Shock/Sepsis/Trauma/Critical CareElevations in Circulating sST2 Levels Are Associated With In-Hospital Mortality and Adverse Clinical Outcomes After Blunt Trauma
Introduction
Trauma is a well-recognized global pandemic condition and the most common cause of death and morbidity in people younger than 55 y.1 Massive blood loss and direct injury to vital organs are responsible for the vast majority of prehospital and early in-hospital mortality, whereas most delayed in-hospital complications and deaths are secondary to complex pathophysiological processes.2, 3 These processes include an imbalanced systemic immune response characterized by an excessive proinflammatory response that is paradoxically associated with concomitant immunosuppression.4, 5 Consequently, these responses, ranging in intensity from mild and transient to overwhelming and sustained, promote the propagation of injury to remote organs, leading to multiple organ dysfunction syndrome (MODS), nosocomial infection (NI), and persistent inflammation catabolism syndrome.2, 6, 7, 8 Beyond extended intensive care unit (ICU) stays and late hospital mortality, these conditions are major determinants of long-term functional outcomes, independent of the initial injury severity.9, 10
A hallmark of trauma-induced inflammation involves the activation of multiple immune pathways that are largely orchestrated by inflammatory mediators including, but not limited to, complement, damage-associated molecular pattern molecules, cytokines, and chemokines.5, 11 Studies on levels of inflammation biomarkers have shown a significant correlation between the plasma concentration of specific cytokines in the initial posttraumatic period and the development of NI and multiple organ failure.2, 7, 12, 13, 14 A study examining the expression of genes in critically injured patients suggested that large changes in leukocyte genomic gene expression occur in the first 12 h after injury and are sustained for days or weeks.7 According to this study, proinflammatory and anti-inflammatory phases occur simultaneously and the phenotype of trauma-induced immunosuppression may not be fully manifested until days after injury. However, there is now considerable evidence that there are major qualitative and quantitative differences in inflammatory mediator levels and gene expression patterns in patients prone to complications, including death, infections, and MODS.2, 15, 16, 17 Furthermore, many of these differences can be detected within hours of injury. We and others5, 18, 19, 20, 21 have suggested that levels of circulating biomarkers, measured early or over time, could be useful for predicting adverse clinical outcomes.
We reported recently that circulating interleukin (IL)-33 levels are elevated in patients after polytrauma at the time of admission.22 IL-33 exerts many of its extracellular actions by binding to the cell surface receptor suppression of tumorigenicity 2 (ST2). The soluble isoform of ST2 (soluble suppression of tumorigenicity 2 [sST2]) acts as a decoy receptor and blocks the actions of extracellular IL-33.23, 24 Soluble ST2 has emerged as an interesting prognostic biomarker for a number of diseases associated with tissue injury or systemic inflammation.25, 26, 27, 28, 29, 30, 31, 32, 33 Specifically, sST2 has been recently introduced as a clinically useful predictive biomarker that correlates with mortality and disease severity in conditions such as heart failure34, 35, 36, 37 and sepsis.38, 39 Although we found that sST2 levels are also elevated early after trauma in humans, peaking slightly later than IL-33, the association of sST2 with injury severity or clinical outcomes has not been characterized. To address this, we carried out an extensive time course analysis of circulating sST2 within the initial 24 h and up to day 5 after injury in a large cohort of blunt trauma patients admitted to the ICU. These data were then used to (1) test the hypothesis that circulating sST2 levels on admission can differentiate patients who either die (after surviving the initial 24 h) or those who survive to discharge and (2) correlate serum sST2 with a panel of innate and lymphoid-derived biomarkers and their association with adverse in-hospital clinical outcomes. We found that sST2 levels at admission and over time correlate with injury severity, acidosis, coagulopathy, and mortality. Moreover, we identified an inverse relationship between IL-33 and sST2 in patients presenting with high injury severity and patients who died after admission to the ICU.
Section snippets
Patient enrollment and sampling
All human sampling was done after approval by the University of Pittsburgh Institutional Review Board, and informed consent was obtained from each patient or next of kin as per Institutional Review Board regulations. Patients eligible for enrollment in the study were at least 18 y old, admitted to the ICU after being resuscitated, and per treating physician, were expected to live more than 24 h. Reasons for ineligibility were isolated head injury, pregnancy, and penetrating trauma. Laboratory
Nonsurvivors exhibited higher and sustained plasma sST2 levels compared with survivors
We first compared changes in circulating sST2 levels between survivors and nonsurviving trauma patients. The nonsurvivor cohort included 19 patients (16 males and 3 females; mean age: 58.8 ± 4.5; ISS: 23.3 ± 2.1) and the survivor cohort, 472 trauma patients (330 males and 142 females; mean age: 48.4 ± 0.87; ISS: 19.6 ± 0.48). As reported previously,15 the nonsurvivors presented with a significantly higher ISS (23 ± 2; P = 0.04) and had statistically significantly longer ICU LOS (P = 0.002) and
Discussion
sST2 has emerged as a biomarker of adverse inflammatory responses in a number of clinical settings.27, 37, 38, 52 To assess the relationship between circulating sST2 and clinical characteristics in trauma patients, we examined the changes of plasma sST2 in a large cohort of blunt trauma patients comprising 472 survivors and 19 nonsurvivors. We demonstrate that sST2 correlates with presenting parameters of injury severity, including ISS, elevated BD, and the presence of TIC. sST2 levels measured
Acknowledgment
This work was supported, in part, by National Institutes of Health grant P50-GM-53789.
Authors' contributions: I.B., T.R.B., and R.N. contributed to conception and design of the study; I.B., J.G., O.A.M., Y.V., and R.N. contributed to acquisition of data, analysis, and data interpretation; I.B., Y.V., T.R.B., and R.N. contributed to drafting the article or revising it critically for important intellectual content; I.B., Y.V., T.R.B., and R.N. provided final approval of the version to be
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2021, Journal of the American College of SurgeonsCitation Excerpt :The relationship between circulating sphingolipid and inflammatory mediators is striking. Of note, there was no difference among lipid subgroups in either calculated injury severity by either ISS or sST2, a marker that we have shown to correlate well with severity.55 However, the failure to elevate sphingolipids was associated with a pattern of marked early elevation of pro-inflammatory cytokines and chemokines.
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