Assessment of immunological status in the critically ill

The systemic inflammatory response (SIRS) results from various types of injuries such as severe infection, trauma, ischemia-reperfusion and major surgery including cardiac surgery with cardio-pulmonary bypass. This response involves immune cell activation and a complex network of proinflammatory cytokines, which may induce multiple organ failure when uncontrolled. The monocyte plays a central role in the response to infection with the release of TNF, IL-1, and IL-12. In addition, monocytes present antigens to T lymphocytes. An optimal antigen presentation requires the expression of MHC class II HLA-DR on monocytes surface and of co-stimulatory molecules such as CD54 on monocytes and LFA-1 on lymphocytes. It has become increasingly apparent that the pro-inflammatory response is balanced by concomitant anti-inflammatory mechanisms that results in monocyte deactivation, characterized by a decrease in HLA-DR expression and the release of anti-inflammatory cytokines such as IL-10. This counterregulatory response, if prolonged or predominant, may predispose the patient to a higher risk of infection. Further studies need to be conducted to precise: 1) the intensity of depression of the surface molecule expression assessing monocyte function, such as HLA DR and CD54; 2) the level of IL-10 and IL-12 release in patients with severe sepsis; 3) the immunomodulating effects of frequently used treatments in these patients with severe sepsis and in surgical patients; 4) the time course of recovery; 5) if the monitoring of HLA-DR, CD54, IL-10 and IL-12 will better predict the clinical outcome than clinical parameters.     

Sepsis: a pro- and anti-inflammatory disequilibrium syndrome

Severe sepsis and probably most prolonged critical illnesses reflect a paradox of combined increased activation and depression of the immune apparatus. The increased activation of the inflammatory response is evidenced from the increased levels of circulating proinflammatory cytokines in the blood, increased endothelial activation with increased expression of inducible nitric oxide synthase, and increased de novo CD11b expression on circulating immune effector cells, such as PMNs, monocytes and lymphocytes. However, coexisting with this proinflammatory process is a profound anti-inflammatory state characterized by increased circulating levels of anti-inflammatory species that both directly block the binding of proinflammatory stimuli to their cell surface receptors (IL-1ra, soluble TNF receptors) and also induce an anti-inflammatory state on their own (IL-10, TFG-beta). This humoral anti-inflammatory state is mirrored at the cellular levels by decreased monocyte ability to process antigen, characterized by a reduced HLA-DR expression and impaired PMN upregulation in response to clearly proinflammatory stimuli. Accordingly, severe sepsis reflects a combined pro- and anti-inflammatory state. Both the pro- and anti-inflammatory arms have protective and destructive aspects, making their modulation by treatment less predictable than if their actions were purely beneficial or detrimental.     

Monocyte deactivation correlates with injury severity score, but not with heme oxygenase-1 levels in trauma patients

Traumatic injury induces a local and systemic release of pro-inflammatory cytokines, acute phase proteins, hormones, and other inflammatory mediators. The excessive release of these mediators plays an important role in the pathogenesis of shock. In parallel to this pro-inflammatory response, there is a regulatory response characterized by the release of anti-inflammatory mediators, which is thought to represent the host's attempt to restore immunological equilibrium. Studies in septic patients have suggested the compensatory anti-inflammatory response may result in an "immunodeficient state" that leaves the host susceptible to further infectious insults. A key feature of the anti-inflammatory state in septic patients is a change in the responsiveness of monocytes that has been termed "monocyte deactivation." This is supported by data that link monocyte deactivation to increased mortality in septic patients. Monocytes with reduced HLA-DR expression have been described in trauma patients. We collected blood from 25 severely injured patients and evaluated peripheral blood mononuclear cells (PBMC) for HLA-DR expression and TNF-α response to LPS stimulation as markers of monocyte deactivation. Levels of intracellular HO-1 were determined in each patient, as HO-1 has been implicated in monocyte deactivation in patients with severe systemic inflammatory response syndrome (SIRS). HLA-DR expression correlated inversely with Injury Severity Scores and TNF-α response to LPS stimulation, but failed to correlate with HO-1 levels in these patients. HLA-DR expression was decreased in normal monocytes stimulated with patient plasma, but this treatment had no effect on HO-1 levels. These results suggest monocyte deactivation in trauma patients is unlikely to be mediated by HO-1.     

