Circulating cell death biomarker TRAIL is associated with increased organ dysfunction in sepsis.
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ABSTRACT:
SUBMITTER: Schenck EJ
PROVIDER: S-EPMC6538332 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
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Circulating cell death biomarker TRAIL is associated with increased organ dysfunction in sepsis.
Schenck Edward J EJ Ma Kevin C KC Price David R DR Nicholson Thomas T Oromendia Clara C Gentzler Eliza Rose ER Sanchez Elizabeth E Baron Rebecca M RM Fredenburgh Laura E LE Huh Jin-Won JW Siempos Ilias I II Choi Augustine Mk AM
JCI insight 20190502 9
<h4>Background</h4>In sepsis, there may be dysregulation in programed cell death pathways, typified by apoptosis and necroptosis. Programmed cell death pathways may contribute to variability in the immune response. TRAIL is a potent inducer of apoptosis. Receptor-interacting serine/threonine protein kinase-3 (RIPK3) is integral to the execution of necroptosis. We explored whether plasma TRAIL levels were associated with in-hospital mortality, organ dysfunction, and septic shock. We also explored ...[more]
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Project description:BackgroundSepsis is a heterogeneous syndrome, and the identification of clinical subphenotypes is essential. Although organ dysfunction is a defining element of sepsis, subphenotypes of differential trajectory are not well studied. We sought to identify distinct Sequential Organ Failure Assessment (SOFA) score trajectory-based subphenotypes in sepsis.MethodsWe created 72-h SOFA score trajectories in patients with sepsis from four diverse intensive care unit (ICU) cohorts. We then used dynamic time warping (DTW) to compute heterogeneous SOFA trajectory similarities and hierarchical agglomerative clustering (HAC) to identify trajectory-based subphenotypes. Patient characteristics were compared between subphenotypes and a random forest model was developed to predict subphenotype membership at 6 and 24 h after being admitted to the ICU. The model was tested on three validation cohorts. Sensitivity analyses were performed with alternative clustering methodologies.ResultsA total of 4678, 3665, 12,282, and 4804 unique sepsis patients were included in development and three validation cohorts, respectively. Four subphenotypes were identified in the development cohort: Rapidly Worsening (n = 612, 13.1%), Delayed Worsening (n = 960, 20.5%), Rapidly Improving (n = 1932, 41.3%), and Delayed Improving (n = 1174, 25.1%). Baseline characteristics, including the pattern of organ dysfunction, varied between subphenotypes. Rapidly Worsening was defined by a higher comorbidity burden, acidosis, and visceral organ dysfunction. Rapidly Improving was defined by vasopressor use without acidosis. Outcomes differed across the subphenotypes, Rapidly Worsening had the highest in-hospital mortality (28.3%, P-value < 0.001), despite a lower SOFA (mean: 4.5) at ICU admission compared to Rapidly Improving (mortality:5.5%, mean SOFA: 5.5). An overall prediction accuracy of 0.78 (95% CI, [0.77, 0.8]) was obtained at 6 h after ICU admission, which increased to 0.87 (95% CI, [0.86, 0.88]) at 24 h. Similar subphenotypes were replicated in three validation cohorts. The majority of patients with sepsis have an improving phenotype with a lower mortality risk; however, they make up over 20% of all deaths due to their larger numbers.ConclusionsFour novel, clinically-defined, trajectory-based sepsis subphenotypes were identified and validated. Identifying trajectory-based subphenotypes has immediate implications for the powering and predictive enrichment of clinical trials. Understanding the pathophysiology of these differential trajectories may reveal unanticipated therapeutic targets and identify more precise populations and endpoints for clinical trials.
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Project description:OBJECTIVES:Limited data exist about the timing and significance of mitochondrial alterations in children with sepsis. We therefore sought to determine if alterations in mitochondrial respiration and content within circulating peripheral blood mononuclear cells were associated with organ dysfunction in pediatric sepsis. DESIGN:Prospective observational study SETTING:: Single academic PICU. PATIENTS:One-hundred sixty-seven children with sepsis/septic shock and 19 PICU controls without sepsis, infection, or organ dysfunction. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Mitochondrial respiration and content were measured in peripheral blood mononuclear cells on days 1-2, 3-5, and 8-14 after sepsis recognition or once for controls. Severity and duration of organ dysfunction were determined using the Pediatric Logistic Organ Dysfunction score and organ failure-free days through day 28. Day 1-2 maximal uncoupled respiration (9.7?±?7.7 vs 13.7?±?4.1 pmol O2/s/10 cells; p = 0.02) and spare respiratory capacity (an index of bioenergetic reserve: 6.2?±?4.3 vs 9.6?±?3.1; p = 0.005) were lower in sepsis than controls. Mitochondrial content, measured by mitochondrial DNA/nuclear DNA, was higher in sepsis on day 1-2 than controls (p = 0.04) and increased in sepsis patients who had improving spare respiratory capacity over time (p = 0.005). Mitochondrial respiration and content were not associated with day 1-2 Pediatric Logistic Organ Dysfunction score, but low spare respiratory capacity was associated with higher Pediatric Logistic Organ Dysfunction score on day 3-5. Persistently low spare respiratory capacity was predictive of residual organ dysfunction on day 14 (area under the receiver operating characteristic, 0.72; 95% CI, 0.61-0.84) and trended toward fewer organ failure-free days although day 28 (? coefficient, -0.64; 95% CI, -1.35 to 0.06; p = 0.08). CONCLUSIONS:Mitochondrial respiration was acutely decreased in peripheral blood mononuclear cells in pediatric sepsis despite an increase in mitochondrial content. Over time, a rise in mitochondrial DNA tracked with improved respiration. Although initial mitochondrial alterations in peripheral blood mononuclear cells were unrelated to organ dysfunction, persistently low respiration was associated with slower recovery from organ dysfunction.
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