Daily Ards Research Analysis

Alveolar hypercoagulation and fibrinolytic inhibition are key drivers of refractory hypoxemia in acute respiratory distress syndrome (ARDS). Orosomucoid 1 (ORM1), associated with coagulation and the NF-κB pathway, is hypothesized to regulate these processes in ARDS via NF-κB. By using LPS-induced ARDS rats and alveolar epithelial type II (AEC II) cells, we measured ORM1 expression and its effects on tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1). NF-κB pathway involvement was assessed. Clinically, bronchoalveolar lavage fluid (BALF) ORM1 levels and their correlation with TF/PAI-1 were analyzed in ARDS patients. In ARDS rats, ORM1 was upregulated in lung tissue and BALF, correlating with increased TF, PAI-1, and type III collagen. In vitro, ORM1 promoted TF and PAI-1 expression in LPS-stimulated AEC II cells. These effects were mediated through the NF-κB pathway. Clinically, BALF ORM1 levels were elevated in ARDS patients and positively correlated with TF and PAI-1. ORM1 regulates alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS via the NF-κB pathway, identifying it as a promising therapeutic target.

OBJECTIVES: Hyperinflammatory and hypoinflammatory molecular subphenotypes in sepsis and acute respiratory distress syndrome have divergent mortality and treatment responses in secondary analyses of randomized controlled trials. However, the prevalence of immunocompromise is low in these populations, and how preexisting immunocompromise contributes to subphenotypes is unknown. We studied two observational sepsis cohorts to test associations between immunocompromise and the hyperinflammatory subphenotype and to assess whether the prognostic relevance of molecular subphenotypes is generalizable to immunocompromised populations. DESIGN: Observational cohort study. SETTING: Prospective data from two ICU cohorts in the United States. PATIENTS: We included 1826 patients from two combined sepsis cohorts. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We defined immunocompromise as a history of solid organ transplant, AIDS, hematologic malignancy, solid malignancy on chemotherapy, or immunosuppressive medication use. Subphenotype was previously assigned using latent class analysis. We used logistic regression to investigate associations between type of immunocompromise and hyperinflammatory subphenotype. Models were repeated with individual covariates known or hypothesized to be associated with the hyperinflammatory subphenotype. Kaplan-Meier survival plots were used to assess mortality differences by subphenotype. Hematologic malignancy was strongly associated with the hyperinflammatory subphenotype (odds ratio [OR], 4.3; p < 0.0001), an association that persisted after adjustment for identified pathogen, presence of bacteremia, or illness severity. History of solid organ transplantation was also associated with the hyperinflammatory subphenotype (OR, 1.6; p = 0.02) but was no longer significant after accounting for bacteremia. Hyperinflammatory classification was associated with a decreased likelihood of survival in hematologic malignancy, but not in organ transplant or solid malignancy populations. CONCLUSIONS: Preexisting immune status is associated with subphenotype assignment and may influence its prognostic utility.

INTRODUCTION: Tie2 is an endothelial surface receptor critically involved in angiogenesis, cell-integrity, and survival. During inflammatory disorders such as sepsis and ARDS, the receptor is shed from the endothelial surface, contributing to a reduction of its protective downstream signaling ultimately contributing to endothelial permeability and thereby capillary leakage. This study investigates the association of the soluble form of Tie2 (sTie2), with multiorgan failure, requirement of dialysis and mortality. METHODOLOGY: We conducted a biomarker study using serum samples from sepsis and/or ARDS patients admitted to the medical intensive care unit (ICU) of Hannover Medical School. sTie2 was quantified by Multiplex Luminex Assay in serum samples collected on the day of ICU admission. Correlations between sTie2 levels and baseline SOFA-score, duration of vasopressor therapy, and duration of mechanical ventilation were evaluated using Pearson's correlation coefficient. The Wilcoxon rank-sum test was employed to compare sTie2 levels between individuals with and without renal replacement therapy, as well as between survivors and non-survivors. Cox regression models were applied to assess the independent association of sTie2 with 28-day mortality. RESULTS: sTie2 levels showed an inverse correlation with the SOFA-score (R = -0.2, p = 0.003) and were lower in patients requiring renal replacement therapy (17.4 [12.25-22.48] vs. 21.35 [14.91-29.08] ng/ml, p = 0.003) and in non-survivors (14.54 [10.96-15.02] vs. 21.01 [15-28.12] ng/ml, p < 0.001). No correlation was found between sTie2 and the number of days requiring vasopressor therapy or mechanical ventilation. Using multivariable cox regression, sTie2 was independently associated with mortality at 28-days (sTie2, log(ng/ml) - HR 0.35, 95% CI 0.21-0.57, p < 0.001). CONCLUSION: In this study of severely ill ICU patients, sTie2 was inversely related to severity of disease and to outcome. If the decrease in sTie2 is adaptive or maladaptive remains unclear but future investigations are required analysing the exact pathophysiological role of sTie2 to evaluate the biomarker as a potential target for the treatment of capillary leakage in patients with sepsis and/or ARDS.