Daily Ards Research Analysis

BACKGROUND: Sepsis is a common indirect insult leading to acute respiratory distress syndrome (ARDS). Circulating extracellular vesicles (EVs) have been reported to participate in the pathogenesis of sepsis. However, the alteration of EV-bound S100A8/A9 during septic shock, along with the role of S100A8/A9 in driving acute lung injury, remains unexplored. METHODS: EVs were isolated from the plasma of patients upon admission with sepsis or septic shock, as well as from healthy controls. Levels of EV S100A8/A9 were assayed via ELISA. To examine the effects and underlying mechanisms of septic shock EVs in acute lung injury, these EVs were administered intratracheally into wild-type C57BL/6 mice or mice with a deficiency of advanced glycation end-products (RAGE). In addition, a mouse model of polymicrobial sepsis was introduced using cecal ligation and puncture (CLP). RESULTS: Levels of EV S100A8/A9 were significantly elevated in patients with sepsis or septic shock compared to healthy controls. Receiver operating characteristic (ROC) analysis demonstrated that EV S100A8/A9 effectively distinguished between septic shock and sepsis and had predictive potential for the development of ARDS. Notably, the levels of S100A8/A9 in EVs and alveolar macrophages from CLP mice were significantly higher than those in sham mice. Intratracheal administration of septic shock EVs directly induced acute lung injury and M1 macrophage polarization in a lipopolysaccharide-independent manner. Septic shock EVs were efficiently taken up by alveolar macrophages in vivo, leading to a significant increase in S100A8/A9 levels, which was inhibited by preincubating the EVs with an S100A8/A9 neutralizing antibody. Additionally, mice with deficiency in RAGE, a receptor for S100A8/A9, were partially protected from acute lung injury induced by septic shock EVs. In vitro, septic shock EVs prompted a proinflammatory response in bone marrow-derived macrophages. This response was blocked by preincubating the EVs with the S100A8/A9 neutralizing antibody. CONCLUSIONS: Our results suggested that EV S100A8/A9 has potential value in distinguishing septic shock from sepsis and predicting the development of ARDS. Septic shock EVs-induced lung injury is at least partially mediated through S100A8/A9-RAGE pathway, involving the activation of alveolar macrophages.

CONTEXT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019, causing the COVID-19 pandemic. While most infected people experienced mild illness, others progressed to severe disease, characterized by hyperinflammation and respiratory distress. There is still much to learn about the innate immune response to this virus. Interferon regulatory factor 3 (IRF3) is a transcription factor that is activated when pattern recognition receptors detect viruses. Upon activation, IRF3 induces the expression of interferon beta (IFN-β) and interferon-stimulated genes, which protect the host from viral infection. However, coronaviruses antagonize this pathway, delaying type 1 IFN production. It is, therefore, unclear how IRF3 influences COVID-19 disease. Our prior reports showed that IRF3 promotes harmful inflammation during bacterial sepsis in mice. HYPOTHESIS: We hypothesized that IRF3 cannot effectively control the SARS-CoV-2 viral load and instead promotes harmful inflammation during severe COVID-19. METHODS AND MODELS: We used mice transgenic for the human angiotensin converting-enzyme 2 transgene, driven by the keratin 18 promoter (K18-ACE2 mice) that were IRF3 deficient or IRF3 sufficient to test how IRF3 influences COVID-19 disease. RESULTS: Upon infection with SARS-CoV-2, K18-ACE2 mice showed a dose-dependent disease, characterized by mortality, lethargy, weight loss, and lung pathology, reminiscent of clinical COVID-19. However, K18-ACE2 mice lacking IRF3 were protected from severe disease with reduced mortality (84.6% vs. 100%) and disease score. We found that IRF3 promoted IFN-β production in the lungs and reprogrammed the cytokine profile, while viral load in the lungs was similar in the presence or absence of IRF3. INTERPRETATIONS AND CONCLUSIONS: These data indicated that IRF3 played a detrimental role in murine COVID-19 associated with changes in IFN-β and inflammatory cytokines.

PURPOSE: To assess the incidence and clinical impact of CMV infection in critically ill COVID-19 patients, examining ICU and hospital mortality, and length of hospital stay. METHODS: In this single-center, prospective observational study (March 2020 - September 2022), 431 patients with COVID-19 pneumonia and moderate to severe ARDS were included. An active CMV surveillance protocol was implemented, analyzing CMV DNA in plasma and bronchoalveolar lavage (BAL). Clinical characteristics and outcomes were compared between CMV-COVID co-infected patients and those without CMV reactivation. RESULTS: CMV-COVID co-infection was detected in 14.8% (64/431) of the cohort. Patients with CMV-COVID co-infection exhibited significantly higher ICU mortality (43.8% vs. 13.6%; p < 0.001) and hospital mortality (48.4% vs. 13.6%; p < 0.001) compared to patients without CMV. CMV infection was an independent predictor of hospital mortality (OR 4.91; 95% CI 2.76-8.75; p = 0.019). Earlier CMV reactivation was associated with an increased risk of hospital mortality (HR = 0.94; 95% CI: 0.90-0.98; p = 0.003). Additionally, CMV-COVID patients had a higher incidence of ICU-acquired infections and a prolonged hospital stay. CONCLUSIONS: In critically ill patients with SARS-CoV-2 pneumonia, CMV infection was frequently observed, and associated with increased ICU and hospital mortality. CMV co-infection correlated with a higher incidence of ICU-acquired bacterial and fungal infections and prolonged hospital stays. This emphasizes the importance of early CMV monitoring upon ICU admission, as timely detection and intervention could potentially mitigate its impact on patient outcomes.