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

Abstract

BackgroundSevere trauma induces a widespread response of the immune system. This “genomic storm” can lead to poor outcomes, including Multiple Organ Dysfunction Syndrome (MODS). MODS carries a high mortality and morbidity rate and adversely affects long-term health outcomes. Contemporary management of MODS is entirely supportive, and no specific therapeutics have been shown to be effective in reducing incidence or severity. The pathogenesis of MODS remains unclear, and several models are proposed, such as excessive inflammation, a second-hit insult, or an imbalance between pro- and anti-inflammatory pathways. We postulated that the hyperacute window after trauma may hold the key to understanding how the genomic storm is initiated and may lead to a new understanding of the pathogenesis of MODS.Methods and findingsWe performed whole blood transcriptome and flow cytometry analyses on a total of 70 critically injured patients (Injury Severity Score [ISS] ≥ 25) at The Royal London Hospital in the hyperacute time period within 2 hours of injury. We compared transcriptome findings in 36 critically injured patients with those of 6 patients with minor injuries (ISS ≤ 4). We then performed flow cytometry analyses in 34 critically injured patients and compared findings with those of 9 healthy volunteers. Immediately after injury, only 1,239 gene transcripts (4%) were differentially expressed in critically injured patients. By 24 hours after injury, 6,294 transcripts (21%) were differentially expressed compared to the hyperacute window. Only 202 (16%) genes differentially expressed in the hyperacute window were still expressed in the same direction at 24 hours postinjury. Pathway analysis showed principally up-regulation of pattern recognition and innate inflammatory pathways, with down-regulation of adaptive responses. Immune deconvolution, flow cytometry, and modular analysis suggested a central role for neutrophils and Natural Killer (NK) cells, with underexpression of T- and B cell responses.In the transcriptome cohort, 20 critically injured patients later developed MODS. Compared with the 16 patients who did not develop MODS (NoMODS), maximal differential expression was seen within the hyperacute window. In MODS versus NoMODS, 363 genes were differentially expressed on admission, compared to only 33 at 24 hours postinjury. MODS transcripts differentially expressed in the hyperacute window showed enrichment among diseases and biological functions associated with cell survival and organismal death rather than inflammatory pathways. There was differential up-regulation of NK cell signalling pathways and markers in patients who would later develop MODS, with down-regulation of neutrophil deconvolution markers. This study is limited by its sample size, precluding more detailed analyses of drivers of the hyperacute response and different MODS phenotypes, and requires validation in other critically injured cohorts.ConclusionsIn this study, we showed how the hyperacute postinjury time window contained a focused, specific signat...

Innate immune responses to trauma

“…This disruption constitutes the beginning of a rapidly activated innate immune response 1 that aims to end the dangerous situation for the recipient of the traumatic insult but can also result in severe complications and death 2–5 . The innate immune response after severe tissue trauma or life-threatening multiple injury (polytrauma) results in a multi-faceted systemic disease with a complex and heterogeneous, although mainly compartmentalized, response 6–8 . To cover the organ systems most frequently affected by severe trauma—the head, chest and abdomen (in descending prevalence) 9,10 —this Review addresses mainly those systems, plus the endothelium as a ‘meta-organ’, and their interrelated changes in innate immunity after trauma.…”

Data driven analysis reveals shared transcriptome response and immune cell composition across aetiologies of critical illness

“…These recent genome wide results have suggested a new model consisting of the parallel upregulation of innate immunity with the suppression of adaptive immunity (2). In a longitudinal analysis of gene expression levels and cell factions in the hyperacute phase of trauma showed a relatively limited upregulation of transcriptomics (3). Only 4.2%, 21.4% and 21.0% of total genes were differentially expressed in samples taken within 2 hours of injury, 24 and 72 hours of admission, respectively.…”

“…Supporting this interpretation are prior studies that correlate pure fractions of leukocytes to clinical course and outcome. Deconvolution of leukocyte fractions in trauma showed increased risk of Multi Organ Dysfunction Syndrome (MODS) with elevated dendritic cell counts but depleted neutrophil levels (3) which corresponds to the configuration of subgroup 1. Given the limitation of our dataset further studies are required to confirm the association of subgroup 2 with MODS in critical illness.…”

“…Host responses to critical illness such as infection or trauma are highly variable between patients (1–3). Specific examples of this complexity include the reprioritization patterns in gene expression (2,4,5) and the coexistence of proinflammatory and immunosuppressed states (1–3,6,7) in critically ill patients. Understanding this diversity in systemic response is highly important to treatment planning and recovery prediction.…”

Washing or filtering of blood products does not improve outcome in a rat model of trauma and multiple transfusion

“…Also, following trauma, both pro‐ and anti‐inflammatory profiles have been reported . A proinflammatory response can contribute to MOF, while an immunosuppressive response following blood transfusion in trauma patients is thought to predispose patients to postinjury infection …”