Circulating phospholipase A2 activity associated with sepsis and septic shock is indistinguishable from that associated with rheumatoid arthritis

Elevation of circulating phospholipase A₂ (PLA₂) activity is associated with sepsis and septic shock. Elevated levels of PLA₂ activity also are seen in association with chronic inflammatory disorders such as rheumatoid arthritis. The relationship between these phospholipases is unclear. We have developed a highly specific enzyme-linked immunosorbent assay (ELISA) capable of measuring human synovial PLA₂ in plasma, using monoclonal antibodies raised to recombinant synovial PLA₂. This ELISA has been used to quantitate circulating PLA₂ levels in patients clinically diagnosed with sepsis. These elevated levels positively correlated with the elevation seen in plasma PLA₂ enzyme activity. The antibodies also have been used to purify immunoreactive PLA₂ from plasma of patients with sepsis, thus enabling characterization of the purified protein by amino-terminal sequence analysis. We conclude from this study that the increase in PLA₂ activity seen in association with sepsis and septic shock results from a dramatic elevation in levels of a circulating PLA₂ enzyme. This inflammatory PLA₂ is indistinguishable, both immunologically and chemically, from that associated with rheumatoid arthritis. Therapeutic agents directed towards inhibition of this inflammatory PLA₂ enzyme may have utility in the treatment of both chronic and acute inflammatory disease.     

Multiplex cytokine profiling in patients with sepsis

A major goal for the clinical research in sepsis is mapping the various mediators driving the systemic manifestations of infection. Identifying relevant mediators responsible for the physiological alterations during sepsis may offer diagnostic and therapeutic opportunities. We aimed to explore the novel approach of simultaneously measuring several biomolecules using the multiplex technique and to study its relevance in diagnosing and monitoring septic patients. In 30 patients fulfilling American College of Chest Physicians and the Society of Critical Care Medicine sepsis criteria, we simultaneously measured 17 cytokines during the first 7 days after admission. We analysed the results with respect to the presence of septic shock and survival. Five patients died during the study. We found a significant positive correlation between the monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1β and interleukin (IL)-8 levels in the first 3 days and Sepsis-related Organ Failure Assessment score on day 1. Most cytokines showed no significant difference between patients with mild or severe sepsis. The initial levels of MIP-1β and granulocyte macrophage colony-stimulating factor were lower in patients with septic shock than in patients without shock. IL-8 and MCP-1 early after admission were higher in the non-survivors (p < 0.05). In the multivariate logistical regression, the initial levels of IL-8 were the most predictive for fatal outcome. Moreover, IL-1β, IL-6, IL-8, IL-12, interferon-γ, granulocyte colony-stimulating factor and tumour necrosis factor-α exhibited persistent increases in non-survivors. The simultaneous evaluation of multiple cytokines in sepsis may identify complex cytokine patterns that reflect the systemic response associated with shock and mortality.     

Present possibilities of therapy of septic shock in surgical patients]

The authors present a review of contemporary possibilities of septic shock in surgical patients. As mentioned by the authors, the most frequent cause of Gram-negative sepsis in surgery are intraabdominal inflammatory diseases or septic complications after planned surgery. Based on an experimental study on acute endotoxin shock in dogs and treatment with hydrocortisone, dopamine and antihypertensive drugs (mepamil and metazosine), the authors present some principles of the therapeutic procedure in endotoxin shock under clinical conditions. They emphasize in particular administration of antibodies against endotoxin and cytokines. In the clinical part they submit results of comprehensive therapy of intraabdominal sepsis in patients hospitalized at the intensive care unit of the Surgical Clinic at the Third Medical Faculty in Prague. They give an account of the principles of peroperative and postoperative treatment within the framework of differentiated care. During the postoperative period it is important to ensure prevention and treatment of septic complications such as septic shock and the syndrome of multiorgan systemic failure as well as rational antimicrobial therapy, immunotherapy and adequate nutrition. The authors emphasize that it is essential that specific antibodies are available and indications of their administration must be defined. The expected effect of immunotherapy is limited by the period of administration in relation to early stages of sepsis.     

Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock

Soluble phospholipase A₂ has been implicated in the pathogenesis of local and systemic inflammatory reactions. Elevated levels of circulating phospholipase A₂ (PLA₂) correlate with the severity of circulatory collapse and pulmonary dysfunction in gram-negative septic shock. Characterization of septic shock serum PLA₂ revealed a calcium-dependent enzyme with absolute 2-acyl specificity with a pH optimum of 7.5. We tested a number of therapeutic agents for their ability to inhibit PLA₂ from human septic shock serum. Chloroquine, chlorpromazine, dexamethasone base, dexamethasone sodium phosphate, indomethacin, lidocaine, oleic acid, palmitic acid, promethazine, trans-retinoic acid, rutin and dl--tocopherol were all studied over the range of 10^–2 to 10^–7 M. All agents, with the sole exception of dexamethasone base, inhibited PLA₂ activity at concentrations greater than 10^–3M. PLA₂ inhibition by dexamethasone sodium phosphate was factitious, due to the formation of calcium-phosphate complexes. Of the 11 agents studied, chlorpromazine was the most effective, with an IC₅₀ of 7.5×10^–5 M, a membrane concentration achievable within its therapeutic range. Inhibition was non-competitive, with an apparent Ki of 5 nM. Since serum PLA₂ levels correlate with mortality in both experimental endotoxemia and clinical gram-negative septic shock, and chlorpromazine was previously shown to improve survival in these conditions, we postulate that its therapeutic efficacy resides at least in part in its PLA₂-inhibitory activity.Supported by grants-in-aid from: The Arthritis Society and the Medical Research Council of Canada.     

GILZ in sepsis: “Poor is the pupil who does not surpass his master”

With the legendary saying of Leonardo da Vinci in the title, we suggest that Glucocorticoid Induced Leucine Zipper (GILZ) may have more promising effects against polymicrobial sepsis, than glucocorticoids (GC). Indeed, the use of GCs in sepsis remains a matter of debate. The rationale for their use in sepsis is to modulate the exaggerated inflammatory response while maintaining innate immunity. However, GC resistance and side-effects limit their therapeutic value in sepsis. Hence, there is a growing interest in understanding the mechanisms by which GCs modulate immune responses upon infection. In this issue of the European Journal of Immunology, Ellouze et al. provide data demonstrating that deregulated expression of GILZ, a GC-induced protein, in monocytes/macrophages (M/M) recovered from septic shock patients may contribute to the pathogenesis. Furthermore, the authors demonstrate that GILZ overexpression in M/M improves outcome in septic animals by limiting systemic inflammation while increasing bacterial clearance. Overall, these data provide evidence that GCs may modulate immune responses via GILZ and that GILZ is a valuable alternative for GC therapy in sepsis.     

Comparison between procalcitonin and C-reactive protein for early diagnosis of children with sepsis or septic shock

Objective and design

The objective of the paper is to examine the behavior of C-reactive protein (CRP) and procalcitonin (PCT) in the first 12 h of admission and verify which performs better to differentiate children with septic conditions.

Subjects

Septic children aged between 28 days and 14 years were divided into sepsis (SG; n = 46) and septic shock (SSG; n = 41) groups. CRP and PCT were measured at admission (T0) and 12 h later (T12 h). PCT results were classed as: 0.5 ng/ml = sepsis unlikely; ≥0.5 to <2 = sepsis possible; ≥2 to <10 = systemic inflammation; ≥10 = septic shock.

Results

At T0, there was a higher frequency of SSG with PCT >10 compared to SG [SSG: 30 (73.1%) > SG: 14 (30.4%); P < 0.05]. Similar results were observed at T12 h. Pediatric Risk of Mortality I score was significantly higher for SSG patients with higher PCT than SG patients. CRP levels were not statistically different for groups and time points.

Conclusions

PCT was better than CRP for diagnosing sepsis and septic shock, mainly at admission, and is related to disease severity.     

