Abstract Background Mucus plugging represents a significant pathological feature in COPD, contributing to airway obstruction, faster decline in lung function (FEV1), and increased risk of exacerbations and mortality. While blood eosinophil-mucus plug associations have been reported in COPDGene and ECLIPSE cohorts, the generalizability of this relationship and its underlying molecular mechanisms remain unexplored. Methods Mucus plug pathobiology in the COPD lungs was investigated using a systematic multi-level framework: 1) CT scans from 233 COPD patients (GOLD stage 1∼4) in the SPIROMICS cohort were analyzed and mucus plug distribution was quantified across 20 airway segments. Mucus plug score ranging from 0 to 20 was generated to indicate the number of affected airway segments. 2) The structural correlates of airway obstruction were characterized using CT-derived metrics and previously reported clinical association of mucus-plug scores with blood eosinophil counts (BEC) and lung function parameters were validated. 3) Multi-Omic profiling data (blood transcriptomics 300 (P-value=0.0478). Among patients with mucus plugs, there is a trend for those with BEC≥300 having higher degree of mucus plugging (P-value=0.082). Patients with mucus plugs have worse lung function, indicated by lower FEV1 (P-value=5.54e-9), FEV1/FVC (P-value=6.46e-11), thicker airway wall (by pi10, P-value=0.00488), higher expiratory total volume (P-value=3.19e-8) and lower airway to lung ratio (P-value=5.88e-5). Patients with mucus plugs show higher IgE levels (P-value=0.0250), with highest levels in those with BEC≥300 and severe mucus plugging (score11). Additionally, analysis of blood transcriptomic data revealed enrichment of IL-4 signaling pathway (adj. P=0.00499) and enrichment of dupilumab in-vitro signature (adj. P=0.026) in patients with mucus plugs. We also observed enrichment of neutrophil degranulation (adj. P=1.49e-8) in these patients, suggesting that neutrophilic inflammation might also contribute to mucus pathobiology, alongside or independently of type 2 inflammation. Conclusion Our multi-omics analysis revealed key indicators of type 2 inflammation associated with COPD mucus plugs, characterized by elevated plasma IgE and enriched IL-4 signaling pathway. These complementary mechanisms, together with validation of the previous findings of eosinophil-mucus plug relationship, provide mechanistic evidence for type 2 inflammation and suggest that therapies targeting type 2 inflammation, including Dupixent, might reduce mucus plugging in COPD patients. This abstract is funded by: SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C, 75N92024D00012), grants from the NIH/NHLBI (U01HL137880, U24HL141762, R01HL182622, R01HL144718, and R01HL093081), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from Amgen; AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Bristol Myers Squibb; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; Genentech; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; MGC Diagnostics; Novartis Pharmaceuticals Corporation; Nycomed GmbH; Polarean; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; Theravance Biopharma; Verona; and Mylan/Viatris. This study was sponsored by Sanofi and Regeneron Pharmaceuticals.
Han et al. (Fri,) studied this question.