Infections are a leading cause of morbidity and mortality in patients with acute CNS injury. It has recently become clear that CNS injury significantly increases susceptibility to infection by brain-specific mechanisms: CNS injury induces a disturbance of the normally well balanced interplay between the immune system and the CNS. As a result, CNS injury leads to secondary immunodeficiency - CNS injury-induced immunodepression (CIDS) - and infection. CIDS might serve as a model for the study of the mechanisms and mediators of brain control over immunity. More importantly, understanding CIDS will allow us to work on developing effective therapeutic strategies, with which the outcome after CNS damage by a host of diseases could be improved by eliminating a major determinant of poor recovery.

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Central nervous system injury-induced immune deficiency syndrome

Normal responses to injury prevent systemic inflammation and can be immunosuppressive.

The concept of ‘Compensatory anti-inflammatory response syndrome’ (CARS) was proposed in 1997 by Roger Bone (1941–1997) to qualify the consequences of the counter-regulatory mechanisms initiated to limit the overzealous inflammatory process in patients with infectious (sepsis) or non-infectious systemic inflammatory response syndrome (SIRS). One major consequence of CARS is the modification of the immune status that could favour the enhanced susceptibility of intensive care patients to nosocomial infections. Indeed, most animal ‘two-hit’ models illustrate an enhanced sensitivity to infection after a first insult. However, this observation is highly dependent on the experimental procedure. Numerous functions of circulating leukocytes are altered in sepsis and SIRS patients, as well as in animal models of sepsis or SIRS. However, this is rather a reprogramming of circulating leukocytes, since there is not a global defect of the immune cells functions. Furthermore, within tissues, leukocytes are rather primed or activated than immunosuppressed. Thus, CARS may be considered as an adapted compartmentalized response with the aim to silence some acute proinflammatory genes, and to maintain the possible expression of certain genes involved in the anti-infectious process.

Compensatory anti-inflammatory response syndrome.

ObjectiveTo investigate the relation of the biallelic Nco1 restriction fragment length polymorphism in the first intron of the tumor necrosis factor (TNF) β gene with the development of severe sepsis in multiply injured patients.Summary Background DataThe biallelic Nco1 polymorphism of the TNFβ gene

Relation of a TNF gene polymorphism to severe sepsis in trauma patients.

A recent hypothesis postulates that sepsis moves through different phases, with periods of enhanced inflammation alternating with periods of immune suppression. In this study we determined the levels of inflammation present during early and late septic deaths to examine whether death was due to hyperinflammation or immunosuppression. The murine model of sepsis induced by cecal ligation and puncture (CLP) was used. Complete blood counts, plasma interleukin-6 (IL-6) levels, and body weights were determined. Mice that died within the first 4 days had increased plasma levels of IL-6, indicating that there was activation of the immune system. Cecal resection on day 4 after CLP resulted in decreased abscess size, lower circulating neutrophil counts, decreased anemia, and improved survival compared to the results for mice that received only antibiotic and fluid therapy. All of the mice that died in the chronic phase of infection (after day 4) had positive peritoneal cultures containing significantly more bacteria than the cultures for surviving mice. After day 4, none of the surviving mice exhibited increases in the plasma levels of IL-6. Dying mice exhibited mixed IL-6 responses; for 41% of the mice there was never an increase in the IL-6 levels in the chronic phase, while for other mice the levels of IL-6 transiently increased prior to death. Peritoneal macrophages were obtained in the late phase of sepsis from moribund and healthy mice and were stimulated ex vivo. The cells from the moribund mice produced significantly less IL-6 than the cells obtained from healthy mice produced. These results indicate that in mice that die in the early phase there is uniformly increased inflammation. However, during the chronic phase of sepsis, some mice die with evidence of immunosuppression (increased bacterial growth and low IL-6 levels), while other mice die with immunostimulation (high IL-6 levels and bacterial growth). Determining the inflammatory status of individual patients may help guide appropriate, targeted therapy.

