Association between emergency department disposition and mortality in patients with COVID-19 acute respiratory distress syndrome.

Objectives: Patients hospitalized for COVID-19 frequently develop hypoxemia and acute respiratory distress syndrome (ARDS) after admission. In non-COVID-19 ARDS studies, admission to hospital wards with subsequent transfer to intensive care unit (ICU) is associated with worse outcomes. We hypothesized that initial admission to the ward may affect outcomes in patient with COVID-19 ARDS. Methods: This was a retrospective study of consecutive adults admitted for COVID-19 ARDS between March 2020 and March 2021 at Stanford Health Care. Mortality scores at hospital admission (Coronavirus Clinical Characterization Consortium Mortality Score [4C score]) and ICU admission (Simplified Acute Physiology Score III [SAPS-III]) were calculated, as well as ROX index for patients on high flow nasal oxygen. Patients were classified by emergency department (ED) disposition (ward-first vs. ICU-direct), and 28- and 60-day mortality and highest level of respiratory support within 1 day of ICU admission were compared. A second cohort (April 2021‒July 2022, n = 129) was phenotyped to validate mortality outcome. Results: A total of 157 patients were included, 48% of whom were first admitted to the ward (n = 75). Ward-first patients had more comorbidities, including lung disease. Ward-first patients had lower 4C and similar SAPS-III score, yet increased mortality at 28 days (32% vs. 17%, hazard ratio [HR] 2.0, 95% confidence interval [95% CI] 1.0‒3.7, p = 0.039) and 60 days (39% vs. 23%, HR 1.83, 95% CI 1.04‒3.22, p = 0.037) compared to ICU-direct patients. More ward-first patients escalated to mechanical ventilation on day 1 of ICU admission (36% vs. 14%, p = 0.002) despite similar ROX index. Ward-first patients who upgraded to ICU within 48 h of ED presentation had the highest mortality. Mortality findings were replicated in a sensitivity analysis. Conclusion: Despite similar baseline risk scores, ward-first patients with COVID-19 ARDS had increased mortality and escalation to mechanical ventilation compared to ICU-direct patients. Ward-first patients requiring ICU upgrade within 48 h were at highest risk, highlighting a need for improved identification of this group at ED admission.

Molecular Endotypes of Idiopathic Pulmonary Fibrosis: A Latent Class Analysis of Two Multicenter Observational Cohorts.

Rationale: Idiopathic pulmonary fibrosis (IPF) causes irreversible fibrosis of the lung parenchyma. Although antifibrotic therapy can slow IPF progression, treatment response is variable. There exists a critical need to develop a precision medicine approach to IPF. Objectives: To identify and validate biologically driven molecular endotypes of IPF. Methods: Latent class analysis (LCA) was independently performed in prospectively recruited discovery (n = 875) and validation (n = 347) cohorts. Twenty-five plasma biomarkers associated with fibrogenesis served as class-defining variables. The association between molecular endotype and 4-year transplant-free survival was tested using multivariable Cox regression adjusted for baseline confounders. Endotype-dependent differential treatment response to future antifibrotic exposure was then assessed in a pooled cohort of patients naive to antifibrotic therapy at the time of biomarker measurement (n = 555). Measurements and Main Results: LCA independently identified two latent classes in both cohorts (P < 0.0001). WFDC2 (WAP four-disulfide core domain protein 2) was the most important determinant of class membership across cohorts. Membership in class 2 was characterized by higher biomarker concentrations and a higher risk of death or transplant (discovery, hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.64-2.48; P < 0.001; validation, HR, 1.95; 95% CI, 1.34-2.82; P < 0.001). In pooled analysis, significant heterogeneity in treatment effect was observed between endotypes (P = 0.030 for interaction), with a favorable antifibrotic response in class 2 (HR, 0.64; 95% CI, 0.45-0.93; P = 0.018) but not in class 1 (HR, 1.19; 95% CI, 0.77-1.84; P = 0.422). Conclusions: In this multicohort study, we identified two novel molecular endotypes of IPF with divergent clinical outcomes and responses to antifibrotic therapy. Pending further validation, these endotypes could enable a precision medicine approach for future IPF clinical trials.

Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19.

BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. RESULTS: Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. CONCLUSIONS: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

The Plasma Lipidomic Landscape in Patients with Sepsis due to Community-acquired Pneumonia.

Rationale: The plasma lipidome has the potential to reflect many facets of the host status during severe infection. Previous work is limited to specific lipid groups or was focused on lipids as prognosticators.Objectives: To map the plasma lipidome during sepsis due to community-acquired pneumonia (CAP) and determine the disease specificity and associations with clinical features.Methods: We analyzed 1,833 lipid species across 33 classes in 169 patients admitted to the ICU with sepsis due to CAP, 51 noninfected ICU patients, and 48 outpatient controls. In a paired analysis, we reanalyzed patients still in the ICU 4 days after admission (n = 82).Measurements and Main Results: A total of 58% of plasma lipids were significantly lower in patients with CAP-attributable sepsis compared with outpatient controls (6% higher, 36% not different). We found strong lipid class-specific associations with disease severity, validated across two external cohorts, and inflammatory biomarkers, in which triacylglycerols, cholesterol esters, and lysophospholipids exhibited the strongest associations. A total of 36% of lipids increased over time, and stratification by survival revealed diverging lipid recovery, which was confirmed in an external cohort; specifically, a 10% increase in cholesterol ester levels was related to a lower odds ratio (0.84; P = 0.006) for 30-day mortality (absolute mortality, 18 of 82). Comparison with noninfected ICU patients delineated a substantial common illness response (57.5%) and a distinct lipidomic signal for patients with CAP-attributable sepsis (37%).Conclusions: Patients with sepsis due to CAP exhibit a time-dependent and partially disease-specific shift in their plasma lipidome that correlates with disease severity and systemic inflammation and is associated with higher mortality.

Elevated ferritin, mediated by IL-18 is associated with systemic inflammation and mortality in acute respiratory distress syndrome (ARDS).

BACKGROUND: Inflammatory subphenotypes have been identified in acute respiratory distress syndrome (ARDS). Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict benefit with immunomodulation. Our aim was to determine if raised ferritin identified a subphenotype in patients with ARDS. METHODS: Baseline plasma ferritin concentrations were measured in patients with ARDS from two randomised controlled trials of simvastatin (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction-2 (HARP-2); discovery cohort, UK) and neuromuscular blockade (ROSE; validation cohort, USA). Results were analysed using a logistic regression model with restricted cubic splines, to determine the ferritin threshold associated with 28-day mortality. RESULTS: Ferritin was measured in 511 patients from HARP-2 (95% of patients enrolled) and 847 patients (84% of patients enrolled) from ROSE. Ferritin was consistently associated with 28-day mortality in both studies and following a meta-analysis, a log-fold increase in ferritin was associated with an OR 1.71 (95% CI 1.01 to 2.90) for 28-day mortality. Patients with ferritin >1380 ng/mL (HARP-2 28%, ROSE 24%) had a significantly higher 28-day mortality and fewer ventilator-free days in both studies. Mediation analysis, including confounders (acute physiology and chronic health evaluation-II score and ARDS aetiology) demonstrated a statistically significant contribution of interleukin (IL)-18 as an intermediate pathway between ferritin and mortality. CONCLUSIONS: Ferritin is a clinically useful biomarker in ARDS and is associated with worse patient outcomes. These results provide support for prospective interventional trials of immunomodulatory agents targeting IL-18 in this hyperferritinaemic subgroup of patients with ARDS.