Elsevier

Journal of Surgical Research

Volume 244, December 2019, Pages 23-33
Journal of Surgical Research

Shock/Sepsis/Trauma/Critical Care
Elevations in Circulating sST2 Levels Are Associated With In-Hospital Mortality and Adverse Clinical Outcomes After Blunt Trauma

https://doi.org/10.1016/j.jss.2019.05.057Get rights and content

Abstract

Background

Soluble suppression of tumorigenicity 2 (sST2), a decoy receptor for interleukin (IL)-33, has emerged as a novel biomarker in various disease processes. Recent studies have elucidated the role of the sST2/IL-33 complex in modulating the balance of Th1/Th2 immune responses after tissue stress. However, the role of sST2 as a biomarker after traumatic injury remains unclear. To address this, we evaluated serum sST2 correlations with mortality and in-hospital adverse outcomes as endpoints in blunt trauma patients.

Methods

We retrospectively analyzed clinical and biobank data of 493 blunt trauma victims 472 survivors (mean age: 48.4 ± 0.87; injury severity score [ISS]: 19.6 ± 0.48) and 19 nonsurvivors (mean age: 58.8 ± 4.5; ISS: 23.3 ± 2.1) admitted to the intensive care unit. Given the confounding impact of age on the inflammatory response, we derived a propensity-matched survivor subgroup (n = 19; mean age: 59 ± 3; ISS: 23.4 ± 2) using an IBM SPSS case-control matching algorithm. Serial blood samples were obtained from all patients (3 samples within the first 24 h and then once daily from day [D] 1 to D5 after injury). sST2 and twenty-nine inflammatory biomarkers were assayed using enzyme-linked immunosorbent assay and Luminex, respectively. Two-way analysis of variance on ranks was used to compare groups (P < 0.05). Spearman rank correlation was performed to determine the association of circulating sST2 levels with biomarker levels and in-hospital clinical outcomes.

Results

Circulating sST2 levels of the nonsurvivor cohort were statistically significantly elevated at 12 h after injury and remained elevated up to D5 when compared either to the overall 472 survivor cohort or a matched 19 survivor subcohort. Admission sST2 levels obtained from the first blood draw after injury in the survivor cohort correlated positively with admission base deficit (correlation coefficient [CC] = 0.1; P = 0.02), international normalized ratio (CC = 0.1, P = 0.03), ISS (CC = 0.1, P = 0.008), and the average Marshall multiple organ dysfunction score between D2 and D5 (CC = 0.1, P = 0.04). Correlations with ISS revealed a positive correlation of ISS with plasma sST2 levels across the mild ISS (CC = 0.47, P < 0.001), moderate ISS (CC = 0.58, P < 0.001), and severe ISS groups (CC = 0.63, P < 0.001). Analysis of biomarker correlations in the matched survivor group over the initial 24 h after injury showed that sST2 correlates strongly and positively with IL-4 (CC = 0.65, P = 0.002), IL-5 (CC = 0.57, P = 0.01), IL-21 (CC = 0.52, P = 0.02), IL-2 (CC = 0.51, P = 0.02), soluble IL-2 receptor-α (CC = 0.5, P = 0.02), IL-13 (CC = 0.49, P = 0.02), and IL-17A (CC = 0.48, P = 0.03). This was not seen in the matched nonsurvivor group. sST2/IL-33 ratios were significantly elevated in nonsurvivors and patients with severe injury based on ISS ≥ 25.

Conclusions

Elevations in serum sST2 levels are associated with poor clinical trajectories and mortality after blunt trauma. High sST2 coupled with low IL-33 associates with severe injury, mortality, and worse clinical outcomes. These findings suggest that sST2 could serve as an early prognostic biomarker in trauma patients and that sustained elevations of sST2 could contribute to a detrimental suppression of IL-33 bioavailability in patients with high injury severity.

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

References (73)

  • A. Becerra et al.

    Elevated levels of soluble ST2 protein in dengue virus infected patients

    Cytokine

    (2008)
  • D. Bergis et al.

