Trauma-Induced Long-Term Alterations of Human T Cells and Monocytes-Results of an Explorative, Cross-Sectional Study.

BACKGROUND: Major trauma leads to complex immune reactions, known to result in a transient immunodeficiency. The long-term consequences of severe trauma on immune function and regulation as well as its clinical impact remain unclear. METHODS: Six months (ranging from -12 to +5 days) after a major trauma event, 12 former trauma patients (Injury Severity Score ≥ 16) and 12 healthy volunteers were enrolled. The current clinical status and infection history since discharge were assessed by a standardized questionnaire. Immune cell subsets (cluster of differentiation (CD)4, CD8, CD14), cell surface receptor expression (programmed cell death protein 1 (PD-1), B- and T-lymphocyte attenuator (BTLA), cytotoxic T-lymphocyte-associated protein 4, toll-like receptor (TLR)-2, -4, and -5, Dectin-1, programmed death ligand 1 (PD-1L)), and human leucocyte antigen D-related receptor (HLA-DR)-expression were quantified by flow cytometry. Cytokine secretion (IL-2, -4, -6, -10, and 17A, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ) was assessed after stimulation of whole blood with LPS-, α-CD3/28, or zymosan. RESULTS: Analysis of surface receptors on T cells revealed a significant elevation of PD-1 expression on CD4 T cells, whereas BTLA expression on CD4 and CD8 T cells was significantly suppressed in the trauma cohort. Monocytes showed a significantly reduced expression of TLR-2 and -4 as well as a reduced proportion of TLR-4 monocytes. HLA-DR receptor density revealed no significant changes between both cohorts. LPS-induced IL-6 and TNF-α secretion showed non-significant trends toward reduced values. No differences regarding clinical apparent infections could be detected. CONCLUSIONS: Six months following major trauma, changes of cell surface receptors on CD4 and CD8 T cells as well as on CD14 monocytes were present, hinting toward an immunosuppressive phenotype. Following major trauma, although IL-6 and TNF-α release after stimulation were reduced, they did not reach statistical significance. Overall, further studies are necessary to evaluate the clinical implications of these findings. TRIAL REGISTRATION: DRKS00009876, Internet Portal of the German Clinical Trials Register (DRKS), registration date 11.08.2016, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00009876.

Hypotension Prediction Index based protocolized haemodynamic management reduces the incidence and duration of intraoperative hypotension in primary total hip arthroplasty: a single centre feasibility randomised blinded prospective interventional trial.

The "Hypotension Prediction Index (HPI)" represents a newly introduced monitoring-tool that aims to predict episodes of intraoperative hypotension (IOH) before their occurrence. In order to evaluate the feasibility of protocolized care according to HPI monitoring, we hypothesized that HPI predicts the incidence of IOH and reduces the incidence and duration of IOH. This single centre feasibility randomised blinded prospective interventional trial included at total of 99 patients. One group was managed by goal-directed therapy algorithm based on HPI (HPI, n = 25), which was compared to a routine anaesthetic care cohort (CTRL, n = 24) and a third historic control group (hCTRL, n = 50). Primary endpoints included frequency (n)/h, absolute and relative duration (t (min)/% of total anaesthesia time) of IOH. Significant reduction of intraoperative hypotension was recorded in the HPI group compared to the control groups (HPI 48%, CTRL 87.5%, hCTRL 80%; HPI vs. CTRL, respectively hCTRL p < 0.001). Perioperative quantity of IOH was significantly reduced in the interventional group compared to both other study groups (HPI: 0 (0-1), CTRL: 5 (2-6), hCTRL: 2 (1-3); p < 0.001). Same observations were identified for absolute (HPI: 0 (0-140) s, CTRL: 640 (195-1315) s, hCTRL 660 (180-1440) s; p < 0.001) and relative duration of hypotensive episodes (minutes MAP ≤ 65 mmHg in  % of total anaesthesia time; HPI: 0 (0-1), CTRL: 6 (2-12), hCTRL 7 (2-17); p < 0.001). The HPI algorithm combined with a protocolized treatment was able to reduce the incidence and duration of hypotensive events in patients undergoing primary hip arthroplasty.Trial registration: NCT03663270.

Host-Derived Delta-Like Canonical Notch Ligand 1 as a Novel Diagnostic Biomarker for Bacterial Sepsis-Results From a Combinational Secondary Analysis.

