Background Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials. Methods In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo. Results Of the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval [CI], 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, −1.0; 95% CI, −2.5 to 0; P=0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points (95% CI, –7.6 to 8.2; nominal P=0.94). Conclusions In this randomized trial involving hospitalized patients with severe Covid-19 pneumonia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann–La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov number, NCT04320615 .)

We provide a single-cell atlas of idiopathic pulmonary fibrosis (IPF), a fatal interstitial lung disease, by profiling 312,928 cells from 32 IPF, 28 smoker and nonsmoker controls, and 18 chronic obstructive pulmonary disease (COPD) lungs. Among epithelial cells enriched in IPF, we identify a previously unidentified population of aberrant basaloid cells that coexpress basal epithelial, mesenchymal, senescence, and developmental markers and are located at the edge of myofibroblast foci in the IPF lung. Among vascular endothelial cells, we identify an ectopically expanded cell population transcriptomically identical to bronchial restricted vascular endothelial cells in IPF. We confirm the presence of both populations by immunohistochemistry and independent datasets. Among stromal cells, we identify IPF myofibroblasts and invasive fibroblasts with partially overlapping cells in control and COPD lungs. Last, we confirm previous findings of profibrotic macrophage populations in the IPF lung. Our comprehensive catalog reveals the complexity and diversity of aberrant cellular populations in IPF.

Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for IL-17A. After exposure to bleomycin (BLM), but not Schistosoma mansoni eggs, IL-17A produced by CD4+ and γδ+ T cells induced significant neutrophilia and pulmonary fibrosis. Studies conducted with C57BL/6 il17a−/− mice confirmed an essential role for IL-17A. Mechanistically, using ifnγ−/−, il10−/−, il10−/−il12p40−/−, and il10−/−il17a−/− mice and TGF-β blockade, we demonstrate that IL-17A–driven fibrosis is suppressed by IL-10 and facilitated by IFN-γ and IL-12/23p40. BLM-induced IL-17A production was also TGF-β dependent, and recombinant IL-17A–mediated fibrosis required TGF-β, suggesting cooperative roles for IL-17A and TGF-β in the development of fibrosis. Finally, we show that fibrosis induced by IL-1β, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A. IL-17A and IL-1β were also increased in the bronchoalveolar lavage fluid of patients with IPF. Together, these studies identify a critical role for IL-17A in fibrosis, illustrating the potential utility of targeting IL-17A in the treatment of drug and inflammation-induced fibrosis.