Type 2 inflammation signature using sputum transcriptomics is associated with COPD clinical characteristics

<b>Introduction:</b> Eosinophilia is a hallmark of type 2 (T2) inflammation that has been implicated as a possible contributor to the pathology of chronic obstructive pulmonary disease (COPD). However, standardized methods to quantify T2 inflammation are lacking. Here, we constructed a novel airway T2 signature (T2S) and examined its relationship with COPD clinical characteristics. <b>Methods:</b> We analyzed induced sputum cells gene expression from participants in the Guangzhou Institute of Respiratory Health (GIRH) cohort (n=153 COPD, n=36 healthy controls) to calculate T2-related module’s epigengene (Epi). Besides, T2S scores were constructed from the principal component (PC) of a T2-associated gene set from an asthma cohort, and the enrichment score (ES) for an ILC2 gene set. Then, the T2S scores were analyzed for correlation with clinical parameters. <b>Results:</b> The Epi T2S score positively correlated with sputum and blood eosinophil concentrations, emphysema index, symptom scores, pack-years of smoking, serum MMP-10 and sputum IL-5, and significantly associated with greater longitudinal exacerbations rates and lung function improvement. In contrast, the Epi T2S score negatively correlated with post-FEV1% predicted, sputum macrophage concentrations and BMI. The Epi T2S scores were higher in participants with eosinophilic COPD and showed a strong positive correlation with other T2S scores, especially with PC T2S. Interestingly, ILC2 ES was the only score that correlated with blood hsCRP and D-dimer levels. <b>Conclusions:</b> Sputum-derived transcriptomic signature of T2 inflammation in COPD is associated with clinical outcomes and T2 transcriptomic signature from an asthma cohort.