Daily Ards Research Analysis

PURPOSE: Despite optimal antimicrobial therapy, the treatment failure rate of hospital-acquired pneumonia (HAP) routinely reaches 40% in critically ill patients. Subphenotypes have been identified within sepsis and acute respiratory distress syndrome with important predictive and possibly therapeutic implications. We derived prognosis subphenotypes for HAP and explored whether they were associated with biological markers and response to treatment. METHODS: We separately analysed data from four cohorts of critically ill patients in France (PNEUMOCARE, n = 511, ATLANREA, n = 401), Netherlands (MARS, n = 1351) and Europe-South America (ENIRRI, n = 900) to investigate HAP heterogeneity using unsupervised clustering based on clinical and routine biological variables available at HAP diagnosis. Then, we developed a machine learning-based workflow to create a simplified classification model using discovery data sets. This model was validated by applying it to an independent replication data set from an international randomized clinical trial comparing linezolid and tedizolid for the treatment of HAP (VITAL, n = 726 patients). The primary outcome was the association of subphenotypes with 28-day all-cause mortality. Secondary analyses included subphenotype associations with treatment failure at test-of-cure, respiratory microbiome and cytokine profiles in the ATLANREA subgroup, and treatment response in the VITAL trial. RESULTS: We tested twelve metrics and determined that a two-cluster model best fits all cohorts. HAP subphenotype 2 had greater disease severity, lower body temperature, and worse PaO2/FiO2 ratio than subphenotype 1 patients. Although the prevalence of subphenotype 2 ranged from 26.9 to 66.9% across the four derivation cohorts, the rates of 28-day mortality and treatment failure at test-of-cure were consistently higher to subphenotype 1 (p < 0.01 for all comparisons). Subphenotype 2 was associated with greater respiratory microbiome dysbiosis and higher levels of proinflammatory cytokines in the ATLANREA cohort, as well as with statistically significant tedizolid effect modification in the VITAL trial (Relative Risk of treatment failure with tedizolid = 1.52; 95% CI 1.12-2.06 in subphenotype 1 vs. = 0.98; 95% CI 0.7-1.38 in subphenotype 2). CONCLUSIONS: We identified two robust clinical subphenotypes by extensively analyzing HAP data sets. Their associations with respiratory microbiome composition, systemic inflammation, and treatment efficacy in independent data sets highlight their potential for prognostic value and predictive enrichment in future clinical trials aimed at personalized therapies.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by severe hypoxemia and high mortality. Ferroptosis, a form of regulated cell death driven by iron accumulation and lipid peroxidation, has emerged as a critical mechanism in ARDS pathogenesis. However, the molecular regulators of ferroptosis in ARDS remain unclear. This study integrates multi-omics analysis and experimental validation to identify ferroptosis-related targets in ARDS. Bronchoalveolar lavage fluid (BALF) samples from ARDS patients and healthy controls were subjected to proteomics and metabolomics analysis. Transcriptomic data from the GSE243066 dataset and ferroptosis-related gene databases were integrated to identify key genes. Functional enrichment analyses were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. An LPS-induced ARDS mouse model was established for experimental validation, including Western blotting, histopathology, and ferroptosis-related biochemical assays. Multi-omics analysis identified YWHAE as a ferroptosis-associated gene significantly upregulated in ARDS. Functional enrichment revealed key pathways, including ferroptosis, hypoxia-inducible factor-1 signaling, and oxidative stress responses. Proteomic and transcriptomic integration highlighted 51 overlapping differentially expressed genes, with YWHAE emerging as a central hub in the protein-protein interaction network. Metabolomics analysis further revealed glutathione and cysteine metabolism as critical pathways linked to ferroptosis. In the ARDS mouse model, ferroptosis inhibitor ferrostatin-1 (Fer-1) attenuated LPS-induced lung injury, reduced oxidative stress markers, and downregulated YWHAE expression. This study identifies YWHAE as a novel ferroptosis-related target in ARDS through multi-omics analysis and experimental validation. These findings provide new insights into the molecular mechanisms of ferroptosis in ARDS and highlight YWHAE as a potential therapeutic target for future interventions.

PURPOSE: Acute hypoxemic respiratory failure (ARF) is a major challenge in immunocompromised patients, often complicated by severe respiratory distress and organ dysfunction. High-flow nasal oxygen (HFNO) therapy is the standard of care, but data on its effectiveness and outcomes are limited. This study evaluated the outcomes of HFNO in this population, predictors of invasive mechanical ventilation (IMV), and factors associated with 28-day mortality. METHODS: We analyzed data from a multicenter cohort of 986 immunocompromised patients with ARF treated with HFNO. Predictive factors for IMV and mortality were assessed using multivariable survival models, and the predictive value of the respiratory rate‑oxygenation (ROX) index for IMV was evaluated. RESULTS: Patients had a median age of 63 years [IQR 54-70], and 66% were male. Primary causes of immunosuppression included hematologic malignancies (55%), solid tumors (30%), and solid-organ transplantation (10%). Bacterial pneumonia (40%) and opportunistic infections (15%) were the most common ARF etiologies. IMV was required in 46% of patients. Day 28 mortality was 33%, with better outcomes for solid-organ transplant recipients compared to hematologic malignancy or solid tumor (70% vs. 48% vs. 51% mortality, respectively). Predictors of IMV included a lower ROX index, higher respiratory rates, and lower PaO CONCLUSIONS: HFNO outcomes in immunocompromised patients with ARF vary widely, influenced by immunosuppression type, ARF etiology, and clinical factors. Optimizing treatment and identifying high-risk patients could improve outcomes. Prospective studies are needed to enhance HFNO strategies.