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Identifying patients at high mortality risk can improve outcomes in SARS-CoV-2 pneumonia (COVID-19). We validate a prognostic model for mortality in patients hospitalized with COVID-19 receiving dexamethasone using a retrospective multi-centered study. This is a retrospective cohort study using the National COVID Cohort Collaborative (NC3) including 9,708 adult patients admitted for COVID-19 who received dexamethasone within 24 h of admission and remained hospitalized for 72 h. Previous work from a single-center cohort informed selection of prognostic variables including A ge, day 3 neutrophil-lymphocyte R atio, and day 3 C -reactive protein level ( ARC Score). Variables from the development cohort were analyzed in a training cohort, and the resulting model was tested in a validation cohort. Age and day 3 measures of the neutrophil-lymphocyte ratio and C-reactive protein level were included in a logistic regression model to predict 28-day mortality. The 28-day mortality in this patient population was 15.4%. The area under the curve for the ARC model was 0.77 (95% confidence interval, 0.74–0.79). The A ge, neutrophil-lymphocyte R atio, and C -reactive protein (ARC) score identifies COVID-19 patients with a high risk of mortality within 28 days of hospitalization using clinical information on day 3 of hospitalization. ARC scores perform well across all variants of concern.

Reverse triggering is an underdiagnosed form of patient-ventilator asynchrony in which a passive ventilator-delivered breath triggers a neural response resulting in involuntary patient effort and diaphragmatic contraction. Reverse triggering may significantly impact patient outcomes, and the unique physiology underscores critical potential implications for drug-device-patient interactions. The purpose of this review is to summarize what is known of reverse triggering and its pharmacotherapeutic consequences, with a particular focus on describing reported cases, physiology, historical context, epidemiology, and management. The PubMed database was searched for publications that reported patients presenting with reverse triggering. The current body of evidence suggests that deep sedation may predispose patients to episodes of reverse triggering; as such, providers may consider decreasing sedation or modifying ventilator settings in patients exhibiting ventilator asynchrony as an initial measure. Increased clinician awareness and research focus are necessary to understand appropriate management of reverse triggering and its association with patient outcomes.

Background Foxp3 + regulatory T cells (Tregs) play essential roles in immune homeostasis and repair of damaged lung tissue. We hypothesized that patients whose lung injury resolves quickly, as measured by time to liberation from mechanical ventilation, have a higher percentage of Tregs amongst CD4 + T cells in either airway, bronchoalveolar lavage (BAL) or peripheral blood samples. Methods We prospectively enrolled patients with ARDS requiring mechanical ventilation and collected serial samples, the first within 72 h of ARDS diagnosis (day 0) and the second 48–96 h later (day 3). We analyzed immune cell populations and cytokines in BAL, tracheal aspirates and peripheral blood, as well as cytokines in plasma, obtained at the time of bronchoscopy. The study cohort was divided into fast resolvers (FR; n = 8) and slow resolvers (SR; n = 5), based on the median number of days until first extubation for all participants (n = 13). The primary measure was the percentage of CD4 + T cells that were Tregs. Results The BAL of FR contained more Tregs than SR. This finding did not extend to Tregs in tracheal aspirates or blood. BAL Tregs expressed more of the full-length FOXP3 than a splice variant missing exon 2 compared to Tregs in simultaneously obtained peripheral blood. Conclusion Tregs are present in the bronchoalveolar space during ARDS. A greater percentage of CD4 + cells were Tregs in the BAL of FR than SR. Tregs may play a role in the resolution of ARDS, and enhancing their numbers or functions may be a therapeutic target.

The immunologic responses that occur early in the acute respiratory distress syndrome (ARDS) elicit immune‐mediated damage. The mechanisms underlying the resolution of ARDS, particularly the role of signaling molecules in regulating immune cell kinetics, remain important questions. Th1‐mediated responses can contribute to the pathogenesis of acute lung injury (ALI). Interferon‐gamma (IFN‐γ) orchestrates early inflammatory events, enhancing immune‐mediated damage. The current study investigated IFN‐γ during resolution in several experimental models of ALI. The absence of IFN‐γ resulted in altered kinetics of lymphocyte and macrophage responses, suggesting that IFN‐γ present in this microenvironment is influential in ALI resolution. Genetic deficiency of IFN‐γ or administering neutralizing IFN‐γ antibodies accelerated the pace of resolution. Neutralizing IFN‐γ decreased the numbers of interstitial and inflammatory macrophages and increased alveolar macrophage numbers during resolution. Our results underline the complexity of lung injury resolution and provide insight into the effects through which altered IFN‐γ concentrations affect immune cell kinetics and the rate of resolution. These findings suggest that therapies that spatially or temporally control IFN‐γ signaling may promote ALI resolution. Identifying and elucidating the mechanisms critical to ALI resolution will allow the development of therapeutic approaches to minimize collateral tissue damage without adversely altering the response to injury. Neutralizing IFN‐γ decreased the numbers of interstitial and inflammatory macrophages and increased the alveolar macrophage numbers during resolution. These results underline the complexity of lung injury resolution and provide insight into the effects through which altered IFN‐γ concentrations affect immune cell kinetics and the rate of resolution. These findings suggest that therapies that spatially or temporally control IFN‐γ signaling may promote ALI resolution.

