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Angiopoietin-2 (Ang-2) is associated with vascular endothelial injury and permeability in the acute respiratory distress syndrome (ARDS) and sepsis. Elevated circulating Ang-2 levels may identify critically ill patients with distinct pathobiology amenable to targeted therapy. We hypothesized that plasma Ang-2 measured shortly after hospitalization among patients with sepsis would be associated with the development of ARDS and poor clinical outcomes. To test this hypothesis, we measured plasma Ang-2 in a cohort of 757 patients with sepsis, including 267 with ARDS, enrolled in the emergency department or early in their ICU course before the COVID-19 pandemic. Multivariable models were used to test the association of Ang-2 with the development of ARDS and 30-day morality. We found that early plasma Ang-2 in sepsis was associated with higher baseline severity of illness, the development of ARDS, and mortality risk. The association between Ang-2 and mortality was strongest among patients with ARDS and sepsis as compared to those with sepsis alone (OR 1.81 vs. 1.52 per log Ang-2 increase). These findings might inform models testing patient risk prediction and strengthen the evidence for Ang-2 as an appealing biomarker for patient selection for novel therapeutic agents to target vascular injury in sepsis and ARDS.

Experimental models of sepsis in small and large animals and a variety of in vitro preparations have established several basic mechanisms that drive endothelial injury. This review is focused on what can be learned from the results of clinical studies of plasma biomarkers of endothelial injury and inflammation in patients with sepsis. There is excellent evidence that elevated plasma levels of several biomarkers of endothelial injury, including von Willebrand factor antigen (VWF), angiopoietin-2 (Ang-2), and soluble fms-like tyrosine kinase 1 (sFLT-1), and biomarkers of inflammation, especially interleukin-8 (IL-8) and soluble tumor necrosis factor receptor (sTNFr), identify sepsis patients with a higher mortality. There are also some data that elevated levels of endothelial biomarkers can identify which patients with non-pulmonary sepsis will develop acute respiratory distress syndrome (ARDS). If ARDS patients are divided among those with indirect versus direct lung injury, then there is an association of elevated levels of endothelial biomarkers in indirect injury and markers of inflammation and alveolar epithelial injury in patients with direct lung injury. New research suggests that the combination of biologic and clinical markers may make it possible to segregate patients with ARDS into hypo- versus hyper-inflammatory phenotypes that may have implications for therapeutic responses to fluid therapy. Taken together, the studies reviewed here support a primary role of the microcirculation in the pathogenesis and prognosis of ARDS after sepsis. Biological differences identified by molecular patterns could explain heterogeneity of treatment effects that are not explained by clinical factors alone.

Background Cystatin C is a well-validated marker of glomerular filtration rate in chronic kidney disease. Higher plasma concentrations of cystatin C are associated with worse clinical outcomes in heterogenous populations of critically ill patients and may be superior to creatinine in identifying kidney injury in critically ill patients. We hypothesized that elevated levels of plasma cystatin C in patients with acute respiratory distress syndrome (ARDS) would be associated with mortality risk. Methods In a retrospective study, cystatin C was measured by nephelometry on plasma obtained at enrollment from 919 patients in the Fluid and Catheter Treatment Trial. Multivariable logistic regression was performed testing the association between quartiles of cystatin C and 60-day mortality. Analyses were stratified by acute kidney injury (AKI) status identified in the first 7 days after enrollment by Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Results Cystatin C was significantly higher among those patients who died compared to those who survived to 60 days [1.2 (0.9–1.9) mg/L vs. 0.8 (0.6–1.2) mg/L, p  < 0.001]. Compared to the lower three quartiles, subjects in the highest quartile of cystatin C had a significantly higher odds of death at 60 days [OR 1.8 (1.2–2.6), p  = 0.003 in adjusted analyses]; the odds of death incrementally rose in higher cystatin C quartiles compared to the lowest quartile (OR 1.1, 1.8, and 2.5). In adjusted analyses stratified by AKI status, compared to subjects in the lower three quartiles, subjects in the highest quartile of cystatin C with AKI had a significantly higher odds of death at 60 days both in participants with AKI [OR 1.6 (1.0–2.4), p  = 0.048] and those without AKI [OR 2.4 (1.2–5.0), p  = 0.017]. In adjusted analyses, there was no significant association between sex-stratified baseline creatinine quartiles and mortality. Conclusions Higher plasma levels of cystatin C on enrollment were strongly associated with mortality at 60 days in patients with ARDS with and without AKI identified by creatinine-based definitions. Compared to creatinine, cystatin C may be a better biomarker of kidney function in patients with ARDS and therefore identify patients with multiple organ failure at higher risk of death.

