Post-operative immune suppression is mediated via reversible, Interleukin-10 dependent pathways in circulating monocytes following major abdominal surgery.

INTRODUCTION: Post-operative infections occur frequently following major surgery. The magnitude of the post-operative immune response is associated with an increased risk of post-operative infections, although the mechanisms driving post-operative immune-dysfunction and the potential reversibility of this response with immune stimulants are not well understood. This study aims to describe the immediate immune response to major surgery and establish links to both post-operative infection and functional aspects of immune dysregulation. We also investigate the potential of clinically available immune stimulants to reverse features of post-operative immune-dysfunction. METHODS: Patients over 45 years old undergoing elective gastro-intestinal surgery with planned post-operative surgical ICU admission were recruited. The expression of selected genes was determined pre-operatively and at 2, 24 and 48 hours post-operatively using qRT-PCR. Circulating levels of Interleukin-10 protein were determined by ELISA. Peri-operative cell surface monocyte HLA-DR (mHLA-DR) expression was determined using flow cytometry. Gene expression and mHLA-DR levels were determined in healthy monocytes cultured in peri-operative serum with and without neutralising antibodies and immune stimulants. RESULTS: 119 patients were recruited; 44 developed a post-operative infection. Interleukin-10 mRNA and protein increased 4-fold post-operatively (P<0.0001), peaking within 2 hours of the procedure. Higher post-operative Interleukin-10 mRNA (P = 0.007) and protein (P = 0.001) levels were associated with an increased risk of infection. Cell surface mHLA-DR expression fell post-operatively (P<0.0001). Reduced production, rather than intracellular sequestration, accounted for the post-operative decline in cell surface mHLA-DR expression. Interleukin-10 antibody prevented the decrease in mHLA-DR expression observed when post-operative serum was added to healthy monocytes. GM-CSF and IFN-γ prevented the decline in mHLA-DR production through distinct pathways. CONCLUSIONS: Monocyte dysfunction and features of immune suppression occur frequently after major surgery. Greater post-operative Interleukin-10 production is associated with later infection. Interleukin-10 is an important mediator of post-operative reductions in mHLA-DR expression, while clinically available immune stimulants can restore mHLA-DR levels.

Pre-hospital National Early Warning Score (NEWS) is associated with in-hospital mortality and critical care unit admission: A cohort study.

BACKGROUND: National Early Warning Score (NEWS) is increasingly used in UK hospitals. However, there is only limited evidence to support the use of pre-hospital early warning scores. We hypothesised that pre-hospital NEWS was associated with death or critical care escalation within the first 48 h of hospital stay. METHODS: Planned secondary analysis of a prospective cohort study at a single UK teaching hospital. Consecutive medical ward admissions over a 20-day period were included in the study. Data were collected from ambulance report forms, medical notes and electronic patient records. Pre-hospital NEWS was calculated retrospectively. The primary outcome was a composite of death or critical care unit escalation within 48 h of hospital admission. The secondary outcome was length of hospital stay. RESULTS: 189 patients were included in the analysis. The median pre-hospital NEWS was 3 (IQR 1-5). 13 patients (6.9%) died or were escalated to the critical care unit within 48 h of hospital admission. Pre-hospital NEWS was associated with death or critical care unit escalation (OR, 1.25; 95% CI, 1.04-1.51; p = 0.02), but NEWS on admission to hospital was more strongly associated with this outcome (OR, 1.52; 95% CI, 1.18-1.97, p < 0.01). Neither was associated with hospital length of stay. CONCLUSION: Pre-hospital NEWS was associated with death or critical care unit escalation within 48 h of hospital admission. NEWS could be used by ambulance crews to assist in the early triage of patients requiring hospital treatment or rapid transport. Further cohort studies or trials in large samples are required before implementation.

A single-centre cohort study of National Early Warning Score (NEWS) and near patient testing in acute medical admissions.

