Biomarkers of Acute Respiratory Distress Syndrome: Current State and Future Prospects.

Biomarkers are an important tool aiding researchers in the study of acute respiratory distress syndrome (ARDS). Mechanisms involving injury to the alveolar-capillary membrane, endothelium and epithelium resulting in lung inflammation and alterations in coagulation pathways have been validated in human trials and have been used to discover promising phenotypes that share similar characteristics and differential treatment responses. The emergence of powerful point-of-care technologies will enable the prospective study of biomarkers for future enrichment trials with the goal of transforming biomarkers into the clinical realm to inform delivery of personalized medicine at the bedside.

Electronic health record biobank cohort recapitulates an association between the promoter polymorphism and ARDS in critically ill adults.

Background: Large population-based DNA biobanks linked to electronic health records (EHRs) may provide novel opportunities to identify genetic drivers of ARDS.

Research Question: Can we develop an EHR-based algorithm to identify ARDS in a biobank database, and can this validate a previously reported ARDS genetic risk factor?

Study Design And Methods: We analyzed two parallel genotyped cohorts: a prospective biomarker cohort of critically ill adults (VALID), and a retrospective cohort of hospitalized participants enrolled in a de-identified EHR biobank (BioVU). ARDS was identified by clinician-investigator review in VALID and an EHR algorithm in BioVU (EHR-ARDS).

Signs of Hemolysis Predict Mortality and Ventilator Associated Pneumonia in Severe Acute Respiratory Distress Syndrome Patients Undergoing Veno-Venous Extracorporeal Membrane Oxygenation.

Cell-free hemoglobin (CFH) is used to detect hemolysis and was recently suggested to trigger acute lung injury. However, its role has not been elucidated in severe acute respiratory distress syndrome (ARDS) patients undergoing extracorporeal membrane oxygenation (ECMO). We investigated the association of carboxyhemoglobin (COHb) and haptoglobin-two indirect markers of hemolysis-with mortality in critically ill patients undergoing veno-venous ECMO (VV-ECMO) with adjusted and longitudinal models (primary aim).

Long-term air pollution exposure and the risk of primary graft dysfunction after lung transplantation.

Background: Primary graft dysfunction (PGD) contributes substantially to both short- and long-term mortality after lung transplantation, but the mechanisms that lead to PGD are not well understood. Exposure to ambient air pollutants is associated with adverse events during waitlisting for lung transplantation and chronic lung allograft dysfunction, but its association with PGD has not been studied. We hypothesized that long-term exposure of the lung donor and recipient to high levels of ambient air pollutants would increase the risk of PGD in lung transplant recipients.

Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis.

The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored mechanisms of silica-induced pulmonary fibrosis in human lung samples collected from patients with occupational exposure to silica and in a longitudinal mouse model of silicosis using multiple modalities including whole-lung single-cell RNA sequencing and histological, biochemical, and physiologic assessments. In addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor κΒ ligand (RANKL) in pulmonary lymphocytes, and alveolar type II cells.

Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial.

Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates.

Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo.

Design, Setting, And Participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up.

Causes and attributable fraction of death from ARDS in inflammatory phenotypes of sepsis.

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) in hypoinflammatory and hyperinflammatory sepsis, and to determine the primary cause of death within each phenotype.

Systemic inflammation and delirium during critical illness.

Purpose: The purpose of this study was to determine associations between markers of inflammation and endogenous anticoagulant activity with delirium and coma during critical illness.

Methods: In this prospective cohort study, we enrolled adults with respiratory failure and/or shock treated in medical or surgical intensive care units (ICUs) at 5 centers. Twice per day in the ICU, and daily thereafter, we assessed mental status using the Richmond Agitation Sedation Scale (RASS) and the Confusion Assessment Method-Intensive Care Unit (CAM-ICU).

Cell-type-specific and disease-associated expression quantitative trait loci in the human lung.

Common genetic variants confer substantial risk for chronic lung diseases, including pulmonary fibrosis. Defining the genetic control of gene expression in a cell-type-specific and context-dependent manner is critical for understanding the mechanisms through which genetic variation influences complex traits and disease pathobiology. To this end, we performed single-cell RNA sequencing of lung tissue from 66 individuals with pulmonary fibrosis and 48 unaffected donors.

Development and External Validation of Models to Predict Persistent Hypoxemic Respiratory Failure for Clinical Trial Enrichment.