The OpenOximetry Dataset stores clinical and lab pulse oximetry data. It supports measurements of arterial oxygen saturation (SaO2) by arterial blood gas co-oximetry and pulse oximetry (SpO2), alongside processed and unprocessed photoplethysmography (PPG) data and other metadata. This includes skin color measurements, finger diameter, vital signs (e.g., arterial blood pressure, end-tidal carbon dioxide), and arterial blood gas parameters (e.g., acid-base balance, hemoglobin concentration). All data, from desaturation studies to clinical trials, are collected prospectively to ensure accuracy. A common data model and standardized protocols for consistent archival and interpretation ensure consistent data archival and interpretation. The dataset aims to facilitate research on pulse oximeter performance across diverse human characteristics, addressing performance issues and promoting accurate pulse oximeters. The initial release includes controlled lab desaturation studies (CLDS), with ongoing updates planned as further data from clinical trials and CLDS become available.

RationaleUsing latent class analysis (LCA), two subphenotypes of acute respiratory distress syndrome (ARDS) have consistently been identified in five randomised controlled trials (RCTs), with distinct biological characteristics, divergent outcomes and differential treatment responses to randomised interventions. Their existence in unselected populations of ARDS remains unknown. We sought to identify subphenotypes in observational cohorts of ARDS using LCA.MethodsLCA was independently applied to patients with ARDS from two prospective observational cohorts of patients admitted to the intensive care unit, derived from the Validating Acute Lung Injury markers for Diagnosis (VALID) (n=624) and Early Assessment of Renal and Lung Injury (EARLI) (n=335) studies. Clinical and biological data were used as class-defining variables. To test for concordance with prior ARDS subphenotypes, the performance metrics of parsimonious classifier models (interleukin 8, bicarbonate, protein C and vasopressor-use), previously developed in RCTs, were evaluated in EARLI and VALID with LCA-derived subphenotypes as the gold-standard.ResultsA 2-class model best fit the population in VALID (p=0.0010) and in EARLI (p<0.0001). Class 2 comprised 27% and 37% of the populations in VALID and EARLI, respectively. Consistent with the previously described ‘hyperinflammatory’ subphenotype, Class 2 was characterised by higher proinflammatory biomarkers, acidosis and increased shock and worse clinical outcomes. The similarities between these and prior RCT-derived subphenotypes were further substantiated by the performance of the parsimonious classifier models in both cohorts (area under the curves 0.92–0.94). The hyperinflammatory subphenotype was associated with increased prevalence of chronic liver disease and neutropenia and reduced incidence of chronic obstructive pulmonary disease. Measurement of novel biomarkers showed significantly higher levels of matrix metalloproteinase-8 and markers of endothelial injury in the hyperinflammatory subphenotype, whereas, matrix metalloproteinase-9 was significantly lower.ConclusionPreviously described subphenotypes are generalisable to unselected populations of non-trauma ARDS.

Background Hypoinflammatory and hyperinflammatory phenotypes have been identified in both Acute Respiratory Distress Syndrome (ARDS) and sepsis. Attributable mortality of ARDS in each phenotype of sepsis is yet to be determined. We aimed to estimate the population attributable fraction of death from ARDS (PAF ARDS ) in hypoinflammatory and hyperinflammatory sepsis, and to determine the primary cause of death within each phenotype. Methods We studied 1737 patients with sepsis from two prospective cohorts. Patients were previously assigned to the hyperinflammatory or hypoinflammatory phenotype using latent class analysis. The PAF ARDS in patients with sepsis was estimated separately in the hypo and hyperinflammatory phenotypes. Organ dysfunction, severe comorbidities, and withdrawal of life support were abstracted from the medical record in a subset of patients from the EARLI cohort who died (n = 130/179). Primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support. Results The PAF ARDS was 19% (95%CI 10,28%) in hypoinflammatory sepsis and, 14% (95%CI 6,20%) in hyperinflammatory sepsis. Cause of death differed between the two phenotypes (p < 0.001). Respiratory failure was the most common cause of death in hypoinflammatory sepsis, whereas circulatory shock was the most common cause in hyperinflammatory sepsis. Death with severe underlying comorbidities was more frequent in hypoinflammatory sepsis (81% vs. 67%, p = 0.004). Conclusions The PAF ARDS is modest in both phenotypes whereas primary cause of death among patients with sepsis differed substantially by phenotype. This study identifies challenges in powering future clinical trials to detect changes in mortality outcomes among patients with sepsis and ARDS.