INTRODUCTION: The utility of an early warning score may be improved when used with near patient testing. However, this has not yet been investigated for National Early Warning Score (NEWS). We hypothesised that the combination of NEWS and blood gas variables (lactate, glucose or base-excess) was more strongly associated with clinical outcome compared to NEWS alone. METHODS: This was a prospective cohort study of adult medical admissions to a single-centre over 20days. Blood gas results and physiological observations were recorded at admission. NEWS was calculated retrospectively and combined with the biomarkers in multivariable logistic regression models. The primary outcome was a composite of mortality or critical care escalation within 2days of hospital admission. The secondary outcome was hospital length of stay. RESULTS: After accounting for missing data, 15 patients out of 322 (4.7%) died or were escalated to the critical care unit. The median length of stay was 4 (IQR 7) days. When combined with lactate or base excess, NEWS was associated with the primary outcome (OR 1.18, p=0.01 and OR 1.13, p=0.03). However, NEWS alone was more strongly associated with the primary outcome measure (OR 1.46, p<0.01). The combination of NEWS with glucose was not associated with the primary outcome. Neither NEWS nor any combination of NEWS and a biomarker were associated with hospital length of stay. CONCLUSION: Admission NEWS is more strongly associated with death or critical care unit admission within 2days of hospital admission, compared to combinations of NEWS and blood-gas derived biomarkers.

Does major surgery induce immune suppression and increase the risk of postoperative infection?

PURPOSE OF REVIEW: Infection is the commonest cause of a postoperative complication. Following major surgery alterations in immune function are commonplace and these may contribute to an enhanced susceptibility to acquire nosocomial infections. This review will discuss postoperative infections in the context of an altered perioperative immune response and the factors influencing this response. RECENT FINDINGS: Up to 10% of patients undergoing elective in-patient surgery may develop a postoperative infection. Laboratory advances now permit systematic monitoring of single-cell immune signatures, which enable a clearer description of the interaction between tissue damage, immune modulation and clinical outcomes. Traditional candidate gene expression has identified pathways that define the detrimental immune modulating effects of perioperative allogeneic blood transfusion. Large clinical studies have demonstrated that the choice of anaesthetic technique may have an impact on postoperative infections through differential immune modulation. SUMMARY: Point of care tests are emerging that allow monitoring of the perioperative immune response. These could be further developed to introduce personalised care pathways. Consideration must also be given to anaesthesia techniques and perioperative treatments that may be associated with poor outcomes through immune modulation.

Features of Postoperative Immune Suppression Are Reversible With Interferon Gamma and Independent of Interleukin-6 Pathways.

OBJECTIVE: The aim of this study was to evaluate the role of interleukin (IL)-6 pathways in postoperative immune suppression and to assess the reversibility of this phenomenon. BACKGROUND: The postoperative period is characterized by increased IL-6 production and features of immune suppression. In vitro, IL-6 mediates anti-inflammatory effects through inhibition of interferon gamma (IFN-γ) pathways. The significance of the immunomodulatory effects of IL-6 in the clinical setting of postoperative immune suppression remains unclear. METHODS: Patients over 45 years old undergoing elective surgery, involving the gastrointestinal tract, were recruited. IL-6 levels were assayed using an enzyme linked immunosorbent assay preoperatively, and at 24 and 48 hours. Peripheral blood mononuclear cells from healthy volunteers were cultured in perioperative serum and CD14Human Leukocyte Antigen-DR (HLA-DR) [monocyte HLA-DR (mHLA-DR)] geometric mean florescent intensity was measured in the presence and absence of IL-6 neutralizing antibody and recombinant IFN-γ. RESULTS: Of the 108 patients, 41 developed a postoperative infection. The IL-6 levels increased 19-fold from the preoperative sample to 24 hours postoperatively (P < 0.0001). Higher IL-6 levels at 24 (P = 0.0002) and 48 hours (P = 0.003) were associated with subsequent postoperative infectious complications. mHLA-DR mean florescent intensity fell when healthy peripheral blood mononuclear cells were cultured with postoperative serum compared with preoperative serum (P = 0.008). This decrease was prevented by the presence of IFN-γ in the culture media, but not by the presence of IL-6-neutralizing antibody. CONCLUSIONS: IL-6 levels increase after a major surgery and are associated with an increased susceptibility to postoperative infections. Serum obtained from postoperative patients induces an immunosuppressive response, reflected in reduced mHLA-DR levels, mediated through IL-6 independent pathways and is reversible with IFN-γ. These data may have therapeutic implications for the prevention of infection in patients undergoing major surgery.