Objectives: Improving the efficiency of clinical trials in acute hypoxemic respiratory failure (HRF) depends on enrichment strategies that minimize enrollment of patients who quickly resolve with existing care and focus on patients at high risk for persistent HRF. We aimed to develop parsimonious models predicting risk of persistent HRF using routine data from ICU admission and select research immune biomarkers.

Design: Prospective cohorts for derivation ( n = 630) and external validation ( n = 511).

Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis.

The human lung is structurally complex, with a diversity of specialized epithelial, stromal and immune cells playing specific functional roles in anatomically distinct locations, and large-scale changes in the structure and cellular makeup of this distal lung is a hallmark of pulmonary fibrosis (PF) and other progressive chronic lung diseases. Single-cell transcriptomic studies have revealed numerous disease-emergent/enriched cell types/states in PF lungs, but the spatial contexts wherein these cells contribute to disease pathogenesis has remained uncertain. Using sub-cellular resolution image-based spatial transcriptomics, we analyzed the gene expression of more than 1 million cells from 19 unique lungs.

Ascorbate protects human kidney organoids from damage induced by cell-free hemoglobin.

Sepsis-associated acute kidney injury is associated with high morbidity and mortality in critically ill patients. Cell-free hemoglobin (CFH) is released into the circulation of patients with severe sepsis and the levels of CFH are independently associated with mortality. CFH treatment increased cytotoxicity in the human tubular epithelial cell line HK-2.

Genomic Variant Is Associated with NKG2D-mediated Acute Lung Injury and Death.

Acute lung injury (ALI) carries a high risk of mortality but has no established pharmacologic therapy. We previously found that experimental ALI occurs through natural killer (NK) cell NKG2D receptor activation and that the cognate human ligand, MICB, was associated with ALI after transplantation. To investigate the association of a common missense variant, , with ALI.

Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlled trials.

Background: In sepsis and acute respiratory distress syndrome (ARDS), heterogeneity has contributed to difficulty identifying effective pharmacotherapies. In ARDS, two molecular phenotypes (hypoinflammatory and hyperinflammatory) have consistently been identified, with divergent outcomes and treatment responses. In this study, we sought to derive molecular phenotypes in critically ill adults with sepsis, determine their overlap with previous ARDS phenotypes, and evaluate whether they respond differently to treatment in completed sepsis trials.

Liraglutide pretreatment attenuates sepsis-induced acute lung injury.

There are no effective targeted therapies to treat acute respiratory distress syndrome (ARDS). Recently, the commonly used diabetes and obesity medications, glucagon-like peptide-1 (GLP-1) receptor agonists, have been found to have anti-inflammatory properties. We, therefore, hypothesized that liraglutide pretreatment would attenuate murine sepsis-induced acute lung injury (ALI).

A New Global Definition of Acute Respiratory Distress Syndrome.

Since publication of the 2012 Berlin definition of acute respiratory distress syndrome (ARDS), several developments have supported the need for an expansion of the definition, including the use of high-flow nasal oxygen, the expansion of the use of pulse oximetry in place of arterial blood gases, the use of ultrasound for chest imaging, and the need for applicability in resource-limited settings. A consensus conference of 32 critical care ARDS experts was convened, had six virtual meetings (June 2021 to March 2022), and subsequently obtained input from members of several critical care societies. The goal was to develop a definition that would ) identify patients with the currently accepted conceptual framework for ARDS, ) facilitate rapid ARDS diagnosis for clinical care and research, ) be applicable in resource-limited settings, ) be useful for testing specific therapies, and ) be practical for communication to patients and caregivers.

Exposure to ambient air pollutants and acute respiratory distress syndrome risk in sepsis.

Purpose: Exposures to ambient air pollutants may prime the lung enhancing risk of acute respiratory distress syndrome (ARDS) in sepsis. Our objective was to determine the association of short-, medium-, and long-term pollutant exposures and ARDS risk in critically ill sepsis patients.

Methods: We analyzed a prospective cohort of 1858 critically ill patients with sepsis, and estimated short- (3 days), medium- (6 weeks), and long- (5 years) term exposures to ozone, nitrogen dioxide (NO), sulfur dioxide (SO), carbon monoxide (CO), particulate matter < 2.

Genome-wide Association Study for AKI.

Key Points: Two genetic variants in the DISP1-TLR5 gene locus were associated with risk of AKI. DISP1 and TLR5 were differentially regulated in kidney biopsy tissue from patients with AKI compared with no AKI.

Background: Although common genetic risks for CKD are well established, genetic factors influencing risk for AKI in hospitalized patients are poorly understood.