Sepsis after major visceral surgery is associated with sustained and interferon-gamma-resistant defects of monocyte cytokine production

BACKGROUND: Recent clinical trials failed to demonstrate beneficial effects of anti-inflammatory sepsis therapy. The present study therefore asked the following questions: Is there evidence for immunosuppression during postoperative sepsis? When, during the septic course, may immunosuppression develop? Can defective cellular functions be restored by in vitro treatment with interferon-gamma (IFN-gamma)? METHODS: The study included 35 patients with sepsis after major visceral surgery and 85 control patients. Monocyte secretion of interleukin (IL)-1 beta, IL-12 p40 and p70, IL-18, tumor necrosing factor, and IL-10 with or without IFN-gamma treatment and its correlation with the course and outcome of postoperative sepsis were determined. RESULTS: Postoperative sepsis was associated with an immediate defect of endotoxin-stimulated monocyte production of IL-12 p40, IL-1 beta, and IL-10 in both surviving and nonsurviving patients. During the final phase of postoperative sepsis, a significant recovery of IL-12 p40 and IL-1 beta secretion, but not of IL-10 production, correlated with survival. Despite the exposure of monocytes in vitro to IFN-gamma for 16 hours, the production of the biologically active IL-12 p70 heterodimer was severely suppressed both in survivors and nonsurvivors, although the secretion of the p40 subunit was restored. In contrast, IFN-gamma treatment resulted in a significant suppression of monocyte IL-1 beta production in all patient subgroups. Alterations of monocyte tumor necrosing factor secretion were not observed. The production of IL-18 was below the limits of detection in all samples. CONCLUSIONS: Postoperative sepsis was associated with immediate monocyte defects that affected both pro- and anti-inflammatory cytokine secretion, which suggests that immunosuppression is a primary rather than a compensatory response to a septic challenge. Sepsis survival correlated with the recovery of the proinflammatory, but not the anti-inflammatory, response. The treatment of monocytes with IFN-gamma did not reconstitute defective proinflammatory cytokine production.     

Cytokine balance and immunosuppressive changes at cardiac surgery: contrasting response between patients and isolated CPB circuits

In vitro work suggests that IL-10 plays a pivotal role in controlling the balance of pro- and anti-inflammatory cytokines and monocyte HLA-DR expression. In 20 patients undergoing cardiac surgery, we investigated elaboration of interleukin 10 (IL-10) and its relationship to pro- and anti-inflammatory cytokines and leucocyte expression of HLA-DR and adhesion molecules. There were small increases in pro-inflammatory cytokines (IL-1, IL-8 and tumour necrosis factor (TNF) after induction, returning to baseline on induction of cardiopulmonary bypass (CPB). After CPB another transient increase in IL-8 occurred (P < 0.05). The anti-inflammatory response began with elevated IL-10 during CPB (P < 0.001), which peaked early in recovery (P < 0.001), by which time IL-1 receptor antagonist (IL-1ra) and the TNF soluble receptors (TNFsr) had also increased (P < 0.01). The next day IL-10 and IL-1ra were decreasing but TNFsr continued to increase. Induction of anaesthesia caused HLA-DR downregulation. The IL-10 peak was associated with further monocyte HLA-DR downregulation (P < 0.001) and return towards baseline of granulocyte adhesion molecule expression which transiently increased during CPB (P < 0.001). To determine which aspects of the immune response arose from the interaction of blood with the CPB apparatus, the above variables were studied within an isolated CPB circuit and the influence of fentanyl on the magnitude of any such changes determined. Five healthy volunteers donated two, 250-ml samples of blood to which was added either fentanyl 175 micrograms with heparin 1050 u. or heparin alone 1050 u. These were used to prime two identical isolated CPB circuits and circulation was conducted under identical conditions for 90 min. Of the pro-inflammatory cytokines, only IL-8 was elevated at 90 min CPB (P < 0.05). There was no increase in anti- inflammatory cytokines and TNFsr decreased (P < 0.001). Granulocyte adhesion molecules were increased during CPB. In the fentanyl group, the CD11b increase was greater and preceded CPB. The reduction in lymphocyte HLA-DR expression, observed throughout the study period (P < 0.01), was greater with fentanyl (P < 0.05). Monocyte HLA-DR expression increased (P < 0.05), but to a lesser extent with fentanyl (P > 0.05). In contrast with the in vivo response where there was a phased anti- inflammatory response beginning with IL-10, in the isolated CPB model no anti-inflammatory cytokine response occurred.      

