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Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous smoking-related disease characterized by airway obstruction and inflammation. This inflammation may persist even after smoking cessation and responds variably to corticosteroids. Personalizing treatment to biologically similar "molecular phenotypes" may improve therapeutic efficacy in COPD. IL-17A is involved in neutrophilic inflammation and corticosteroid resistance, and thus may be particularly important in a COPD molecular phenotype., Methods: We generated a gene expression signature of IL-17A response in bronchial airway epithelial brushings from smokers with and without COPD (n = 238), and validated it using data from 2 randomized trials of IL-17 blockade in psoriasis. This IL-17 signature was related to clinical and pathologic characteristics in 2 additional human studies of COPD: (a) SPIROMICS (n = 47), which included former and current smokers with COPD, and (b) GLUCOLD (n = 79), in which COPD participants were randomized to placebo or corticosteroids., Results: The IL-17 signature was associated with an inflammatory profile characteristic of an IL-17 response, including increased airway neutrophils and macrophages. In SPIROMICS the signature was associated with increased airway obstruction and functional small airways disease on quantitative chest CT. In GLUCOLD the signature was associated with decreased response to corticosteroids, irrespective of airway eosinophilic or type 2 inflammation., Conclusion: These data suggest that a gene signature of IL-17 airway epithelial response distinguishes a biologically, radiographically, and clinically distinct COPD subgroup that may benefit from personalized therapy., Trial Registration: ClinicalTrials.gov NCT01969344., Funding: Primary support from the NIH, grants K23HL123778, K12HL11999, U19AI077439, DK072517, U01HL137880, K24HL137013 and R01HL121774 and contracts HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C and HHSN268200900020C.

Purpose of Review: The asthma-COPD overlap syndrome (ACOS) has reemerged in the medical literature. This review addresses our current understanding of ACOS as a clinical and biological entity and how new and existing therapies may be targeted to this group., Recent Findings: Many studies suggest that ACOS is common and associated with more morbidity than asthma and COPD in general. However, there is no consensus on an ACOS definition, likely due to the heterogeneity of the disease. Variable definitions have led to variable results in ACOS studies. Given this clinical variability, biomarkers (e.g., eosinophils and type 2 inflammatory markers) are increasingly being used to identify an ACOS molecular phenotype which appears to be more responsive to inhaled corticosteroids. Although ACOS has become a popular diagnosis, it is unclear whether identifying ACOS as a separate disease entity is clinically useful. Future studies should focus on identifying key clinical features and biomarkers that characterize vulnerable and treatment-responsive patients.