Clinical and biological significance of interleukin-10 plasma levels in patients with septic shock

Interleukin-10 is a potent macrophage-deactivating cytokine that inhibits lipopolysaccharide-induced tumor necrosis factor production. We determined the plasma levels of immunoreactive interleukin-10 in 16 patients with septic shock and in 11 patients with circulatory shock of nonseptic origin. In septic shock, interleukin-10 levels peaked during the first 24 h (median: 48 pg/ml) and decreased progressively till Day 5. In nonseptic shock, interleukin-10 plasma levels also increased during the first 24 h but to a lesser extent (median: 17 pg/ml). In septic shock patients, interleukin-10 plasma levels were positively correlated with tumor necrosis factor (r=0.8,p=0.01) and with parameters of shock severity including lactate levels (r=0.56, p<0.05) and correlated negatively with blood platelet counts (r=–0.65,p<0.05). The decreased production of tumor necrosis factor- and interleukin-6 afterin vitro incubation of whole blood from septic shock patients with lipopolysaccharide was not influenced byin vitro neutralization of interleukin-10. We conclude that interleukin-10 is produced in patients with circulatory shock of septic and nonseptic origin and that the production of this anti-inflammatory cytokine during septic shock correlates positively with the intensity of the inflammatory response.     

Evaluation of serum C-reactive protein, procalcitonin, tumor necrosis factor alpha, and interleukin-10 levels as diagnostic and prognostic parameters in patients with community-acquired sepsis, severe sepsis, and septic shock

The diagnostic value of procalcitonin, C-reactive protein, tumor necrosis factor-alpha, and interleukin-10 levels in differentiating sepsis from severe sepsis and the prognostic value of these levels in predicting outcome were evaluated and compared in patients with community-acquired sepsis, severe sepsis, and septic shock in the first 72 h of admission to the hospital. Thirty-nine patients were included in the study. The severe sepsis and septic shock cases were combined in a single “severe sepsis” group, and all comparisons were made between the sepsis (n=21 patients) and the severe sepsis (n=18 patients) groups. Procalcitonin levels in the severe sepsis group were found to be significantly higher at all times of measurements within the first 72 h and were significantly higher at the 72nd hour in patients who died. Procalcitonin levels that remain elevated at the 72nd hour indicated a poor prognosis. C-reactive protein levels were not significantly different between the groups, nor were they indicative of prognosis. No significant differences in the levels of tumor necrosis factor-alpha were found between the sepsis and severe sepsis groups; however, levels were higher at the early stages (at admission and the 24th hour) in patients who died. Interleukin-10 levels were also higher in the severe sepsis group and significantly higher at all times of measurement in patients who died. When the diagnostic and prognostic values at admission were evaluated, procalcitonin and interleukin-10 levels were useful in discriminating between sepsis and severe sepsis, whereas tumor necrosis factor-alpha and interleukin-10 levels were useful in predicting which cases were likely to have a fatal outcome.     

A simple scoring system based on neutrophil count in sepsis patients

Background

The assessment of critically ill patients is often a challenge for clinicians. There are a number of scoring systems such as Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA) and C-reactive protein test (CRP), which have been shown to correlate with outcome in a variety of Intensive Care Unit (ICU) patients. Therefore, use of repeated measures of these preexisting scores over time is a reasonable attempt to assess the severity of organ dysfunction and predict outcome in critically ill patients. Several reports suggest that the neutrophil is a useful marker of sepsis. However, since both a large number and a small number of neutrophils indicate a severe situation, neutrophil count is difficult to use to directly predict patients’.

The hypothesis

We proposed a novel scoring system identify predictive factors using a simple blood cell count that may be associated with mortality in ICU patients. Our novel scoring system (n-score) was calculated as follows: ranges of neutrophils of 0–4999 cells/mm³ and 5000–9999 cells/mm³ were defined as 3 and 1 points, respectively. When the neutrophil count was over 10,000 cells/mm³, the score was calculated by dividing the number of cells by 10,000. Then, 1 or 2 points were added when patients were female or male, respectively. We hypothesize that n-score may be a simple and easy scoring system to estimate mortality of the patients with sepsis and severe sepsis/septic shock without requirement of special methods or special measuring equipment, and may be as reliable as the APACHE II score or SOFA score.