Reduced expression of Toll-like receptor 4 contributes to impaired cytokine response of monocytes in uremic patients

Toll-like receptors (TLRs) play a pivotal role in pathogen recognition and subsequent cytokine synthesis by immune cells. Uremic patients have a high infectious morbidity, but it remains unclear if this arises from the defective innate immune responses related to TLRs. We studied TLR4 expression in monocytes and their intracellular cytokine synthesis in response to lipopolysaccharide (LPS) stimulation in 35 predialysis patients with chronic kidney disease (CKD) with or without predisposition to bacterial infections and 16 age-matched controls. Expression of TLR4 in unstimulated peripheral monocytes was determined by staining with anti-TLR4 antibody and analysis with flow cytometry. Monocytes were then stimulated by LPS, labeled with anti-CD14 antibody, and subjected to intracellular cytokine staining and flow cytometry. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-8 synthesis was examined in CD14(+) monocytes. TLR4 expression was constitutively diminished in CKD patients with reduced expression being more severe in those CKD patients who were predisposed to infections. Monocytes from these infection prone CKD patients exhibited significantly reduced synthesis of TNF-alpha, IL-1beta, IL-6, and IL-8 in response to LPS challenge compared with those from control subjects. The intensity of synthesis of each cytokine significantly correlated with TLR4 expression levels in monocytes (P<0.01). The capacity of monocytes to synthesize proinflammatory cytokines was significantly reduced in infection prone CKD patients, and this may possibly be due to the reduced monocyte expression of TLR4. Abnormal TLR4 expression by monocytes may play a role in the susceptibility of such patients to bacterial infections.     

Interleukin 13 and inflammatory markers in human sepsis

BACKGROUND: Interleukin (IL) 13 is an anti-inflammatory cytokine that reduces inflammatory cytokine production, and enhances monocyte survival and MHC class II and CD23 expression. The only report of IL-13 in human sepsis noted no increase in IL-13 concentration, in contrast to animal data. This study further examined the expression of IL-13 in relation to human sepsis. METHODS: In a prospective observational study of 31 patients (24 men) with sepsis or septic shock, high-sensitivity enzyme-linked immunoabsorbent assay (ELISA) was used to quantify levels of tumour necrosis factor (TNF) alpha on admission, and on days 1, 3, 5 and 7 thereafter. IL-13 and IL-2 were assayed by standard ELISA, and HLA-DR on CD14-positive monocytes was measured by flow cytometry. RESULTS: Twenty-three patients developed septic shock. Monocyte HLA-DR levels showed greater depression and a slower recovery in shocked than non-shocked patients. The serum IL-13 concentration was significantly higher in the shocked group from admission to day 3, but subsequently decreased to levels similar to those in the non-shocked group. IL-13 concentrations were higher in non-survivors. The TNF-alpha concentration was higher in those with septic shock than in those without. The TNF-alpha level correlated with IL-13 concentration (r(S) = 0.61, P = 0.002). The IL-13/TNF-alpha ratio was greater in patients with shock than those with sepsis only (P = 0.017). IL-2 was undetectable. CONCLUSION: In human sepsis and septic shock, IL-13 correlated with TNF-alpha expression, but its effect on HLA-DR class II molecules remains unclear.     

