most suitable therapies are providChronic obstructive pulmonary disease (COPD) is a complex and heterogeneous condition whose epidemiology and pathophysiology remain incompletely characterized, partly due to challenges in accurately defining and classifying its diverse subtypes. COPD arises from multiple interacting factors, and affected individuals show marked variability in clinical manifestations, disease progression, and response to available therapies, making a uniform treatment approach ineffective. To address this variability, the concept of clinical phenotyping has emerged, aiming to categorize patients into subgroups with shared characteristics that are associated with distinct clinical outcomes. Phenotyping provides a framework for understanding disease heterogeneity and supports the implementation of personalized therapeutic strategies. Broadly, a phenotype refers to any observable characteristic of an organism. In COPD, a clinical phenotype is defined as a single feature or a combination of disease-related attributes that differentiate patients in terms of clinically relevant outcomes such as symptom burden, exacerbation frequency, response to treatment, rate of lung function decline, and mortality. Identification of these phenotypic traits enables prognostic stratification and guides targeted management. Early recognition of COPD subtypes may facilitate timely intervention and improved healthcare delivery. Recent literature has identified several clinically relevant phenotypes, including emphysema-predominant COPD, chronic bronchitis, asthma–COPD overlap, frequent exacerbator phenotype, COPD with bronchiectasis, combined pulmonary fibrosis and emphysema, COPD with obstructive sleep apnoea, tuberculosis-associated COPD, respiratory bronchiolitis with interstitial lung disease, HIV-associated COPD, obesity-related COPD, and COPD in non-smokers etc. Emerging evidence indicates that such phenotypic diversity significantly influences symptoms, exacerbation risk, therapeutic response, lung function decline, and survival.ed. A phenotype can be broadly defined as ‘any observable characteristic of an organism,’ while a COPD phenotype can be more specifically defined as ‘a single or combination of disease attributes that describe differences between individuals with COPD as they relate to meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death).’ Identifying such phenotypes (also described as phenotypic traits) allows grouping of patients according to their prognostic and therapeutic characteristics. Early classification of the COPD subtype will facilitate superior healthcare provision and early intervention where it is most required. The various phenotypes and associations of COPD that has been recognised in recent literature includes Emphysema phenotype, Chronic Bronchitis, Asthma-COPD overlap phenotype, Frequent Exacerbator phenotype, COPD with Bronchiectasis, Combined pulmonary fibrosis with Emphysema, COPD with Obstructive sleep Apnoea, Tuberculosis associated COPD, Respiratory Bronchiolitis with interstitial disease, HIV associated COPD, Obese COPD, nonsmoker phenotype, etc. In the recent years, clinicians also proved that the heterogeneity of COPD is associated with different clinical outcomes including symptoms, exacerbations, and responses to recommended therapy, decline of lung function and death etc.