Mechanisms of Mortality in Early and Late Sepsis

OBJECTIVE To study whether the endotoxin responsiveness of peripheral blood mononuclear cells correlates with the severity of injury in trauma patients. DESIGN Prospective, observational study. SETTING University trauma center. PATIENTS Fifty-nine patients with blunt trauma (Injury Severity Score [ISS] 4 to 57 points). INTERVENTIONS Standard emergency department care, surgical care, and postoperative intensive care unit treatment. MEASUREMENTS AND MAIN RESULTS Whole blood and serum were obtained 94+/-89 (SD) mins post trauma (day 0) and during a 14-day period postinjury. Endotoxin-induced tumor necrosis factor-alpha (TNF-alpha) synthesis of peripheral blood mononuclear cells ex vivo was tested using a whole blood assay. Serum samples were assayed for TNF-alpha concentrations. A reduced capacity of whole blood to produce TNF-alpha ex vivo with endotoxin treatment was found to be closely correlated with the ISS. The capacity to produce TNF-alpha on endotoxin stimulation of whole blood from patients with an ISS > or =16 points was depressed immediately after trauma and did not reach normal values during the observation period. In patients with an ISS >22 points, maximum depression of the capacity of whole blood to produce TNF-alpha occurs within 100 mins post injury. In contrast, in patients with an ISS <22 points, maximal depression of whole blood TNF-alpha production occurs with a delay of 24 to 48 hrs after trauma. Based on pre- and postoperative values, primary surgical intervention caused a decrease of the endotoxin-stimulated TNF-alpha production of whole blood in the latter patient subgroup, as well as in the entire patient population (ISS 4 to 57) when secondary surgical treatment was necessary 5 to 13 days after trauma. CONCLUSIONS The extent of traumatic tissue damage leads to a graded depression of immunocyte function and appears to be amplified by surgical treatment. The endotoxin responsiveness of peripheral blood mononuclear cells displays a functional marker of the anatomically defined severity of injury and gives insights into the regulation of immunocyte function after severe blunt trauma.

The extent of traumatic damage determines a graded depression of the endotoxin responsiveness of peripheral blood mononuclear cells from patients with blunt injuries.

Background Trauma has been recognized to be accompanied by alterations of leukocyte functions such as cytokine release. The regulatory principles involved in these changes are still poorly defined. To further characterize leukocyte function after multiple trauma, endotoxin-stimulated tumor necrosis factor (TNF) production of trauma patients' whole blood and a possible regulatory mechanism were studied. Methods Endotoxin responsiveness in trauma patients (n = 18, Injury Severity Score = 24 +/- 7) was assayed ex vivo using a whole blood model. TNF release and TNFalpha mRNA levels were determined during a 14-day period. Furthermore, the influence of patients' sera on whole blood TNF production was evaluated. Main results The capacity of trauma patients' whole blood to produce TNF was reduced for 2 to 6 days after trauma and was equally evident for both TNF release and TNFalpha mRNA levels. The reduction of TNF coincides with the appearance of an inhibitory activity for TNF production in trauma patients' sera. No correlation was found between the inhibitory activity and soluble TNF receptors, endotoxin-neutralizing molecules, inhibitory cytokines (interleukin 10 and transforming growth factor beta), or prostaglandins. Conclusions Major trauma leads to the appearance of a circulating inhibitory activity for TNF synthesis that may potentially contribute to an anti-inflammatory response in patients with multiple trauma. The elucidation of its structural and functional properties may contribute to the understanding of the pathogenesis of severely injured patients.

Regulation of whole blood tumor necrosis factor production upon endotoxin stimulation after severe blunt trauma.

Ex-vivo cytokine production after severe trauma: association with posttraumatic clinical course: 400

A circulating inhibitor of cytokine synthesis in the initial phase of polytrauma.: 53

Differential cytokine expression after polytrauma: 430

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