Research Priorities for Noninvasive Sampling of the Lower Respiratory Tract during Acute Respiratory Failure: An Official American Thoracic Society Workshop Report.

Research using lower respiratory tract (LRT) sampling may lead to improved understanding and management of patients with acute respiratory failure (ARF). Research bronchoscopy is a valuable tool for sampling the LRT during ARF. However, bronchoscopy may be limited by challenges with repeated sampling, the inability to sample the most severely ill patients, and increased resource utilization.

Proteomic Analyses in COVID-19-Associated Secondary Hemophagocytic Lymphohistiocytosis.

Context: COVID-19 has been associated with features of a cytokine storm syndrome with some patients sharing features with the hyperinflammatory disorder, secondary hemophagocytic lymphohistiocytosis (sHLH).

Hypothesis: We hypothesized that proteins associated with sHLH from other causes will be associated with COVID-sHLH and that subjects with fatal COVID-sHLH would have defects in immune-related pathways.

Methods And Models: We identified two cohorts of adult patients presenting with COVID-19 at two tertiary care hospitals in Seattle, Washington in 2020 and 2021.

Urinary proteomics identifies distinct immunological profiles of sepsis associated AKI sub-phenotypes.

Background: Patients with sepsis-induced AKI can be classified into two distinct sub-phenotypes (AKI-SP1, AKI-SP2) that differ in clinical outcomes and response to treatment. The biologic mechanisms underlying these sub-phenotypes remains unknown. Our objective was to understand the underlying biology that differentiates AKI sub-phenotypes and associations with kidney outcomes.

The prognostic value of single and repeated ≥10% FEV declines for chronic lung allograft dysfunction.

There is a paucity of data reporting the positive and negative predictive values (PPV, NPV) of acute declines in lung function on chronic lung allograft dysfunction (CLAD). We sought to define the predictive ability of single or repeated forced expiratory volume in the first second (FEV) declines for at least 3 weeks on the development of CLAD or death by 1-year. We analyzed 340 subjects with at least 3 years of follow-up data from two lung transplant centers.

Identification of biomarkers for COVID-19 associated secondary hemophagocytic lymphohistiocytosis.

Objectives: We aimed to define and validate novel biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system.

Design: In two cohorts of adult patients presenting with COVID-19 in 2020 and 2021, clinical lab values and serum proteomics were assessed. Subjects identified as having sHLH were compared to those with COVID-19 without sHLH.

Mediators of monocyte chemotaxis and matrix remodeling are associated with mortality and pulmonary fibroproliferation in patients with severe COVID-19.

Acute respiratory distress syndrome (ARDS) has a fibroproliferative phase that may be followed by pulmonary fibrosis. Pulmonary fibrosis following COVID-19 pneumonia has been described at autopsy and following lung transplantation. We hypothesized that protein mediators of tissue remodeling and monocyte chemotaxis are elevated in the plasma and endotracheal aspirates of critically ill patients with COVID-19 who subsequently develop features of pulmonary fibroproliferation.

PD-L1 and PD-1 Are Associated with Clinical Outcomes and Alveolar Immune Cell Activation in Acute Respiratory Distress Syndrome.

The relationship between the PD-L1 (Programmed Death-Ligand 1)/PD-1 pathway, lung inflammation, and clinical outcomes in acute respiratory distress syndrome (ARDS) is poorly understood. We sought to determine whether PD-L1/PD-1 in the lung or blood is associated with ARDS and associated severity. We measured soluble PD-L1 (sPD-L1) in plasma and lower respiratory tract samples (ARDS1 [ = 59] and ARDS2 [ = 78]) or plasma samples alone (ARDS3 [ = 149]) collected from subjects with ARDS and tested for associations with mortality using multiple regression.

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).

The transcriptional and phenotypic characteristics that define alveolar macrophage subsets in acute hypoxemic respiratory failure.

The transcriptional and phenotypic characteristics that define alveolar monocyte and macrophage subsets in acute hypoxemic respiratory failure (AHRF) are poorly understood. Here, we apply CITE-seq (single-cell RNA-sequencing and cell-surface protein quantification) to bronchoalveolar lavage and blood specimens longitudinally collected from participants with AHRF to identify alveolar myeloid subsets, and then validate their identity in an external cohort using flow cytometry. We identify alveolar myeloid subsets with transcriptional profiles that differ from other lung diseases as well as several subsets with similar transcriptional profiles as reported in healthy participants (Metallothionein) or patients with COVID-19 (CD163/LGMN).

Lung Allocation Score Exceptions in Persons with Cystic Fibrosis Undergoing Lung Transplant.

Lung transplantation can extend the lives of individuals with advanced cystic fibrosis (CF). Until March 2023, the Lung Allocation Score (LAS) was used in the United States to determine transplant priority. Certain clinical events or attributes ("risk events") that are not included in the LAS (e.

Differential absolute plasma IL-6 concentrations between two immunoassay platforms in intensive care unit patients with COVID-19.

