ObjectivesTo examine whether the extent of fibroproliferative changes on high-resolution CT (HRCT) scan influences prognosis, ventilator dependency and the associated outcomes in patients with early acute respiratory distress syndrome (ARDS).DesignA prospective observational cohort study.SettingIntensive care unit in a teaching hospital.Participants85 patients with ARDS who met American-European Consensus Conference Criteria and eligible criteria.InterventionsHRCT scans were performed and prospectively evaluated by two independent observers on the day of diagnosis and graded into six findings according to the extent of fibroproliferation. An overall HRCT score was obtained by previously published method.Primary and secondary outcomesThe primary outcome was 60-day mortality. Secondary outcomes included the number of ventilator-free days, organ failure-free days, the incidence of barotraumas and the occurrence of ventilator-associated pneumonia.ResultsHigher HRCT scores were associated with statistically significant decreases in organ failure-free days as well as ventilator-free days. Multivariate Cox proportional hazards model showed that the HRCT score remained an independent risk factor for mortality (HR 1.20; 95% CI 1.06 to 1.36; p=0.005). Multivariate analysis also revealed that the CT score had predictive value for ventilator weaning within 28 days (OR 0.63; 95% CI 0.48 to 0.82; p=0.0006) as well as for an incidence of barotraumas (OR 1.61; 95% CI 1.08 to 2.38; p=0.018) and for an occurrence of ventilator-associated pneumonia (OR 1.46; 95% CI 1.13 to 1.89; p=0.004). A HRCT score <210 enabled prediction of 60-day survival with 71% sensitivity and 72% specificity and of ventilator-weaning within 28 days with 75% sensitivity and 76% specificity.ConclusionsPulmonary fibroproliferation assessed by HRCT in patients with early ARDS predicts increased mortality with an increased susceptibility to multiple organ failure, including ventilator dependency and its associated outcomes.

Dendritic cells (DCs) play critical roles in innate immunity and adaptive immunity (4). Immature DCs reside in peripheral tissues, where they serve as sentinels for foreign antigens and microbial pathogens. Upon activation, immature DCs undergo maturation and migrate to the lymph nodes. During maturation, DCs acquire an enhanced capacity to form and accumulate peptides, major histocompatibility complex (MHC) class II molecules, costimulatory molecules (such as CD40, CD80, and CD86), and antigens of unknown functions (such as CD83 and DC-LAMP) (10). Mature DCs can prime naïve T cells and initiate primary T-cell-mediated immune responses (4). In addition, there is increasing evidence that DCs in situ induce antigen-specific unresponsiveness or tolerance in central lymphoid organs and in peripheral tissues (4, 31). Thus, DCs play a crucial role during the initiation and regulation of immune responses. Recently, we and others reported that DCs are essential for granuloma formation against bacterial antigens in animal models (12,33,36).Osteopontin (OPN), also known as early T-lymphocyte activation-1 (Eta-1), is a phosphoprotein that contains arginineglycine-aspartate (RGD). Although OPN is classified as an extracellular matrix (ECM) protein, OPN has only recently been shown to be an important component of early cellular immune responses (18). OPN has various functions in chemotaxis for immune cells, tumor metastasis, neovascularization, and host defense, including control of nitric oxide production, control of infection, and control of cell adhesion (3,5,9,21,25). These mechanisms are regulated by posttranslational modifications, such as cleavage by thrombin, addition of a glucose chain, and phosphorylation. Various immunological disorders are associated with high levels of OPN expression (8,15). Analyses of OPN-deficient mice revealed that OPN plays an important immunological role in granuloma formation (23), acid-fast bacillus disease (21), and carcinoma metastasis (5). The role of OPN in inflammation suggests that ECM-related proteins may function as pleiotropic cytokines to regulate immune responses. Activated macrophages, lymphocytes, and natural killer (NK) cells produce OPN in response to various stimuli (23). However, there are no reports of the effects of OPN on DCs, with the exception of a single report of the migratory effect of OPN on cutaneous Langerhans cells and DCs in a mouse allergic cutaneous hypersensitivity model (34). The direct effect of OPN on the development and activation of DCs has not been clarified. Thus, we sought to characterize the functional interaction between OPN and DCs by examining the effects of OPN on differentiation, maturation, and function of human monocyte-derived immature and mature DCs. We report here that human monocyte-derived dendritic cell (Mo-DC) can produce OPN that enhances differentiation, maturation, and survival of DCs by autocrine and/or paracrine pathways. MATERIALS AND METHODSReagents. Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) ...

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

BackgroundAcute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a fatal condition without an established pharmaceutical treatment. Most patients are treated with high-dose corticosteroids and broad-spectrum antibiotics. Azithromycin is a macrolide with immunomodulatory activity and may be beneficial for treatment of acute lung injury. The objective of this study was to determine the effect of azithromycin on survival of patients with idiopathic AE of IPF.MethodsWe evaluated 85 consecutive patients hospitalized in our department for idiopathic AE of IPF from April 2005 to August 2016. The initial 47 patients were treated with a fluoroquinolone-based regimen (control group), and the following 38 consecutive patients were treated with azithromycin (500 mg/day) for 5 days. Idiopathic AE of IPF was defined using the criteria established by the 2016 International Working Group.ResultsMortality in patients treated with azithromycin was significantly lower than in those treated with fluoroquinolones (azithromycin, 26% vs. control, 70%; p < 0.001). Multivariate analysis revealed that the two variables were independently correlated with 60-day mortality as determined by the Acute Physiology and Chronic Health Evaluation II score (p = 0.002) and azithromycin use (p < 0.001).ConclusionAzithromycin may improve survival in patients with idiopathic AE of IPF.