Background: Sepsis is a life-threatening syndrome, resulting from a dysbalanced host response to infection. However, especially the early, pro-inflammatory immune response in sepsis is similar to other inflammatory conditions without infectious cause, e.g., trauma or surgery. This aspect challenges the value of current biomarkers for diagnosis, as these are often broadly induced. We earlier identified Delta-like Protein 1 (DLL1), a canonical Notch ligand, to be released from monocytes upon bacterial stimulation. Considering the importance of monocytes in the pathophysiology of sepsis, we hypothesized that this mechanism might occur also in the clinical setting and DLL1 might serve as a biomarker of life-threatening bacterial infection. Methods: We combined samples from three different studies, including subgroups of patients with sepsis (n = 80), surgical patients (n = 50), trauma patients (n = 36), as well as healthy controls (n = 50). We assessed plasma concentrations of DLL1 using ELISA. We performed Area-under-receiver-operator-curve (AUROC) analysis to evaluate the diagnostic performance of DLL1 compared to leucocytes, C-reactive protein (CRP), and procalcitonin (PCT). Results: Plasma concentrations of DLL1 were strongly elevated already at sepsis onset and maintained elevated until day 7. In contrast, neither surgical patients nor patients after severe trauma presented with elevated levels, while conventional biomarkers of inflammation (e.g., leucocytes and CRP), responded. AUROC analysis revealed a cut-off of 30 ng/ml associated with the best diagnostic performance, yielding a superior accuracy of 91% for DLL1, compared to 75, 79, and 81% for CRP, leucocytes, and PCT. Conclusion: DLL1 is a novel host-derived biomarker for the diagnosis of sepsis with a better performance compared to established ones, most likely due to its high robustness in non-infectious inflammatory responses. Clinical Trial Registration: POCSEP-Trial DRKS00008090; MIRSI DRKS00005463; SPRINT DRKS00010991.

C-Reactive Protein Stimulates Nicotinic Acetylcholine Receptors to Control ATP-Mediated Monocytic Inflammasome Activation.

Blood levels of the acute phase reactant C-reactive protein (CRP) are frequently measured as a clinical marker for inflammation, but the biological functions of CRP are still controversial. CRP is a phosphocholine (PC)-binding pentraxin, mainly produced in the liver in response to elevated levels of interleukin-1ß (IL-1ß) and of the IL-1ß-dependent cytokine IL-6. While both cytokines play important roles in host defense, excessive systemic IL-1ß levels can cause life-threatening diseases such as trauma-associated systemic inflammation. We hypothesized that CRP acts as a negative feedback regulator of monocytic IL-1ß maturation and secretion. Here, we demonstrate that CRP, in association with PC, efficiently reduces ATP-induced inflammasome activation and IL-1ß release from human peripheral blood mononuclear leukocytes and monocytic U937 cells. Effective concentrations are in the range of marginally pathologic CRP levels (IC50 = 4.9 µg/ml). CRP elicits metabotropic functions at nicotinic acetylcholine (ACh) receptors (nAChRs) containing subunits α7, α9, and α10 and suppresses the function of ATP-sensitive P2X7 receptors in monocytic cells. Of note, CRP does not induce ion currents at conventional nAChRs, suggesting that CRP is a potent nicotinic agonist controlling innate immunity without entailing the risk of adverse effects in the nervous system. In a prospective study on multiple trauma patients, IL-1ß plasma concentrations negatively correlated with preceding CRP levels, whereas inflammasome-independent cytokines IL-6, IL-18, and TNF-α positively correlated. In conclusion, PC-laden CRP is an unconventional nicotinic agonist that potently inhibits ATP-induced inflammasome activation and might protect against trauma-associated sterile inflammation.

Longitudinal Evaluation of Plasma Concentrations of Presepsin in Patients after Severe Trauma: A Prospective Observational Study.

BACKGROUND: The high mortality rate of patients suffering from severe trauma is based not only on the mechanism of injury, but also on the higher risk for development of subsequent infections. Therefore, the early recognition of infection after severe trauma is of particular importance for patient outcome. However, early diagnosis is often masked by the consequences of the sterile, damage-triggered immune response. Our study sought to analyze the course of soluble CD14-subtype (sCD14-ST, presepsin) compared with clinically established inflammatory and infectious biomarkers in a cohort of patients with severe trauma. PATIENTS AND METHODS: Between January 2015 and February 2016, 50 patients suffering from severe trauma (Injury Severity Score [ISS] > 16) were enrolled and followed up for seven consecutive days after intensive care unit (ICU) admission. Clinical routine data, signs of infection, and the inflammatory biomarkers presepsin, C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) were assessed. RESULTS: Regarding the well-established biomarkers CRP, PCT, and IL-6, we observed trauma-associated alterations (day 1: CRP 13 mg/L, interquartile range [IQR] 0-129; PCT 1.1 µg/L, IQR 0-13; IL-6 108 pg/mL, IQR 29-795), which did not correlate with the clinical development of systemic inflammatory response syndrome (SIRS), whereas elevated plasma concentrations of presepsin in the clinical course were associated with the presence of SIRS (presepsin: no-SIRS vs. SIRS p = 0.03). CONCLUSION: Our study investigates systematically the kinetic of presepsin compared with established inflammatory and infectious markers after severe trauma. Presepsin is neither affected by the early post-traumatic nor the delayed immune response over seven days after trauma, making it a possible option as a diagnostic biomarker of infection worth further evaluation.