Evaluation of the hypothesis

The retrospective evaluation was conducted at the Department of Emergency, Disaster and Critical Care Medicine at the Hyogo College of Medicine. Seventy-seven patients who were admitted to the emergency center and diagnosed sepsis or severe sepsis/septic shock between June 2007 and December 2012 and gave informed consent were enrolled. The n-score was significantly higher in non-survivors of sepsis and severe sepsis/septic shock (p < 0.01, t-test) than in survivors. The ROC curve showed a sensitivity of 61.5% and a specificity of 80.4% at an n-score of 3.8 points; the area under the curve was 0.736. In addition, n-score correlated with APACHE II score (p < 0.01, R = 0.378) and SOFA score (p < 0.05, R = 0.256) on admission.

Conclusion

Based on these preliminary evaluations, we hypothesize that n-score may be a useful scoring system to detect risk of death in sepsis and severe sepsis/septic shock.     

CCR9(+) macrophages are required for eradication of peritoneal bacterial infections and prevention of polymicrobial sepsis

Sepsis is a systemic inflammatory response to infection associated with multiple organ dysfunction syndrome and a high mortality rate. In septic shock induced by severe peritonitis, early response of peritoneal macrophages against infected microbes is vital in preventing the spread of infection. We found that the mucosal homing receptor CCR9, is induced in peritoneal macrophages in response to inflammatory stimulation. We used a cecal ligation and puncture (CLP) model of sepsis to determine the role of CCR9 with respect to peritoneal macrophages, and controlling peritoneal infection and systemic inflammation. CCR9(-/-) mice showed aggravated septic shock with higher mortality rates compared with wild-type (WT) mice. Six hours after CLP, CCR9(-/-) mice demonstrated a greater inflammatory response. This was associated with higher production of inflammatory cytokines, such as IL-6, TNF and IP-10 in peritoneal lavage compared with WT mice. Although the numbers of peritoneal bacteria were elevated in CCR9(-/-) mice subjected to CLP compared with WT mice, this was normalized in CCR9(-/-) mice subjected to CLP through the adoptive transfer of WT peritoneal macrophages. We conclude that CCR9 is required for recruitment of peritoneal macrophages in the steady state to control systemic sepsis during early phases of peritoneal infection.     

Expression of NK Cell and Monocyte Receptors in Critically Ill Patients – Potential Biomarkers of Sepsis

Sepsis is characterized by activation of both the innate and adaptive immune systems as a response to infection. During sepsis, the expression of surface receptors expressed on immune competent cells, such as NKG2D and NKp30 on NK cells and TLR4 and CD14 on monocytes, is partly regulated by pro‐ and anti‐inflammatory mediators. In this observational study, we aimed to explore whether the expression of these receptors could be used as diagnostic and/or prognostic biomarkers in sepsis. Patients with severe sepsis or septic shock (n = 21) were compared with critically ill non‐septic patients (n = 15). Healthy volunteers (n = 15) served as controls. To elucidate variations over time, all patients were followed for 4 days. Cell surface expression of NKG2D, NKp30, TLR4 and CD14 and serum levels of IL‐1β, IL‐6, IFN‐γ, TNF‐α, IL‐4 and IL‐10 was estimated by flow cytometry. We found that NK cell expression of NKG2D and monocyte expression of CD14 were lower in the septic patients compared with the non‐septic patients, both at ICU admission and during the observation period (P < 0.01 for all comparisons). Both at ICU admission, and during the observation period, levels of IL‐6 and IL‐10 were higher in the septic patients compared with the non‐septic patients (P < 0.001 for all comparisons). Conclusion: As both NKG2D and CD14 levels appear to distinguish between septic and non‐septic patients, both NKG2D and CD14 may be considered potential diagnostic biomarkers of severe sepsis and septic shock.     

