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Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition. Objectives: We hypothesized that the unbiased integration of different COPD lung omics using a novel multilayer approach might unravel mechanisms associated with clinical characteristics. Methods: We profiled mRNA, microRNA and methylome in lung tissue samples from 135 former smokers with COPD. For each omic (layer), we built a patient network on the basis of molecular similarity. The three networks were used to build a multilayer network, and optimization of multiplex modularity was used to identify patient communities across the three distinct layers. Uncovered communities were related to clinical features. Measurements and Main Results: We identified five patient communities in the multilayer network that were molecularly distinct and related to clinical characteristics, such as FEV1 and blood eosinophils. Two communities (C#3 and C#4) had both similarly low FEV1 values and emphysema but were molecularly different: C#3, but not C#4, presented B- and T-cell signatures and a downregulation of secretory (SCGB1A1/SCGB3A1) and ciliated cells. A machine learning model was set up to discriminate C#3 and C#4 in our cohort and to validate them in an independent cohort. Finally, using spatial transcriptomics, we characterized the small airway differences between C#3 and C#4, identifying an upregulation of T-/B-cell homing chemokines and bacterial response genes in C#3. Conclusions: A novel multilayer network analysis is able to identify clinically relevant COPD patient communities. Patients with similarly low FEV1 and emphysema can have molecularly distinct small airways and immune response patterns, indicating that different endotypes can lead to similar clinical presentation. [ABSTRACT FROM AUTHOR]

Introduction: Acute respiratory distress syndrome (ARDS) is characterized by diffuse lung injury. The impact of pre-existing chronic obstructive pulmonary disease (COPD) or emphysema on ARDS pathogenesis is not well characterized. Methods: Secondary analysis of ARDS patients enrolled in the Acute Lung Injury Registry and Biospecimen Repository at the University of Pittsburgh between June 2012 and September 2021. Patients were categorized into two mutually exclusive groups by the prevalence of COPD or emphysema at the time of ARDS diagnosis. The COPD/emphysema group comprised ARDS patients with radiological evidence of emphysema, chart diagnosis of COPD, or both. Demographics, lung mechanics, and clinical outcomes were obtained from the electronic medical record. Host-response biomarkers known to have validated associations with ARDS were previously measured in plasma and lower respiratory tract samples using a customized Luminex assay. Continuous and categorical variables were compared between groups with and without COPD/emphysema. Results: 217 patients with ARDS were included in the study, 57 (27%) had COPD/emphysema. Patients with COPD/emphysema were older (median 62 [interquartile range 55–69] versus 53 [41–64] years, p < 0.01), more likely to be male (62% vs. 44%, p = 0.02) and had a higher prevalence of congestive heart failure (25% vs. 4%, p < 0.01) compared to patients without COPD/emphysema. Baseline demographics, laboratory parameters, and mechanical ventilatory characteristics were otherwise similar between the two groups. No difference in 90-day mortality was observed between groups; however, patients with COPD/emphysema had shorter duration of intensive care unit (ICU) stay (median 10 [7–18] versus 16 [9–28] days, p = 0.04) and shorter duration of mechanical ventilation (median 7 [4–16] vs. 12 [6–20] days, p = 0.01). Host response biomarkers in serum and lower respiratory tract samples did not significantly differ between groups. Conclusion: ARDS patients with COPD or emphysema had similar respiratory mechanics, host response biomarker profiles, and mortality compared to those without COPD or emphysema but with a shorter median duration of mechanical ventilation and ICU length of stay. Future studies should address differences in clinical and biological responses by disease severity, and should investigate the impact of severity of COPD and emphysema on mechanical ventilation and targeted therapeutic strategies in ARDS. Clinical trial number: Not applicable [ABSTRACT FROM AUTHOR]

Airway mucus plugs are frequently identified on CT scans of patients with COPD with a smoking history without mucus-related symptoms (ie, cough, phlegm [silent mucus plugs]). In patients with COPD, what are the risk and protective factors associated with silent airway mucus plugs? Are silent mucus plugs associated with functional, structural, and clinical measures of disease? We identified mucus plugs on chest CT scans of participants with COPD from the COPDGene study. The mucus plug score was defined as the number of pulmonary segments with mucus plugs, ranging from 0 to 18, and categorized into three groups (0, 1-2, and ≥ 3). We determined risk and protective factors for silent mucus plugs and the associations of silent mucus plugs with measures of disease severity using multivariable linear and logistic regression models. Of 4,363 participants with COPD, 1,739 had no cough or phlegm. Among the 1,739 participants, 627 (36%) had airway mucus plugs identified on CT scan. Risk factors of silent mucus plugs (compared with symptomatic mucus plugs) were older age (OR, 1.02), female sex (OR, 1.40), and Black race (OR, 1.93) (all P values <.01). Among those without cough or phlegm, silent mucus plugs (vs absence of mucus plugs) were associated with worse 6-min walk distance, worse resting arterial oxygen saturation, worse FEV 1 % predicted, greater emphysema, thicker airway walls, and higher odds of severe exacerbation in the past year in adjusted models. Mucus plugs are common in patients with COPD without mucus-related symptoms. Silent mucus plugs are associated with worse functional, structural, and clinical measures of disease. CT scan-identified mucus plugs can complement the evaluation of patients with COPD. [Display omitted] [ABSTRACT FROM AUTHOR]