Regional and systemic cytokine responses to acute inflammation of the vermiform appendix

OBJECTIVE: To measure local (peritoneal fluid) and systemic (plasma) cytokine profiles in patients with infection-inflammation of the vermiform appendix, a relatively mild, localized inflammatory process. SUMMARY BACKGROUND DATA: The systemic host response to invading microorganisms, often termed the systemic inflammatory response syndrome (SIRS), includes changes in heart rate, respiratory rate, body temperature, and circulating white blood cell numbers. Although these changes can be induced experimentally by administering proinflammatory cytokines, the mediators that appear in the bloodstream during early, localized infection in humans have not been defined. METHODS: The authors studied 56 patients with pathologically proven appendicitis. Blood was obtained before the induction of anesthesia, when 82% of the patients met the criteria for SIRS. Peritoneal fluid (PF) was obtained by intraoperative lavage. Cytokines were measured by immunoassay. To assess the net impact of the mediators within plasma, the authors studied the ability of patient plasma to augment or suppress bacterial lipopolysaccharide (LPS) stimulation of monocytes in vitro. RESULTS: Of the proinflammatory cytokines, tumor necrosis factor-alpha was present in PF but not in plasma, interleukin (IL)-1beta and interferon-gamma were found in low concentrations in both PF and plasma, and IL-12 (p70) was detectable in plasma but not PF. In contrast, IL-6 and IL-1 receptor antagonist (IL-1ra) were the most abundant cytokines in the PF and plasma, and the concentrations of IL-4 and IL-10 were also elevated in both compartments. Patients with more severe appendicitis had higher plasma levels of IL-6 and IL-10 and lower plasma levels of IL-12 and interferon-gamma than did those with uncomplicated disease. Patient plasma inhibited LPS-induced stimulation of a monocyte cell line, and this inhibition was accentuated by complicated disease. CONCLUSIONS: As judged from the pattern of soluble cytokines in plasma and the effect of the plasma on monocyte activation by LPS, mild, localized infection can induce a systemic response that is predominantly anti-inflammatory.     

Effect of 2 anesthetic techniques on the postoperative proinflammatory and anti-inflammatory cytokine response and cellular immune function to minor surgery

STUDY OBJECTIVE: The aim of this study was to investigate the influence of 2 established anesthetic techniques: total intravenous anesthesia and balanced inhalation anesthesia (BAL) on the perioperative-induced changes of peripheral blood mononuclear cells (PBMCs), changes in lymphocyte subsets, and the balance of proinflammatory and anti-inflammatory cytokines. DESIGN: This is a prospective, randomized, clinical comparison study. SETTINGS: This study was set at a university hospital. PATIENTS: This study involved 50 patients with American Society of Anesthesiologists physical status I who were scheduled for elective minimal invasive partial diskectomy. INTERVENTIONS: There was no intervention involved in this study. MEASUREMENTS: Changes in differential counts, lymphocyte subsets, and proliferation rates were determined before surgery and in the early postoperative period. Plasma concentrations of proinflammatory cytokines (IL-2, IL-6, IL-12, interferon gamma) and anti-inflammatory cytokines (IL-10, IL-1RA, transforming growth factor beta), and plasma concentrations of cortisol, epinephrine, and norepinephrine were measured before, during, and after surgery. MAIN RESULTS: Absolute number of CD3+, CD4+, and CD8+, and expression of HLA-DR and activation marker CD25+, CD26+, and CD69+ decreased more in response to surgery after BAL. Changes in distribution of T-lymphocyte cells seem to be in part related to severe postoperative pain. Plasma concentration of IL-6 significantly increased during and after surgery with BAL without relation to pain. CONCLUSION: Anesthetic management may have varying influences on the postoperative immune response. Surgery-induced inflammatory response and alteration in cell-mediated immunity seem to be more pronounced after BAL. These effects were attributed to the enhanced stress response after BAL.     

