The diagnostic and prognostic value of systems biology research in major traumatic and thermal injury: a review

Abstract

As secondary complications remain a significant cause of morbidity and mortality amongst hospitalised trauma patients, the need to develop novel approaches by which to identify patients at risk of adverse outcome is becoming increasingly important. Centred on the idea that patients who experience "poor" outcome post trauma elicit a response to injury that is distinct from those who experience "good" outcome, tailored therapeutics is an emerging concept aimed at improving current treatment regimens by promoting patient-specific therapies. Making use of recent advancements in the fields of genomics, proteomics and metabolomics, numerous groups have undertaken a systems-based approach to analysing the acute immune and inflammatory response to major traumatic and thermal injury in an attempt to uncover a single or combination of biomarkers that can identify patients at risk of adverse outcome. Early results are encouraging, with all three approaches capable of discriminating patients with "good" outcome from those who develop nosocomial infections, sepsis and multiple organ failure, with differences apparent in blood samples acquired as early as 2 h post injury. In particular, genomic data is proving to be highly informative, identifying patients at risk of "poor" outcome with a higher degree of sensitivity and specificity than statistical models built upon data obtained from existing anatomical and physiological scoring systems. Here, focussing predominantly upon human-based research, we provide an overview of the findings of studies that have investigated the immune and inflammatory response to major traumatic and thermal injury at the genomic, protein and metabolite level, and consider both the diagnostic and prognostic potential of these approaches.

Keywords: Burns; Cytokines; Genomics; Inflammation; Mortality; Sepsis; Trauma.

Fig. 1

Damage Associated Molecular Patterns (DAMPs) release and immune cell activation following sterile traumatic injury. Tissue damage arising from traumatic or thermal injury results in the release into circulation of mitochondrial (e.g. mtDNA, formyl peptides), cytosolic (e.g. F-actin) and nuclear (e.g. HMGB1)-derived damage associated molecular patterns (DAMPs). Through binding to pathogen recognition receptors, DAMPs trigger the activation of circulating immune cells resulting in the secretion of pro- and anti-inflammatory cytokines as well as a series of functional responses, which include the generation of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs). Together, cell activation and cytokine secretion creates an inflammatory environment that favours the development of multiple organ failure, tissue damage and immunoparesis, conditions that are associated with a range of poor patient outcomes, which include a longer length of hospital stay and an increased risk of sepsis and mortality. Tissue damage arising from immune cell activation would lead to the release of further DAMPs, creating a vicious cycle, with continued inflammation and immune activation. ATP adenosine tri phosphate, DAMP damage-associated molecular pattern, F-actin filamentous actin, HMGB1 high-mobility group box 1 protein, IL interleukin, LOS length of stay, MCP-1 monocyte chemoattractant protein 1, MOF multiple organ failure, mtDNA mitochondrial DNA, NETs neutrophil extracellular traps, ROS reactive oxygen species, SIRS systemic inflammatory response syndrome, TNF-α tumour necrosis factor-alpha