Repair of the lung epithelium after injury is a critical component for resolution; however, the processes necessary to drive epithelial resolution are not clearly defined. Published data demonstrate that Foxp3+ regulatory T cells (Tregs) enhance alveolar epithelial proliferation after injury, and Tregs in vitro directly promote type II alveolar epithelial cell (AT2) proliferation, in part by a contact-independent mechanism. Therefore, we sought to determine the contribution of Treg-specific expression of a growth factor that is known to be important in lung repair, keratinocyte growth factor (kgf). The data demonstrate that Tregs express kgf and that Treg-specific expression of kgf regulates alveolar epithelial proliferation during the resolution phase of acute lung injury and in a model of regenerative alveologenesis in vivo. In vitro experiments demonstrate that AT2 cells cocultured with Tregs lacking kgf have decreased rates of proliferation compared with AT2 cells cocultured with wild-type Tregs. Moreover, Tregs isolated from lung tissue and grown in culture express higher levels of two growth factors that are important for lung repair (kgf and amphiregulin) compared with Tregs isolated from splenic tissue. Lastly, Tregs isolated from human lung tissue can be stimulated ex vivo to induce kgf expression. This study reveals mechanisms by which Tregs direct tissue-reparative effects during resolution after acute lung injury, further supporting the emerging role of Tregs in tissue repair.

Leist and Mock discuss the paper by Fessler et al reporting on the antiviral effects of 25HC against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro as well as the role of endogenous 25HC or exogenous administration of 25HC in two different murine models of SARS-CoV-2-induced lung disease. This report will interest those studying the complex interplay of cholesterol biology with infection and immunity.

Here, the authors examine a report about the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which represents the latest threat to global health security, and the pressure to identify effective therapeutics during this pandemic is immense. This stress has led to the use of unproven therapies with greater than minimal risk such as the use of IL-6 receptor antagonists. The prevailing theory is that SARS-CoV-2 induces the production of cytokines, in particular IL-6, and that these cytokines are a key driver of both lung damage and mortality. The authors are critical that it is crucial to recognize the uncertainty surrounding the role of IL-6 in viral infections. In experimental viral infection models, IL-6 is a pleiotropic cytokine with complex interactions with multiple signaling cascades, at times producing either proinflammatory or antiinflammatory effects. As such, it remains unknown whether elevated IL-6 in viral infections represents a therapeutic target or part of a functioning adaptive immune response.

Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1−/− mice received intratracheal LPS. Fibroproliferation was characterized by histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1−/− mice received CD4+CD25+ (Tregs) or CD4+CD25− Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)–CXCR4 pathway in ALI fibroproliferation, Rag-1−/− mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1−/− mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1−/− mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12–CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12–CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.

Acute respiratory distress syndrome (ARDS) is a common and often fatal inflammatory lung condition without effective targeted therapies. Regulatory T cells (Tregs) resolve lung inflammation, but mechanisms that enhance Tregs to promote resolution of established damage remain unknown. DNA demethylation at the forkhead box protein 3 (Foxp3) locus and other key Treg loci typify the Treg lineage. To test how dynamic DNA demethylation affects lung injury resolution, we administered the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) to wild-type (WT) mice beginning 24 hours after intratracheal LPS-induced lung injury. Mice that received DAC exhibited accelerated resolution of their injury. Lung CD4+CD25hiFoxp3+ Tregs from DAC-treated WT mice increased in number and displayed enhanced Foxp3 expression, activation state, suppressive phenotype, and proliferative capacity. Lymphocyte-deficient recombinase activating gene-1–null mice and Treg-depleted (diphtheria toxin-treated Foxp3DTR) mice did not resolve their injury in response to DAC. Adoptive transfer of 2 × 105 DAC-treated, but not vehicle-treated, exogenous Tregs rescued Treg-deficient mice from ongoing lung inflammation. In addition, in WT mice with influenza-induced lung inflammation, DAC rescue treatment facilitated recovery of their injury and promoted an increase in lung Treg number. Thus, DNA methyltransferase inhibition, at least in part, augments Treg number and function to accelerate repair of experimental lung injury. Epigenetic pathways represent novel manipulable targets for the treatment of ARDS.

The complex role of neutrophils in modulating the inflammatory response is increasingly appreciated. Our studies profiled the expression of mRNAs and microRNAs (miRs) in lung neutrophils in mice during S. pneumoniae pneumonia and performed in depth in silico analyses. Lung neutrophils were isolated 24 hours after intratracheal instillation of PBS or S. pneumoniae, and differentially expressed (DE) mRNAs and miRs were identified. Lung neutrophils from mice with S. pneumoniae pneumonia contained 4127 DE mRNAs, 36% of which were upregulated at least 2-fold. During pneumonia, lung neutrophils increase expression of pattern recognition receptors, receptors for inflammatory mediators, transcription factors including NF-κB and AP-1, Nrf2 targets, cytokines, chemokines and other inflammatory mediators. Interestingly, neutrophils responded to Type I interferons, whereas they both produced and responded to Type II interferon. Expression of regulators of the inflammatory and immune response was verified at the mRNA and protein level. Of approximately 1100 miRs queried, 31 increased and 67 decreased more than 2-fold in neutrophils from S. pneumoniae pneumonia. Network analyses of potential DE miR-target DE mRNA interactions revealed candidate key regulatory miRs. Thus, S. pneumoniae modulates mRNA and miR expression by lung neutrophils, increasing their ability to respond and facilitating host defense.