Anti-inflammatory cytokine response and the development of multiple organ failure in severe sepsis

BACKGROUND: The production of proinflammatory cytokines activates the systemic inflammatory response in sepsis. Patients also develop a compensatory anti-inflammatory reaction, which may have an important down-regulatory effect on the overactive inflammation. However, the role of this anti-inflammatory response in sepsis is not completely clarified. In this prospective study, we investigated the relationship between the pro- and anti-inflammatory cytokine profiles in severe sepsis and their role in the development of multiple organ failure (MOF). METHODS: Thirty-eight patients meeting the criteria for severe sepsis were studied. MOF was defined as a maximum SOFA score of 10 or higher. Serial measurements of the proinflammatory IL-6 and IL-1beta and the anti-inflammatory IL-10 and IL-1ra were used. The cytokine samples were taken at the onset of sepsis and on the third and fifth day during the ICU period. RESULTS: The initial IL-10 and IL-1ra responses were identical in patients with or without MOF. The anti-inflammatory cytokine levels remained elevated in the MOF patients, whereas in patients without MOF the levels declined. The IL-6/IL-10 ratio was significantly higher in the MOF patients on days 1 and 3 compared with patients without MOF. CONCLUSIONS: We could not demonstrate overproduction of anti-inflammatory IL-10 in MOF patients. On the contrary, the high IL-6/IL-10 ratio indicates that IL-10 deficiency may contribute to the development of MOF in severe sepsis.     

CD14+单核细胞人类白细胞抗原DR表达率与脓毒症关系的研究

目的了解烧伤延迟复苏时CDl4^＋单核细胞人类白细胞抗原DR（HLA—DR）表达率的变化，分析其与脓毒症的关系。方法选择烧伤面积大于30％TBSA的25例烧伤延迟复苏患者，于伤后1、3、7、14、28d取外周血，其中7例患者住院期间并发脓毒症，于脓毒症发生后连续2d亦取其外周血。另取20例健康体检者外周血作为对照。流式细胞仪检测CD14^＋单核细胞HLA．DR表达率，酶联免疫吸附测定法检测血浆中肿瘤坏死因子α（TNF—α）、白细胞介素10（IL-10）的浓度。结果非脓毒症患者伤后1、3、7、14、28dCD14^＋单核细胞HLA—DR表达率分别为（15±6）％、（74±5）％、（264±17）％、（284-16）％、（474-16）％，明显低于健康体检者[（924±10）％，P〈0．01]；脓毒症患者发生脓毒症后1、2d，该指标亦明显低于健康体检者及非脓毒症患者伤后1、7、14、28d（P〈0．01）。脓毒症患者TNF—d检出率及TNF—α、IL-10浓度，均高于非脓毒症患者和健康体检者（P〈0．05或P〈0．01）。伤后1、7、28d，外周血CD14^＋单核细胞HLA—DR表达率与IL—10浓度呈显著负相关（r分别为-0．9963、-0．7459、-0．8474，P〈0．01）。结论烧伤延迟复苏患者免疫功能低下，促炎性介质释放量增加，并发脓毒症时则更为严重。外周血CD14^＋单核细胞HLA—DR表达率可作为动态检测患者免疫功能状态的有效指标。     

Characterization of circulating monocytes expressing HLA-DR or CD71 and related soluble factors for 2 weeks after severe, non-thermal injury

BACKGROUND: Severe injury is associated with changes in monocytes that may contribute to poor outcomes. Longitudinal characterization of monocyte response patterns after trauma may provide added insight into these immunological alterations. METHODS: Venous blood obtained seven times during post-injury days 1 through 13 from 61 patients with an injury severity score >20 was assessed by flow cytometry for monocytes (CD14+) expressing HLA-DR or CD71 (transferrin receptor) and for circulating levels of interleukin (IL) 1alpha, IL-1beta, IL-6, soluble CD14 (sCD14), tumor necrosis factor-alpha (TNF-alpha), prostaglandin E(2) (PGE(2)), thromboxane B(2) (TXB(2)), and endotoxin. Urine neopterin was measured by high-pressure liquid chromatography, expressed as a neopterin-creatinine ratio. RESULTS: Trauma patients had leucocytosis days 1 through 13, monocytosis days 5 through 13, reduced proportions of CD14+HLA-DR+ cells days 2 through 5, and elevated proportions of CD14+CD71+ cells days 1 through 13. Neopterin was elevated all days, peaking on day 10. sCD14 was elevated days 2 through 13, and there were sporadic elevations of IL-1alpha, IL-1beta, IL-6, TNF-alpha, PGE(2), TXB(2), and endotoxin. Sepsis syndrome patients (n = 6) had larger and more prolonged reductions in CD14+HLA-DR+ cells and higher neopterin values, in comparison with uneventful patient outcomes. CONCLUSIONS: Altered proportions of monocytes expressing HLA-DR and CD71 and elevated sCD14 and urine neopterin levels, for up to 2 weeks after severe injury, underscores an extended period of profound immunological effects. Additional studies to more fully assess temporal monocyte response patterns after severe injury, including activation, may be warranted.     