Explore whether plasma IL-6 levels are similar across biomarker platforms and association with COVID-19 clinical outcomes. Plasma IL-6 concentrations were measured on 191 COVID-19 patients using the Roche Elecsys IL-6 assay and the Meso Scale Discovery assay. Correlation of IL-6 levels between platforms was high (r = 0.

Evaluating construct validity of computable acute respiratory distress syndrome definitions in adults hospitalized with COVID-19: an electronic health records based approach.

Background: Evolving ARDS epidemiology and management during COVID-19 have prompted calls to reexamine the construct validity of Berlin criteria, which have been rarely evaluated in real-world data. We developed a Berlin ARDS definition (EHR-Berlin) computable in electronic health records (EHR) to (1) assess its construct validity, and (2) assess how expanding its criteria affected validity.

Methods: We performed a retrospective cohort study at two tertiary care hospitals with one EHR, among adults hospitalized with COVID-19 February 2020-March 2021.

Biomarker Signatures of Severe Acute Kidney Injury in a Critically Ill Cohort of COVID-19 and Non-COVID-19 Acute Respiratory Illness.

Unlabelled: Kidney and lung injury are closely inter-related during acute respiratory illness, but the molecular risk factors that these organ injuries share are not well defined.

Objectives: We identified plasma biomarkers associated with severe acute kidney injury (AKI) during acute respiratory illness, and compared them to biomarkers associated with severe acute respiratory failure (ARF).

Design Settings And Participants: Prospective observational cohort study enrolling March 2020 through May 2021, at three hospitals in a large academic health system.

Phase 2, randomized, double-blind, placebo-controlled multi-center trial of the clinical and biological effects of anti-CD14 treatment in hospitalized patients with COVID-19 pneumonia.

Background: Severe COVID-19 is associated with innate immunopathology, and CD14, a proximal activator of innate immunity, has been suggested as a potential therapeutic target.

Methods: We conducted the COVID-19 anti-CD14 Treatment Trial (CaTT), a Phase II randomized, double-blind, placebo-controlled trial at 5 US-sites between April 12, 2021 and November 30, 2021 (NCT04391309). Hospitalized adults with COVID-19 requiring supplemental oxygen (<30 LPM) were randomized 1:1 to receive 4 daily doses of intravenous IC14, an anti-CD14 monoclonal antibody, or placebo.

Mitochondrial N-formyl methionine peptides contribute to exaggerated neutrophil activation in patients with COVID-19.

Neutrophil dysregulation is well established in COVID-19. However, factors contributing to neutrophil activation in COVID-19 are not clear. We assessed if N-formyl methionine (fMet) contributes to neutrophil activation in COVID-19.

Mediators of monocyte chemotaxis and matrix remodeling are associated with the development of fibrosis in patients with COVID-19.

Acute respiratory distress syndrome (ARDS) has a fibroproliferative phase that may be followed by pulmonary fibrosis. This has been described in patients with COVID-19 pneumonia, but the underlying mechanisms have not been completely defined. We hypothesized that protein mediators of tissue remodeling and monocyte chemotaxis are elevated in the plasma and endotracheal aspirates of critically ill patients with COVID-19 who subsequently develop radiographic fibrosis.

Association of Trauma Molecular Endotypes With Differential Response to Transfusion Resuscitation Strategies.

Importance: It is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies.

Objective: To derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies.

25-Hydroxycholesterol exacerbates vascular leak during acute lung injury.

Cholesterol-25-hydroxylase (CH25H), the biosynthetic enzyme for 25-hydroxycholesterol (25HC), is most highly expressed in the lung, but its role in lung biology is poorly defined. Recently, we reported that Ch25h is induced in monocyte-derived macrophages recruited to the airspace during resolution of lung inflammation and that 25HC promotes liver X receptor-dependent (LXR-dependent) clearance of apoptotic neutrophils by these cells. Ch25h and 25HC are, however, also robustly induced by lung-resident cells during the early hours of lung inflammation, suggesting additional cellular sources and targets.

Angiopoietin-Like4 Is a Novel Marker of COVID-19 Severity.

Unlabelled: Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak.

Objectives: To assess the role of ANGPTL4 in COVID-19-related outcomes.

Plasma Interleukin-6 Predicts Clinical Decline After Completion of Dexamethasone Therapy in Severe COVID-19.

Unlabelled: To identify and characterize clinical decline after completion of dexamethasone in severe COVID-19 and determine whether interleukin (IL)-6 and other inflammatory biomarkers predict the occurrence of clinical decline.

Design: Prospective observational cohort.

Setting: ICUs in three University of Washington affiliated hospitals between July 2020 and April 2021.

Alveolar Biomarker Profiles in Subphenotypes of the Acute Respiratory Distress Syndrome.

Objectives: We sought to determine whether hyperinflammatory acute respiratory distress syndrome (ARDS) and hypoinflammatory ARDS, which have been associated with differences in plasma biomarkers and mortality risk, also display differences in bronchoalveolar lavage (BALF) biomarker profiles. We then described the relationship between hyperinflammatory ARDS and hypoinflammatory ARDS to novel subphenotypes derived using BALF biomarkers.

Design: Secondary analysis of a randomized control trial testing omega-3 fatty acids for the treatment of ARDS.