Vasopressors and Inotropes in the Treatment of Human Septic Shock: Effect on Innate Immunity?

Catecholamines have been suggested to modulate innate immune responses in experimental settings. The significance hereof in the treatment of human septic shock is unknown. We therefore sought if and how vasopressor/inotropic doses relate to pro-inflammatory mediators during treatment of septic shock. We prospectively studied 20 consecutive septic shock patients. For 3 days after admission, hemodynamic variables, lactate and plasma levels of interleukins (IL)-6 and 8, tumor necrosis factor (TNF)-α, and elastase-α₁-antitrypsin were measured six hourly. Doses of vasoactive drugs were recorded. Of the 20 patients, nine died in the intensive care unit. Dobutamine doses were positively associated and related to TNF-α plasma levels, independently of disease severity, hemodynamics, and outcome, in multivariable models. Dopamine doses were positively associated with IL-6, and norepinephrine was inversely associated with IL-8 and TNF-α levels. Our observations suggest that catecholamines used in the treatment of human septic shock differ in their potential modulation of the innate immune response to sepsis in vivo. Dobutamine treatment may contribute to circulating TNF-α and dopamine to IL-6, independently of activated neutrophils. Conversely, norepinephrine may lack pro-inflammatory actions.     

Methylprednisolone prophylaxis protects against endotoxin-induced death in rabbits

Endotoxemia in patients can lead to sepsis and shock by activation of cellular and plasmatic systems. Corticosteroids are described to have a beneficial effect on these phenomena. In this study of controlled endotoxic shock, we investigated the protective effects of prophylactic corticosteroid treatment against activation of cellular and plasmatic systems. In this respect, a low-dose methylprednisolone (1 mg/kg body wt) treatment was compared with that of a high-dose methylprednisolone (40 mg/kg body wt) treatment. Endotoxin infusion induced death of all rabbits, which was associated with leukopenia, thrombopenia, increased levels of-glucuronidase, and leukotriene B₄ (LTB₄) and decreased levels of complement total hemolytic activity (CH₅₀) and tissue plasminogen activator (t-PA) activity. Both methylprednisolone regimens prevented death of the rabbits after endotoxin infusion, which correlated with a significant decrease of the granulocyte release product-glucuronidase (P < 0.01). The early leukopenia and thrombopenia were not prevented; however, both cell numbers returned more rapidly to baseline values than in the placebo group (P < 0.01,P < 0.05). The LTB₄ and CH₅₀ concentration and t-PA activity did not differ significantly between the treated and placebo groups. These results indicate that although methylprednisolone has no inhibitory effect on the activation of the complement, arachidonic acid, and fibrinolytic systems, it protected the animals from the deleterious effects of endotoxin shock by inhibition of leukocyte activation. In this regard a low dosage of methylprednisolone is equally effective as the most often recommended high dose.     

Interleukin-6 gene variants and the risk of sepsis development in children

A proinflammatory cytokine interleukin-6 (IL-6) plays an important role in the development, pathogenesis and outcome of SIRS, sepsis and septic shock. We have evaluated the role of the IL-6 gene polymorphisms in pediatric patients. A total of 421 consecutive pediatric patients admitted to the pediatric intensive care unit with fever, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, or multiple organ distress syndrome (MODS) were studied together with 644 healthy controls. DNA was isolated and two IL-6 gene polymorphisms (G-174>C and G-572>C) were analyzed. The frequencies of both analyzed variants differ significantly between the group of patients and healthy controls (p = 0.02 for G-174>C and p = 0.049 for G-572>C). In addition, genetic analysis of the G-174>C IL-6 gene variant revealed significant differences between the subgroup of febrile patients and subgroup of septic shock (p = 0.0319) and between the subgroup of SIRS and septic shock (p = 0.038). In both cases the negative genotype was CC. No statistically significant differences for the IL-6 gene polymorphism G-572>C were found between the groups of patients with different diagnosis. IL-6 gene polymorphisms G-174>C and G-572>C could be the predictors of risk of development and/or the predictors of the severity of sepsis in children.     