Systemic Inflammatory Response Syndrome After Major Abdominal Surgery Predicted by Early Upregulation of TLR4 and TLR5.

OBJECTIVES: To study innate immune pathways in patients undergoing hepatopancreaticobiliary surgery to understand mechanisms leading to enhanced inflammatory responses and identifying biomarkers of adverse clinical consequences. BACKGROUND: Patients undergoing major abdominal surgery are at risk of life-threatening systemic inflammatory response syndrome (SIRS) and sepsis. Early identification of at-risk patients would allow tailored postoperative care and improve survival. METHODS: Two separate cohorts of patients undergoing major hepatopancreaticobiliary surgery were studied (combined n = 69). Bloods were taken preoperatively, on day 1 and day 2 postoperatively. Peripheral blood mononuclear cells and serum were separated and immune phenotype and function assessed ex vivo. RESULTS: Early innate immune dysfunction was evident in 12 patients who subsequently developed SIRS (postoperative day 6) compared with 27 who did not, when no clinical evidence of SIRS was apparent (preoperatively or days 1 and 2). Serum interleukin (IL)-6 concentration and monocyte Toll-like receptor (TLR)/NF-κB/IL-6 functional pathways were significantly upregulated and overactive in patients who developed SIRS (P < 0.0001). Interferon α-mediated STAT1 phosphorylation was higher preoperatively in patients who developed SIRS. Increased TLR4 and TLR5 gene expression in whole blood was demonstrated in a separate validation cohort of 30 patients undergoing similar surgery. Expression of TLR4/5 on monocytes, particularly intermediate CD14CD16 monocytes, on day 1 or 2 predicted SIRS with accuracy 0.89 to 1.0 (areas under receiver operator curves). CONCLUSIONS: These data demonstrate the mechanism for IL-6 overproduction in patients who develop postoperative SIRS and identify markers that predict patients at risk of SIRS 5 days before the onset of clinical signs.

Epigenetic regulatory pathways involving microRNAs may modulate the host immune response following major trauma.

BACKGROUND: Posttraumatic nosocomial pneumonia is a common complication resulting in significant morbidity. Trauma-induced immunocompromise is associated with an enhanced susceptibility to pneumonia. In this study, we explore the hypothesis that posttranscriptional epigenetic regulation of gene expression may be an important factor in determining this immune phenotype. We describe the pattern of production of microRNAss (miRs) and their association with nosocomial pneumonia following severe trauma. METHODS: A convenience sample of 30 ventilated polytrauma patients ( UKCRN ID: 5637) and 16 healthy controls were recruited. Messenger RNA and protein levels of key cytokines were quantified within 2 hours of the injury and at 24 hours. Three miRs per cytokine were then selected based on miRBase target prediction scores and quantified using polymerase chain reaction. Nosocomial pneumonia was defined using the Centers for Disease Control and Prevention definitions. RESULTS: Median Injury Severity Score (ISS) was 29, and 47% of the patients developed nosocomial pneumonia. miR-125a and miR-202 decreased by 34% and 77%, respectively, immediately following injury, whereas their target, IL-10, increased messenger RNA levels 3-fold and protein levels 180-fold. Tumor necrosis factor α (TNF-α) and IL-12 gene expression decreased by 68% and 43%, respectively, following injury, and this was mirrored by a 10-fold increase in miR-181, an miR predicted to target TNF-α transcripts. Lower levels of miR-125a and miR-374b were associated with the later acquisition of hospital-acquired pneumonia. CONCLUSION: Alteration in the expression of miRs with highly predicted complementarity to IL-10 and TNF-α may be an important mechanism regulating the posttraumatic immunosuppressive phenotype in intensive care unit patients. LEVEL OF EVIDENCE: Retrospective observational study, level III.

The perioperative immune response.