    High serum levels of the interleukin-33 receptor soluble ST2 as a negative prognostic factor in hepatocellular carcinoma

    Transl Oncol

    (2013)
  • M. De la Fuente et al.

    The IL-33/ST2 axis: role in health and disease

    Cytokine Growth Factor Rev

    (2015)
  • J. Schmitz et al.

    IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines

    Immunity

    (2005)
  • A.S. Mirchandani et al.

    Interleukin-33 and the function of innate lymphoid cells

    Trends Immunol

    (2012)
  • B.M. Matta et al.

    Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD

    Blood

    (2016)
  • L. Dwyer-Lindgren et al.

    US County-Level Trends in mortality rates for major causes of death, 1980-2014

    JAMA

    (2016)
  • R.A. Namas et al.

    Temporal patterns of circulating inflammation biomarker networks differentiate susceptibility to nosocomial infection following blunt trauma in humans

    Ann Surg

    (2016)
  • C. von Ruden et al.

    Outcome after severe multiple trauma: a retrospective analysis

    J Trauma Manag Outcomes

    (2013)
  • R.A. Namas et al.

    Insights into the role of chemokines, damage-associated molecular patterns, and lymphocyte-derived mediators from computational models of trauma-induced inflammation

    Antioxid Redox Signal

    (2015)
  • L.G. Glance et al.

    Outcomes of adult trauma patients admitted to trauma centers in Pennsylvania, 2000-2009

    Arch Surg

    (2012)
  • W. Xiao et al.

    A genomic storm in critically injured humans

    J Exp Med

    (2011)
  • M.D. Rosenthal et al.

    Persistent inflammatory, immunosuppressed, catabolic syndrome (PICS): a new phenotype of multiple organ failure

    J Adv Nutr Hum Metab

    (2015)
  • A.M. Ingraham et al.

    The attributable mortality and length of stay of trauma-related complications: a matched cohort study

    Ann Surg

    (2010)
  • R.M. Roumen et al.

    Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Relation with subsequent adult respiratory distress syndrome and multiple organ failure

    Ann Surg

    (1993)
  • J. Cuschieri et al.

    Early elevation in random plasma IL-6 after severe injury is associated with development of organ failure

    Shock

    (2010)
  • A. Abboud et al.

    Computational analysis supports an early, type 17 cell-associated divergence of blunt trauma survival and mortality

    Crit Care Med

    (2016)
  • C.P. Cabrera et al.

    Signatures of inflammation and impending multiple organ dysfunction in the hyperacute phase of trauma: a prospective cohort study

    PLoS Med

    (2017)
  • J. Hazeldine et al.

    Prehospital immune responses and development of multiple organ dysfunction syndrome following traumatic injury: a prospective cohort study

    PLoS Med

    (2017)
  • A.B. Dekker et al.

    Predictive value of cytokines for developing complications after polytrauma

    World J Crit Care Med

    (2016)
  • M.F. Osuchowski et al.

    Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality

    J Immunol

    (2006)
  • B. Maier et al.

    Early versus late onset of multiple organ failure is associated with differing patterns of plasma cytokine biomarker expression and outcome after severe trauma

    Shock

    (2007)
  • A.J. Lamparello et al.

    A conceptual time window-based model for the early stratification of trauma patients

    J Intern Med

    (2019)
  • J. Xu et al.

    IL33-mediated ILC2 activation and neutrophil IL5 production in the lung response after severe trauma: a reverse translation study from a human cohort to a mouse trauma model

    PLoS Med

    (2017)
  • F.Y. Liew et al.

    Interleukin-33 in health and disease

    Nat Rev Immunol

    (2016)
  • H. Xu et al.

    Role of the IL-33-ST2 axis in sepsis

    Mil Med Res

    (2017)
  • Cited by (9)

    • Analysis of the Plasma Metabolome after Trauma, Novel Circulating Sphingolipid Signatures, and In-Hospital Outcomes

      2021, Journal of the American College of Surgeons
      Citation 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.

    View all citing articles on Scopus
    View full text