Alpha-1-Acid (AAG, Orosomucoid) Glycoprotein: Interaction with Bacterial Lipopolysaccharide and Protection from Sepsis

In the acute phase response to a variety of insults a rise in the levels of the acute phase proteins, including elevations of serum ₁ acid glycoprotein (AAG) occurs. The physiological role of AAG is unknown, however, the time course of AAG production in the acute phase response together with its strong affinity for basic compounds suggests that AAG may function as an immune modulator to bind both exogenous and endogenous inflammatory mediators. Using E. coli lipopolysaccharide (LPS), an initiator of the acute inflammatory response associated with septic shock, we demonstrate that AAG-LPS complexes can activate mouse macrophages in vitro. In a mouse animal model of sepsis, AAG was shown to protect against meningococcal endotoxin.To pursue the mechanism of AAG action we demonstrated that AAG interacts directly with LPS using dynamic light scattering particle sizing and particle mobility. We also determined the enthalpy of interaction of AAG and LPS and showed that AAG leads to agglutination of LPS impregnated rabbit red blood cells.These studies suggest that AAG may function as an immune-modulator in the acute phase response, possibly by counter-regulating the activity of macrophage pro-inflammatory cytokines.     

Safety and efficacy of polymyxin B in multidrug resistant Gram-negative severe sepsis and septic shock

Background and Aims:

The emergence of multidrug resistant strains of Gram-negative bacteria, especially the lactose nonfermenters like Pseudomonas and Acinetobacter, in the intensive care units have prompted renewed worldwide interest in the polymyxins. However, perceived nephrotoxicity has been a major vexation limiting their early and regular use in severe sepsis. This study was conducted to assess the safety and efficacy of polymyxin B in patients with severe sepsis and septic shock.

Materials and Methods:

Forty-five patients with sepsis admitted in our medical-surgical intensive care units were identified from pharmacy records to have received polymyxin B. We retrospectively reviewed the clinical and microbiologic outcomes as well as occurrence of renal failure temporally related to the use of intravenous polymyxin B.

Results:

polymyxin B was used in severe sepsis and septic shock with the isolated organism being resistant to other available antimicrobials or clinical deterioration despite carbapenem use. Overall mortality was 52% and among patients who received at least eight days of intravenous polymyxin B, 67% patients with initial septic shock and 62% with severe sepsis survived. The target multidrug resistant organism was cleared in 88% of subjects evaluated by repeat microbiologic testing. Acute renal failure developed in only two patients (4%).

Conclusions:

Polymyxin B has acceptable effectiveness against nosocomial multidrug resistant Gram-negative sepsis. The associated nephrotoxicity has been found to be significantly lower than previously reported even in patients with background renal impairment and established risk factors of renal failure.     

Procalcitonin kinetics – prognostic and diagnostic significance in septic patients

Introduction

Severe sepsis and septic shock are advanced clinical conditions representing the patient''s response to infection and having a variable but high mortality rate. Early evaluation of sepsis stage and choice of adequate treatment are key factors for survival. Some study results suggest the necessity of daily procalcitonin (PCT) monitoring because of its prognostic and discriminative value.

Material and methods

An observational and prospective study was conducted to evaluate the prognostic and discriminative value of PCT kinetics in comparison to PCT absolute value measurements. In a group of 50 intensive care unit patients with diagnosis of severe sepsis or septic shock, serum PCT measurements were performed on admission, and on the 2^nd, 3^rd and 5^th day of therapy. The level of PCT was determined with a commercially available test according to the manufacturer''s protocol.

Results

The kinetics of PCT assessed by ΔPCT was statistically significant in the survivors vs. the non-survivors subgroup (ΔPCT_3/1, p = 0.022; ΔPCT_5/1, p = 0.021). ΔPCT has no statistical significance in the severe sepsis and septic shock subgroups for all analyzed days. Only the 5^th day PCT level was significantly higher in the non-survivors vs. survivors group (p = 0.008). The 1^st day PCT level in the severe sepsis vs. septic shock group has a discriminative impact (p = 0.009).

