Plasma sTNFR1 and IL8 for prognostic enrichment in sepsis trials: a prospective cohort study.

BackgroundEnrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors.MethodsIn a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies.Measurements and main resultsAn admission sTNFR1 concentration > 8861 pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration > 94 pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level > 9761 pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor.ConclusionsThresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials

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 (NO2), sulfur dioxide (SO2), carbon monoxide (CO), particulate matter < 2.5 μm (PM2.5), and PM < 10 μm (PM10) using weighted averages of daily levels from monitors within 50 km of subjects residences. Subjects were followed for 6 days for ARDS by the Berlin Criteria. The association between each pollutant and ARDS was determined using multivariable logistic regression adjusting for preselected confounders. In 764 subjects, we measured plasma concentrations of inflammatory proteins at presentation and tested for an association between pollutant exposure and protein concentration via linear regression. RESULTS: ARDS developed in 754 (41%) subjects. Short- and long-term exposures to SO2, NO2, and PM2.5 were associated with ARDS risk (SO2: odds ratio (OR) for the comparison of the 75-25th long-term exposure percentile 1.43 (95% confidence interval (CI) 1.16, 1.77); p < 0.01; NO2: 1.36 (1.06, 1.74); p = 0.04, PM2.5: 1.21 (1.04, 1.41); p = 0.03). Long-term exposures to these three pollutants were also associated with plasma interleukin-1 receptor antagonist and soluble tumor necrosis factor receptor-1 concentrations. CONCLUSION: Short and long-term exposures to ambient SO2, PM2.5, and NO2 are associated with increased ARDS risk in sepsis, representing potentially modifiable environmental risk factors for sepsis-associated ARDS

SNP-set analysis replicates acute lung injury genetic risk factors

Abstract Background We used a gene – based replication strategy to test the reproducibility of prior acute lung injury (ALI) candidate gene associations. Methods We phenotyped 474 patients from a prospective severe trauma cohort study for ALI. Genomic DNA from subjects’ blood was genotyped using the IBC chip, a multiplex single nucleotide polymorphism (SNP) array. Results were filtered for 25 candidate genes selected using prespecified literature search criteria and present on the IBC platform. For each gene, we grouped SNPs according to haplotype blocks and tested the joint effect of all SNPs on susceptibility to ALI using the SNP-set kernel association test. Results were compared to single SNP analysis of the candidate SNPs. Analyses were separate for genetically determined ancestry (African or European). Results We identified 4 genes in African ancestry and 2 in European ancestry trauma subjects which replicated their associations with ALI. Ours is the first replication of IL6, IL10, IRAK3, and VEGFA associations in non-European populations with ALI. Only one gene – VEGFA – demonstrated association with ALI in both ancestries, with distinct haplotype blocks in each ancestry driving the association. We also report the association between trauma-associated ALI and NFKBIA in European ancestry subjects. Conclusions Prior ALI genetic associations are reproducible and replicate in a trauma cohort. Kernel - based SNP-set analysis is a more powerful method to detect ALI association than single SNP analysis, and thus may be more useful for replication testing. Further, gene-based replication can extend candidate gene associations to diverse ethnicities.</p

Low to Moderate Air Pollutant Exposure and Acute Respiratory Distress Syndrome after Severe Trauma

RationaleExposure to air pollution has molecular and physiologic effects on the lung that may increase the risk of acute respiratory distress syndrome (ARDS) after injury.ObjectivesTo determine the association of short- and long-term air pollutant exposures and ARDS risk after severe trauma.MethodsWe analyzed data from a prospective cohort of 996 critically ill patients presenting with acute trauma and an injury severity score greater than 15. Exposures to ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide, and particulate matter less than 2.5 μm were assessed by weighted averages of daily levels from all monitors within 50 km of the geocoded location of a patient's residence. Patients were followed for 6 days for the development of ARDS according to Berlin Criteria. The association between each exposure and ARDS was determined via multivariable logistic regression adjusting for potential confounders.Measurements and main resultsARDS developed in 243 (24%) patients. None of the short-term exposures averaged over the 3 days before presentation was associated with ARDS, except sulfur dioxide, which demonstrated a nonlinear association. Nitrogen dioxide, sulfur dioxide, and particulate matter less than or equal to 2.5 μm in aerodynamic diameter exposure over the 6 weeks before presentation was significantly associated with ARDS (P &lt; 0.05). All long-term exposures (3 yr) were associated with ARDS (P &lt; 0.01) in adjusted models, despite exposure levels largely below U.S. and European Union air quality standards.ConclusionsLong-term low- to moderate-level air pollutant exposure is associated with a greater risk of developing ARDS after severe trauma and represents a novel and potentially modifiable environmental risk factor for ARDS

Identification of distinct clinical subphenotypes in critically ill patients with COVID-19

Subphenotypes have been identified in patients with sepsis and acute respiratory distress syndrome (ARDS), and are associated with different outcomes and response to therapies. Can unique subphenotypes be identified among critically ill patients with coronavirus disease 2019 (COVID-19)? & Methods: Using data from a multicenter cohort study that enrolled critically ill patients with COVID-19 from 67 hospitals across the United States, we randomly divided centers into Discovery and Replication cohorts. We utilized latent class analysis independently in each cohort to identify subphenotypes based on clinical and laboratory variables. We then analyzed the associations of subphenotypes with 28-day mortality. Latent class analysis identified four subphenotypes (SP) with consistent characteristics across Discovery (45 centers, n=2,188) and Replication (22 centers, n=1,112) cohorts. SP1 was characterized by shock, acidemia, and multi-organ dysfunction, including acute kidney injury treated with renal replacement therapy. SP2 was characterized by high C-reactive protein, early need for mechanical ventilation, and the highest rate of ARDS. SP3 had the highest burden of chronic diseases, while SP4 had limited chronic disease burden and mild physiologic abnormalities. 28-day mortality in the Discovery cohort ranged from 20.6% (SP4) to 52.9% (SP1). Mortality across subphenotypes remained different after adjustment for demographics, comorbidities, organ dysfunction and illness severity, regional and hospital factors: compared with SP4, SP1 relative risk (RR) 1.67 (95% CI 1.36-2.03); SP2 RR 1.39 (1.17-1.65); SP3 RR 1.39 (1.15-1.67). Findings were similar in the Replication cohort. We identified four subphenotypes of COVID-19 critical illness with distinct patterns of clinical and laboratory characteristics, comorbidity burden, and mortality