Cytokine- and Airflow-Based Clustering Identifies COPD Phenotypes with Differing Quantitative CT Features

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with distinct inflammatory profiles that may be associated with key pathological features, including emphysema and airway wall remodeling. This study aimed to identify COPD subgroups based on circulating pro- and anti-inflammatory cytokine activity and airflow limitation and to examine their clinical, physiological, and quantitative CT characteristics.

Demographic characteristics, symptom scores, pulmonary function parameters, and quantitative CT indices were collected from patients with stable COPD. Serum levels of pro- and anti-inflammatory cytokines were measured using enzyme-linked immunosorbent assay (ELISA). Cluster analysis was performed using a Gaussian mixture model (GMM).

A total of 319 stable COPD patients were included. Four distinct clusters were identified. Cluster 1 (Severe-low inflammation) was characterized by the lowest circulating inflammatory cytokine levels, the greatest symptom burden, the most severe airflow limitation, an increased exacerbation frequency, and the most extensive emphysema. Cluster 2 (Mild-low inflammation) exhibited low levels of pro- and anti-inflammatory cytokines, mild symptoms, relatively preserved lung function, and a low frequency of annual exacerbations. Cluster 3 (Moderate-elevated inflammation) had moderately elevated levels of pro- and anti-inflammatory cytokines, with intermediate mMRC and CAT scores, pulmonary function impairment and exacerbation frequency. Cluster 4 (Extremely high inflammation) was characterized by markedly elevated levels of pro- and anti-inflammatory cytokines, intermediate symptom burden, relatively preserved pulmonary function, pronounced airway wall thickening and a high frequency of moderate-to-severe exacerbations. Further cytokine ratio analysis revealed an IL-6-related shift in Clusters 3 and 4 and an IL-17-related shift predominantly in Cluster 3.

Integrating cytokine profiles with airflow limitation identified four exploratory COPD phenotypes, highlighting a potential dissociation between systemic inflammation and disease severity. External and longitudinal validation is needed to confirm their reproducibility and clinical relevance.