PURPOSE OF REVIEW: A host of immune modulators are now available in clinical practice. The perioperative period is characterized by profound alterations in host immunity, which can result in poor outcomes, which include infection, cancer recurrence and organ failure. Manipulation of the perioperative immune response has the potential to improve outcomes. A complete understanding of the mechanisms and clinical consequences of altered immune function in this setting is therefore imperative. RECENT FINDINGS: Recent in-vivo data have emerged which further our understanding of the interaction between tissue damage, immune modulation and clinical outcomes by utilizing novel laboratory techniques capable of monitoring single-cell immune signatures. Traditional gene expression assays have continued to demonstrate their utility and have been instrumental in defining the host response to perioperative allogeneic blood transfusion. These mechanistic studies are complemented by large clinical studies describing associations between anaesthetic modalities and immune-related outcomes. SUMMARY: Laboratory techniques are now available that can monitor the perioperative immune response and could be further developed to introduce personalized care pathways. Consideration must also be given to anaesthesia techniques and perioperative treatments that, although not immediately harmful, may be associated with poor outcomes temporally distant from the treatment, secondary to induced immunosuppression.

A single-centre observational cohort study of admission National Early Warning Score (NEWS).

INTRODUCTION: Early warning scores are commonly used in hospitals to identify patients at risk of deterioration. The National Early Warning Score (NEWS) has recently been introduced to UK practice. However, it is not yet widely implemented. We aimed to compare NEWS to the early warning score currently used in our hospital--the Patient at Risk Score (PARS). METHODS: We conducted a prospective observational cohort study of all adult general medical patients admitted to a single hospital over a 20-day period. Physiological data and early warning scores recorded in bedside charts were collected on admission and a NEWS score was retrospectively calculated. The patient notes were reviewed at 48 h after admission. The primary outcome was a composite of critical care admission or death within 2 days of admission. The secondary outcome was hospital length of stay. RESULTS: NEWS was more strongly associated with the primary outcome than PARS (odds ratio 1.54, p < 0.001 compared to 1.42, p = 0.056). A NEWS of 3 or more was associated with the primary outcome (odds ratio 7.03, p = 0.003). Neither score was correlated with hospital length of stay. CONCLUSION: NEWS on admission is superior to PARS for identifying patients at risk of death or critical care admission within the first 2 days of hospital stay. Current guidelines advocate a threshold of 5 for triggering a clinical review. However, since a score of 3 or more was associated with a poor outcome, this recommendation should be reviewed. Both scores were poor predictors of hospital length of stay.

Changes in gene expression following trauma are related to the age of transfused packed red blood cells.

BACKGROUND: Transfusion of packed red blood cells (PRBCs) is associated with an increased incidence of nosocomial infections and an increased risk of death. The duration of storage before transfusion may influence these outcomes. Here, we explore the association between the age of transfused PRBCs and specific patterns of inflammatory gene expression in severely injured trauma patients. METHODS: Severely injured trauma patients requiring intensive care unit treatment and receiving transfusion of PRBCs within 24 hours of the injury were recruited. Blood samples were obtained within 2 hours of the trauma, at 24 hours, and at 72 hours. Messenger RNA was extracted from whole blood, and gene expression was quantified using quantitative polymerase chain reaction. The median age of the units of PRBCs transfused to each patient was recorded. The primary outcome measure was the change in candidate gene expression over the initial 72 hours. RESULTS: Sixty-four patients were studied. Fifty-three patients (83%) were male, and the median age was 40.5 years (interquartile range [IQR], 31-59). Median Injury Severity Score (ISS) was 31.5 (IQR, 23-43), and 55 patients (86%) experienced a blunt injury. Forty-one patients (64%) developed a nosocomial infection, and 15 patients (23%) died before hospital discharge. Each patient received a median of 5 U of PRBCs (IQR, 4-9.8 U) during the first 24 hours of hospital admission. The median age of the units of PRBCs transfused in each patient was 20 days (IQR, 17-22 days). Older blood was associated with greater decreases in interleukin 12 (IL-12), IL-23, and RORγt (all p's < 0.05) gene expression over the initial 24 hours, greater decreases in IL-12 gene expression over 72 hours, and a rise in transforming growth factor ß gene expression over the first 72 hours. A multivariate analysis confirmed the independence of these associations. CONCLUSION: Increasing the duration of storage of PRBCs before transfusion is associated with a pattern of gene expression consistent with more severe immunosuppression. LEVEL OF EVIDENCE: Epidemiologic study, level III.