Antibiotics modulate the stimulated cytokine response to endotoxin in a human ex vivo, in vitro model

BACKGROUND: Sepsis may lead to the suppression of stimulated cytokine release after Gram-negative stimuli, correlating with a fatal outcome. Treatment of sepsis includes adequate therapy with antibiotics. The aim of this study was to investigate the role of antibiotics in the modulation of the lipopolysaccharide (LPS)-stimulated cytokine response of human monocytes. METHODS: In this ex vivo, in vitro study, whole blood samples were taken from 10 healthy volunteers, stimulated with LPS in the presence or absence of various antibiotics (penicillin, amoxicillin, cefuroxime, ceftazidime, cefotaxime, piperacillin/tazobactam, imipenem/cilastatin, gentamicin, netilmicin, ciprofloxacin, vancomycin) and cultured for 24 h. Thereafter, tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) were measured in the supernatants by enzyme-linked immunosorbent assay (ELISA). Furthermore, CD14 and HLA-DR expression on monocytes was assessed using flow cytometry. RESULTS: All cephalosporins decreased LPS-stimulated IL-10 release. Cefuroxime and cefotaxime also decreased the expression density of the LPS recognition molecule CD14 on monocytes. An increase in LPS-stimulated IL-10 release was observed with vancomycin. A suppression of LPS-stimulated TNF-alpha and IL-10 release was observed in the presence of ciprofloxacin. CONCLUSION: These results indicate a modulation of the expression density of CD14 on monocytes, together with a shift from a balanced to an inflammatory cytokine release pattern, by cefuroxime and cefotaxime. Vancomycin changes the response to an anti-inflammatory release pattern. After ciprofloxacin, a profound unresponsiveness of immune-competent cells to LPS stimulation is observed. Because of the critical role of a balanced innate immune response, these data may be of importance for the selection of antibiotics in septic patients.     

Cytokine production in surgical stress

Surgical injury influences the function of mononuclear cells, leading to various systemic responses. Proinflammatory cytokines such as tumor necrosis factor alpha (TNF alpha), interleukin (IL)-1, -6, -8, and the antiinflammatory cytokine IL-10, which are mainly produced by mononuclear cells, are known to play an important role in the response to and pathogenesis of surgical stress. TNF alpha production by monocytes is extremely upregulated, but monocyte HLA-DR antigen expression is suppressed in patients with surgical stress. While production of Th1 cytokines such as IL-12 and interferon-gamma by mononuclear cells is suppressed, production of Th2 cytokines and IL-10 is upregulated during surgical stress. Immune suppression following surgical stress has been clarified recently in terms of Th1 and Th2 cytokine production balance mainly caused by mononuclear cells. It is thought to be very important to maintain immunological function after surgical stress by controlling cytokine production and balance.     