Rationale Myocardial injury is common in acute respiratory distress syndrome (ARDS) and sepsis and associated with increased mortality. Two latent class analysis derived subphenotypes are associated with differential risk of mortality in these populations, though the association of troponin-I with mortality within each subphenotype is unknown. Methods The derivation (n = 597 in EARLI) and validation (n = 452 in VALID) cohorts consisted of patients with sepsis or ARDS admitted to the ICU and enrolled in two separate prospective observational studies. Patients with troponin-I measured between hospital presentation and within 24 h of ICU admission were included. A parsimonious classifier model using interleukin-8, soluble tumor necrosis factor receptor-1, and vasopressor use assigned patients to subphenotype. Association between peak troponin-I concentration and 60-day in-hospital mortality within each subphenotype was assessed through logistic regression adjusting for age, admission laboratory values, vasopressor use, invasive ventilation use, and cardiac comorbidities. Results Median peak troponin-I was significantly higher in the hyperinflammatory vs hypoinflammatory subphenotype in both cohorts (0.07 vs 0.04 ng/mL and 0.17 vs 0.07 ng/mL, both p < 0.05). The association between peak troponin-I and mortality differed between inflammatory subphenotypes (p-interaction 0.004, EARLI). In EARLI, each doubling of peak troponin-I was associated with increased adjusted odds of 60-day mortality (aOR 1.14, 95% CI 1.02–1.28) in the hypoinflammatory subphenotype only. These findings were corroborated in VALID (aOR 1.11, 95% CI 1.03–1.21 in hypoinflammatory). Conclusions Admission peak troponin-I is significantly associated with 60-day mortality in patients with sepsis or ARDS. This association was distinctly driven by the hypoinflammatory subphenotype.

Background Rapidly improving acute respiratory distress syndrome (RIARDS) is an increasingly appreciated subgroup of ARDS in which hypoxemia improves within 24 h after initiation of mechanical ventilation. Detailed clinical and biological features of RIARDS have not been clearly defined, and it is unknown whether RIARDS is associated with the hypoinflammatory or hyperinflammatory phenotype of ARDS. The purpose of this study was to define the clinical and biological features of RIARDS and its association with inflammatory subphenotypes. Methods We analyzed data from 215 patients who met Berlin criteria for ARDS (endotracheally intubated) and were enrolled in a prospective observational cohort conducted at two sites, one tertiary care center and one urban safety net hospital. RIARDS was defined according to previous studies as improvement of hypoxemia defined as (i) PaO 2 :FiO 2  > 300 or (ii) SpO2: FiO 2  > 315 on the day following diagnosis of ARDS (day 2) or (iii) unassisted breathing by day 2 and for the next 48 h (defined as absence of endotracheal intubation on day 2 through day 4). Plasma biomarkers were measured on samples collected on the day of study enrollment, and ARDS phenotypes were allocated as previously described. Results RIARDS accounted for 21% of all ARDS participants. Patients with RIARDS had better clinical outcomes compared to those with persistent ARDS, with lower hospital mortality (13% vs. 57%; p value < 0.001) and more ICU-free days (median 24 vs. 0; p value < 0.001). Plasma levels of interleukin-6, interleukin-8, and plasminogen activator inhibitor-1 were significantly lower among patients with RIARDS. The hypoinflammatory phenotype of ARDS was more common among patients with RIARDS (78% vs. 51% in persistent ARDS; p value = 0.001). Conclusions This study identifies a high prevalence of RIARDS in a multicenter observational cohort and confirms the more benign clinical course of these patients. We report the novel finding that RIARDS is characterized by lower concentrations of plasma biomarkers of inflammation compared to persistent ARDS, and that hypoinflammatory ARDS is more prevalent among patients with RIARDS. Identification and exclusion of RIARDS could potentially improve prognostic and predictive enrichment in clinical trials.

