Analysis of Airway Thickening and Serum Cytokines in COPD Patients with Frequent Exacerbations: A Heart of the Matter

BACKGROUND: Differences in lung function for Chronic Obstructive Pulmonary Disease (COPD) cause bias in the findings when identifying frequent exacerbator phenotype-related causes. The aim of this study was to determine whether computed tomographic (CT) biomarkers and circulating inflammatory biomarkers were associated with the COPD frequent exacerbator phenotype after eliminating the differences in lung function between a frequent exacerbator (FE) group and a non-frequent exacerbator (NFE) group. METHODS: A total of 212 patients with stable COPD were divided into a FE group (n=106) and a NFE group (n=106) according to their exacerbation history. These patients were assessed by spirometry, quantitative CT measurements and blood sample measurements during their stable phase. Univariate and multivariate logistic regression were used to assess the association between airway thickening or serum cytokines and the COPD frequent exacerbator phenotype. Receiver operating characteristic (ROC) curves were calculated for Pi10, WA%, IL-1β and IL-4 to identify frequent exacerbators. RESULTS: Compared with NFE group, FE group had a greater inner perimeter wall thickness of a 10 mm diameter bronchiole (Pi10), a greater airway wall area percentage (WA%) and higher concentrations of IL-1β and IL-4 (p<0.001). After adjusting for sex, age, BMI, FEV1%pred and smoking pack-years, Pi10, WA%, IL-β and IL-4 were independently associated with a frequent exacerbator phenotype (p<0.001). Additionally, there was an increase in the odds ratio of the frequent exacerbator phenotype with increasing Pi10, WA%, IL-4, and IL-1β (p for trend <0.001). The ROC curve demonstrated that IL-1β had a significantly larger calculated area under the curve (p < 0.05) than Pi10, WA% and IL-4. CONCLUSION: Pi10, WA%, IL-4, and IL-1β were independently associated with the frequent exacerbator phenotype among patients with stable COPD, suggesting that chronic airway and systemic inflammation contribute to the frequent exacerbator phenotype. TRIAL REGISTRATION: This trial was registered in Chinese Clinical Trial Registry (https://www.chictr.org.cn). Its registration number is ChiCTR2000038700, and date of registration is September 29, 2020.