Lower Airway Dysbiosis Augments Lung Inflammatory Injury in Mild-to-Moderate Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and healthcare costs. Cigarette smoke is a causative factor; however, not all heavy smokers develop COPD. Microbial colonization and infections are contributing factors to disease progression in advanced stages. Objectives: We investigated whether lower airway dysbiosis occurs in mild-to-moderate COPD and analyzed possible mechanistic contributions to COPD pathogenesis. Methods: We recruited 57 patients with a >10 pack-year smoking history: 26 had physiological evidence of COPD, and 31 had normal lung function (smoker control subjects). Bronchoscopy sampled the upper airways, lower airways, and environmental background. Samples were analyzed by 16S rRNA gene sequencing, whole genome, RNA metatranscriptome, and host RNA transcriptome. A preclinical mouse model was used to evaluate the contributions of cigarette smoke and dysbiosis on lower airway inflammatory injury. Measurements and Main Results: Compared with smoker control subjects, microbiome analyses showed that the lower airways of subjects with COPD were enriched with common oral commensals. The lower airway host transcriptomics demonstrated differences in markers of inflammation and tumorigenesis, such as upregulation of IL-17, IL-6, ERK/MAPK, PI3K, MUC1, and MUC4 in mild-to-moderate COPD. Finally, in a preclinical murine model exposed to cigarette smoke, lower airway dysbiosis with common oral commensals augments the inflammatory injury, revealing transcriptomic signatures similar to those observed in human subjects with COPD. Conclusions: Lower airway dysbiosis in the setting of smoke exposure contributes to inflammatory injury early in COPD. Targeting the lower airway microbiome in combination with smoking cessation may be of potential therapeutic relevance.

A Propensity-Matched Cohort Study of Tocilizumab in Patients With Coronavirus Disease 2019.

To determine the impact of tocilizumab, a monoclonal antibody against the interleukin 6 receptor, on survival in patients with coronavirus disease 2019. DESIGN: Observational cohort study of patients hospitalized with coronavirus disease 2019 between March 1, 2020, and April 24, 2020. A propensity-matched (1:1) analysis was used to compare patients who received tocilizumab to controls who did not. Competing risk survival analysis was used to determine the primary outcome of time to mortality, and adjusted log-linear and logistic regression for secondary outcomes. SETTING: Three hospitals within the NYU Langone Health system in New York. PATIENTS: Consecutive adult patients hospitalized with coronavirus disease 2019. INTERVENTION: Tocilizumab 400-mg IV once in addition to standard of care or standard of care alone. MEASUREMENTS AND MAIN RESULTS: Data from 3,580 severe acute respiratory syndrome coronavirus 2 positive qualifying hospitalized patients were included, of whom 497 (13.9%) were treated with tocilizumab. In the analysis of tocilizumab-treated patients and matched controls, fewer tocilizumab-treated patients died (145/497, 29.2%) than did controls (211/497, 42.4%). In the adjusted competing risk regression model, tocilizumab therapy was associated with improved survival relative to controls (hazard ratio = 0.24, 95% CI = 0.18-0.33, p < 0.001). Tocilizumab-treated patients and controls had similar adjusted time to discharge from hospital (hazard ratio = 0.96, 95% CI = 0.78-1.17, p = 0.67). However, they had longer adjusted ICU length of stay (rate ratio = 3.1, 95% CI = 2.5-3.7, p < 0.001) and a higher adjusted infection rate (odds ratio = 4.18, 95% CI = 2.72-6.52, p < 0.001) than controls. CONCLUSIONS: Tocilizumab therapy was associated with significantly improved survival in coronavirus disease 2019 patients. This survival benefit was associated with increased ICU length of stay and increased infection rate, even as more patients in the tocilizumab group were rescued from rapid death. A prospective, randomized, placebo-controlled trial is needed to confirm these findings.