Background Studies quantifying SARS-CoV-2 have focused on upper respiratory tract or plasma viral RNA with inconsistent association with clinical outcomes. The association between plasma viral antigen levels and clinical outcomes has not been previously studied. Our aim was to investigate the relationship between plasma SARS-CoV-2 nucleocapsid antigen (N-antigen) concentration and both markers of host response and clinical outcomes. Methods SARS-CoV-2 N-antigen concentrations were measured in the first study plasma sample (D0), collected within 72 h of hospital admission, from 256 subjects admitted between March 2020 and August 2021 in a prospective observational cohort of hospitalized patients with COVID-19. The rank correlations between plasma N-antigen and plasma biomarkers of tissue damage, coagulation, and inflammation were assessed. Multiple ordinal regression was used to test the association between enrollment N-antigen plasma concentration and the primary outcome of clinical deterioration at one week as measured by a modified World Health Organization (WHO) ordinal scale. Multiple logistic regression was used to test the association between enrollment plasma N-antigen concentration and the secondary outcomes of ICU admission, mechanical ventilation at 28 days, and death at 28 days. The prognostic discrimination of an externally derived “high antigen” cutoff of N-antigen ≥ 1000 pg/mL was also tested. Results N-antigen on D0 was detectable in 84% of study participants. Plasma N-antigen levels significantly correlated with RAGE ( r  = 0.61), IL-10 ( r  = 0.59), and IP-10 ( r  = 0.59, adjusted p  = 0.01 for all correlations). For the primary outcome of clinical status at one week, each 500 pg/mL increase in plasma N-antigen level was associated with an adjusted OR of 1.05 (95% CI 1.03–1.08) for worse WHO ordinal status. D0 plasma N-antigen ≥ 1000 pg/mL was 77% sensitive and 59% specific (AUROC 0.68) with a positive predictive value of 23% and a negative predictive value of 93% for a worse WHO ordinal scale at day 7 compared to baseline. D0 N-antigen concentration was independently associated with ICU admission and 28-day mechanical ventilation, but not with death at 28 days. Conclusions Plasma N-antigen levels are readily measured and provide important insight into the pathogenesis and prognosis of COVID-19. The measurement of N-antigen levels early in-hospital course may improve risk stratification, especially for identifying patients who are unlikely to progress to severe disease.

There remains a need to better identify patients at highest risk for developing severe Coronavirus Disease 2019 (COVID-19) as additional waves of the pandemic continue to impact hospital systems. We sought to characterize the association of receptor for advanced glycation end products (RAGE), SARS-CoV-2 nucleocapsid viral antigen, and a panel of thromboinflammatory biomarkers with development of severe disease in patients presenting to the emergency department with symptomatic COVID-19. Blood samples were collected on arrival from 77 patients with symptomatic COVID-19, and plasma levels of thromboinflammatory biomarkers were measured. Differences in biomarkers between those who did and did not develop severe disease or death 7 days after presentation were analyzed. After adjustment for multiple comparisons, RAGE, SARS-CoV-2 nucleocapsid viral antigen, interleukin (IL)-6, IL-10 and tumor necrosis factor receptor (TNFR)-1 were significantly elevated in the group who developed severe disease (all <0.05). In a multivariable regression model, RAGE and SARS-CoV-2 nucleocapsid viral antigen remained significant risk factors for development of severe disease (both <0.05), and each had sensitivity and specificity >80% on cut-point analysis. Elevated RAGE and SARS-CoV-2 nucleocapsid viral antigen on emergency department presentation are strongly associated with development of severe disease at 7 days. These findings are of clinical relevance for patient prognostication and triage as hospital systems continue to be overwhelmed. Further studies are warranted to determine the feasibility and utility of point-of care measurements of these biomarkers in the emergency department setting to improve patient prognostication and triage.