Monocyte function-associated antigen expression during and after pediatric cardiac surgery

OBJECTIVE: Systemic inflammatory response syndrome and infectious complications are major causes of morbidity and mortality after cardiopulmonary bypass. Recent work in adult patients suggests that the balance between proinflammatory and anti-inflammatory mediators is important. We hypothesized that the expression of different function-related receptors on circulating monocytes might reflect the net response of the inflammatory reaction. METHODS: We performed a prospective and observational study in a tertiary pediatric cardiac center in a population of children (n = 40) undergoing elective cardiac surgery. Expression of receptors on the surface of monocytes was assessed before, during, and after surgical intervention. RESULTS: Early monocyte activation was demonstrated by changes of the expression of the chemokine receptor CCR2, which was inversely correlated with plasma levels of monocyte chemotactic protein 1 (rho = -0.54, P = .002). High levels of monocyte chemotactic protein 1 were found in children with high expression of the adhesion receptor CD11b/CD18 on circulating monocytes. The intensity of human leukocyte antigen DR expression rapidly decreased in all children after the onset of cardiopulmonary bypass ( P < .001). Low human leukocyte antigen DR expression was correlated with increased plasma levels of interleukin 10 postoperatively. Children who had signs of bacterial pneumonia postoperatively had lower levels of human leukocyte antigen DR expression before surgical intervention (relative risk, 13.3; P = .007). CONCLUSIONS: The expression of monocyte function-related receptors is altered after cardiac surgery. Early activation of monocytes by monocyte chemotactic protein 1 possibly released from the heart is followed by an anti-inflammatory response with suppression of monocyte human leukocyte antigen DR expression. The increased risk of bacterial infection after pediatric cardiac surgery can be anticipated by surveillance of monocyte function before surgical intervention.     

Impaired monocyte IL-12 production before surgery as a predictive factor for the lethal outcome of postoperative sepsis

OBJECTIVE: To investigate whether monocyte paralysis resistant to interferon-gamma (IFN-gamma) costimulation may exist before surgery and postoperative infection and may correlate with the outcome of postoperative sepsis. SUMMARY BACKGROUND DATA: Several studies have correlated monocyte paralysis during the course of sepsis with lethal outcome. Although the authors' previous work indicated that preoperative defects in monocyte interleukin (IL)-12 production are associated with the development of severe postoperative sepsis, the functional state of monocytes before surgery and infection and its significance for sepsis requires further analysis. METHODS: In a prospective study, monocyte functions of 1,113 consecutive patients were examined before major visceral surgery. Monocytes were isolated from peripheral blood and were stimulated in vitro with IFN-gamma and lipopolysaccharide. The secretion of IL-12 p70, IL-12 p40, IL-10, and tumor necrosis factor was measured. RESULTS: Preoperative monocyte secretion of IL-12 p70 and IL-12 p40 was significantly reduced in patients who developed lethal postoperative sepsis compared with sepsis survivors and patients with uneventful postoperative recovery. Moreover, preoperative monocyte IL-12 production was an independent predictive factor for the lethal outcome of postoperative sepsis by multivariate analysis. Preoperative monocyte IL-10 production was impaired in the sepsis group but did not correlate with death from sepsis. Preoperative monocyte tumor necrosis factor secretion was comparable between patients with uneventful recovery, sepsis survivors, and nonsurvivors. Thus, impaired preoperative monocyte IL-12 secretion in patients developing lethal postoperative sepsis did not result from an overproduction of IL-10 or from a generalized monocyte paralysis. The association between impaired preoperative monocyte IL-12 production and death from sepsis was also not explained by gender differences, underlying malignant disease, tumor type, neoadjuvant therapy, or age. CONCLUSIONS: These results identify a selective preoperative defect in monocyte IL-12 production as a predictive factor for the lethal outcome of postoperative sepsis. These data suggest that a partial preoperative monocyte paralysis severely impairs the host defense against postoperative infection, resulting in an increased risk of lethal sepsis.     

