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Background: Interleukin (IL)-6 trans-signalling (IL-6TS) is emerging as a pathogenic mechanism in chronic respiratory diseases; however, the drivers of IL-6TS in the airways and the phenotypic characteristic of patients with increased IL-6TS pathway activation remain poorly understood., Objective: Our aim was to identify and characterise COPD patients with increased airway IL-6TS and to elucidate the biological drivers of IL-6TS pathway activation., Methods: We used an IL-6TS-specific sputum biomarker profile (soluble IL-6 receptor (sIL-6R), IL-6, IL-1β, IL-8, macrophage inflammatory protein-1β) to stratify sputum data from patients with COPD (n=74; Biomarkers to Target Antibiotic and Systemic Corticosteroid Therapy in COPD Exacerbation (BEAT-COPD)) by hierarchical clustering. The IL-6TS signature was related to clinical characteristics and sputum microbiome profiles. The induction of neutrophil extracellular trap formation (NETosis) and IL-6TS by Haemophilus influenzae were studied in human neutrophils., Results: Hierarchical clustering revealed an IL-6TS-high subset (n=24) of COPD patients, who shared phenotypic traits with an IL-6TS-high subset previously identified in asthma. The subset was characterised by increased sputum cell counts (p=0.0001), persistent sputum neutrophilia (p=0.0004), reduced quality of life (Chronic Respiratory Questionnaire total score; p=0.008), and increased levels of pro-inflammatory mediators and matrix metalloproteinases in sputum. IL-6TS-high COPD patients showed an increase in Proteobacteria, with Haemophilus as the dominating genus. NETosis induced by H. influenzae was identified as a potential mechanism for increased sIL-6R levels. This was supported by a significant positive correlation between sIL-6R and NETosis markers in bronchoalveolar lavage fluid from COPD patients., Conclusion: IL-6TS pathway activation due to chronic colonisation with Haemophilus may be an important disease driver in a subset of COPD patients., Competing Interests: Conflict of interest: S. Winslow is an employee and a share/stockholder of AstraZeneca. Conflict of interest: L. Odqvist is an employee and a share/stockholder of AstraZeneca. Conflict of interest: S. Diver has nothing to disclose. Conflict of interest: R. Riise is an employee and a share/stockholder of AstraZeneca. Conflict of interest: S. Abdillahi is an employee and a share/stockholder of AstraZeneca. Conflict of interest: C. Wingren is an employee and a share/stockholder of AstraZeneca. Conflict of interest: H. Lindmark is an employee and a share/stockholder of AstraZeneca. Conflict of interest: A. Wellner is an employee and a share/stockholder of AstraZeneca. Conflict of interest: S. Lundin is an employee and a share/stockholder of AstraZeneca. Conflict of interest: L. Yrlid is an employee and a share/stockholder of AstraZeneca. Conflict of interest: E. Ax is an employee and a share/stockholder of AstraZeneca. Conflict of interest: R. Djukanovic reports personal fees for lectures and consultancy from TEVA and Novartis, personal fees for consultancy from Synairgen, personal fees for meeting participation from GlaxoSmithKline, outside the submitted work. Conflict of interest: S. Sridhar is an employee and a share/stockholder of AstraZeneca. Conflict of interest: A. Higham has nothing to disclose. Conflict of interest: D. Singh reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Theravance, Verona, outside the submitted work. Conflict of interest: T. Southworth has nothing to disclose. Conflict of interest: C.E. Brightling reports personal fees from GSK, AstraZeneca/MedImmune, Boehringer Ingelheim, Novartis, Roche and Chiesi, outside the submitted work. Conflict of interest: H.K. Olsson is an employee and a share/stockholder of AstraZeneca. Conflict of interest: Z. Jevnikar is an employee and a share/stockholder of AstraZeneca., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)