Conclusions

According to the results, single serum PCT measurement, regardless of absolute value, has a discriminative impact but no prognostic significance, during the first 2 days of therapy. The PCT kinetics is of prognostic value from the 3^rd day and is of earlier prognostic significance in comparison to changes in the patient''s clinical condition evaluated by SOFA score kinetics.     

Serum-induced macrophage activation is related to the severity of septic shock

Backgroud:  It seems that a balance between anti and pro-inflammatory responses must be kept to eliminate the pathogen without inducing inflammatory damage in the host. Thus we determined the relation between macrophage activation and the severity and clinical outcome in septic patients. Material and Methods:  This was a prospective study at a tertiary general intensive care unit. Thirty-three patients admitted with sepsis, severe sepsis or septic shock were included. As a control group, healthy volunteers were included matched to septic patients by age and sex. Peritoneal rat macrophages were cultured with 2% serum from healthy volunteers or from septic patients for determination of phagocytic potential or the capacity to produce cytokines. Results:  TNF and IL1 secretion by macrophages activated with serum from sepsis and severe sepsis patients was higher than with serum from healthy controls. In addition, proinflammatory cytokines released in vitro from macrophages, but not determined directly in the serum from patients, were lower in non-survivor septic patients when compared to survivors. In contrast, IL-10 secretion by macrophages activated with serum from septic patients was higher in nonsurvivors. In the septic shock group we observed a diminution in the phagocytic index compared to sepsis and severe sepsis groups, and the phagocytic index was higher in sepsis survivors. Conclusions:  Markers of antiinflammation are predominant in more severe types of sepsis suggesting that antiinflammation is related to mortality. Received 2 May 2008; returned for revision 23 June 2008; received from final revision 4 June 2008; accepted by C. Kasserra 17 June 2008     

Elevation of IL-18 in Human Sepsis

Interleukin-18 (IL-18) is a recently identified immunoregulatory cytokine that shares biochemical features with IL-1 and acts in part by inducing interferon-gamma (IFN-). Endotoxic bacterial lipopolysaccharide (LPS) (1 or 2 ng/kg) was insufficient to increase plasma IL-18 in five healthy adults measured 3, 12, and 24 hr following challenge. In contrast, in the first 96 hr of admission to the surgical intensive care unit, mean maximal serum IL-18 was elevated (1122 ± 259 pg/ml) in nine septic patients compared to six healthy adults (191 ± 42 pg/ml), P < 0.01). Serum IL-18 concentrations in septic patients did not correlate with other measured inflammatory mediators: tumor necrosis factor, IL-6, IL-10, or secretory leukocyte protease inhibitor. Therefore, IL-18 circulates in healthy adults and is a component of the human systemic inflammatory response. Further, stimuli other than LPS may induce IL-18 production in vivo in human sepsis.     

Administration of C1 Inhibitor Reduces Neutrophil Activation in Patients with Sepsis

Forty patients with severe sepsis or septic shock recently received C1 inhibitor. In the present study we studied the effect of C1 inhibitor therapy on circulating elastase-α₁-antitrypsin complex (EA) and lactoferrin (LF) levels in these patients to gain further insight about agonists involved in the activation of neutrophils in human sepsis. Elevated levels of EA and LF were found in 65 and 85% of the septic patients, respectively. Patients with elevated EA levels had higher organ dysfunction scores, higher levels of cytokines, and higher levels of complement activation products than patients with normal EA levels. C1 inhibitor therapy reduced EA as well as complement activation and IL-8 release in the patients with elevated EA on admission. We conclude that neutrophil activation in human sepsis correlates with the severity of organ dysfunction and involves complement and interleukin-8 as agonists. The effect of C1 inhibitor therapy on neutrophils may provide an explanation for the beneficial, although mild, effects of this treatment on organ dysfunction in sepsis.