脓毒症大鼠外周血免疫细胞相关黏附分子的表达

目的：探讨脓毒症模型大鼠淋巴细胞、单核细胞和中性粒细胞CD11b/c、CD62L、CD54和CD31的表达意义。方法：以盲肠结扎穿孔法制作脓毒症大鼠模型,采用流式细胞术检测模型大鼠外周血淋巴细胞、单核细胞和中性粒细胞CD11b/c、CD62L、CD54和CD31的表达情况。结果：与正常组比,脓毒症模型组淋巴细胞占外周血免疫细胞的百分比明显降低,中性粒细胞占外周血免疫细胞的百分比明显增高,而单核细胞数量无明显变化。脓毒症模型组淋巴细胞、单核细胞和粒细胞CD11b/c的表达均有不同程度的增加,而CD62L的表达均有不同程度的降低;淋巴细胞和单核细胞CD54的表达增加,中性粒细胞CD54表达无明显改变。中性粒细胞CD31阳性细胞的百分比与正常组相比明显下降。结论：淋巴细胞、单核细胞和中性粒细胞在脓毒症病理演变过程中发挥了一定作用,其表面黏附分子表达的变化可能是其机制之一。     

HLA-DR expression and soluble HLA-DR levels in septic patients after trauma

OBJECTIVE: To determine if cellular and soluble HLA-DR molecules may be relevant in severely injured patients for the development of gram-positive or gram-negative sepsis. SUMMARY BACKGROUND DATA: HLA-DR molecules play a central role in the specific immune response to infection. The reduced HLA-DR expression on monocytes is considered to correlate with infectious complications and the development of sepsis. Data on the role of HLA-DR expression on T cells and soluble HLA-DR molecules are rare. METHODS: HLA-DR expression on monocytes and T cells was measured by flow cytometry. Plasma levels of soluble HLA-DR were studied by enzyme-linked immunosorbent assay. RESULTS: HLA-DR expression on circulating T cells, calculated as mean fluorescence intensity in channels, was reduced at day 1 after admission in 20 patients with subsequent severe sepsis compared with 46 patients without sepsis. The septic patients immediately after trauma had significantly lower soluble HLA-DR plasma levels than the nonseptic patients. At day 2 after admission, HLA-DR expression on monocytes was significantly lower in the severe sepsis group than in the patients without sepsis, and lasted until day 14 after injury. CONCLUSIONS: In severely injured patients, decreased levels of cellular and soluble HLA-DR appear as early indicators of an immune deviation associated with the development of severe sepsis. Moreover, immune alterations of different cell types may promote distinct kinds of septicemia.     

Die Bedeutung der Zytokine in der posttraumatischen Entzündungsreaktion

Alterations in the immune response after multiple trauma, posttraumatic sepsis and surgery are recognized as physiological reactions of the organism to restore homeostasis. The level of these immunological changes correlates with the degree of tissue damage as well as with the severity of haemorrhage and ischaemia. Cytokines are known to be integral components of this immune response. The local release of pro- and antiinflammatory cytokines after severe trauma indicates their potential to induce systemic immunological alterations. It appears that the balance or imbalance of these different cytokines partly controls the clinical course in these patients. Overproduction of either proinflammatory cytokines or antiinflammatory mediators may result in organ dysfunction. Whereas predominance of the proinflammatory response leads to the systemic inflammatory response syndrome (SIRS), the antiinflammatory reaction may result in immune suppression with an enhanced risk of infectious complications. Systemic inflammation, as well as immune suppression, are thought to play a decisive role in the development of multiple organ dysfunction syndrome (MODS). The major proinflammatory cytokines involved in the response to trauma and surgery include tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6 and IL-8. These cytokines, which are predominantly produced by monocytes and macrophages, mediate a variety of frequently overlapping effects, and their actions can be additive. TNF-α and IL-1β are early regulators of the immune response and both induce the release of secondary cytokines, such as IL-6 and IL-8. IL-10 is an antiinflammatory cytokine which reduces the synthesis of proinflammatory mediators. Other important antiinflammatory mediators are soluble TNF receptors and the IL-1 receptor antagonist, which interfere with the effects of TNF-α and IL-1β. Early evaluation of the prognosis of polytraumatized patients and assessment of their clinical status is known to be difficult. Therefore, in several clinical studies, cytokine levels during the posttraumatic course have been determined with the aim of finding predictive markers of patient outcome. The purpose of this review was to highlight our current knowledge on the interaction of posttraumatic immune reactivity and the development of complications. A better understanding of these mechanisms might lead to the introduction of preventive and therapeutic strategies into clinical practice.