 |
|
Decreased Cytokine Expression in Peripheral Blood Leukocytes of Patients With Severe Sepsis
Neslihan Cabioglu, MD, PhD;
Sema Bilgic, MSc;
Gunnur Deniz, PhD;
Esin Aktas, MSc;
Yalc n Seyhun, MD;
Akif Turna, MD;
Kayhan Gunay, MD;
Figen Esen, MD
Arch Surg. 2002;137:1037-1043.
ABSTRACT
| |
Background High levels of tumor necrosis factor (TNF)  messenger RNAs and interleukin (IL) 8 have been reported in leukocytes of patients with sepsis.
Hypothesis Assessment of leukocyte intracytoplasmic levels of proinflammatory and anti-inflammatory cytokines might be clinically more relevant to determine prognosis in patients with severe sepsis.
Design Cohort study.
Setting Surgical intensive care units of a university hospital.
Patients and Interventions Leukocyte suspensions obtained from 16 patients, 6 during early sepsis or septic shock and 10 during late sepsis or septic shock, were incubated with anti-CD14 and anti-CD2 or anti-CD3 monoclonal antibodies and then with intracytoplasmic anticytokine antibodies staining for interferon- , TNF-, IL-2, IL-6, IL-8, IL-10, and IL-12 and analyzed with a flow cytometer.
Main Outcome Measures Mann-Whitney test and Spearman correlation test were used in statistical evaluations according to the 28-day all-cause mortality rates and multiple organ dysfunction and sepsis-related organ failure assessment scores.
Results Higher serum IL-6, IL-8, C-reactive protein, and procalcitonin levels were found in patients with high multiple organ dysfunction and sepsis-related organ failure assessment scores (greater than or equal to the median values [8 and 11, respectively]), in contrast to decreased T-lymphocyte–associated IL-6 and TNF- and monocyte-associated IL-10 and IL-12 proportions. Furthermore, in 28-day all-cause mortality analysis, there were higher levels of C-reactive protein and procalcitonin in nonsurvivors (n = 9) than in survivors (n = 7), while T-lymphocyte–associated IL-2, IL-6, IL-10, and TNF- and monocyte-associated IL-10 and TNF- proportions decreased in the nonsurvivors.
Conclusion These results suggest that diminished lymphocyte- and monocyte-associated proinflammatory and anti-inflammatory cytokine levels are associated with worse prognosis in patients with severe sepsis.
INTRODUCTION
VARIOUS proinflammatory and anti-inflammatory cytokines have been implicated in the pathogenesis of the sepsis syndrome.1-3 Increased production of proinflammatory tumor necrosis factor (TNF) , interleukin (IL) 6, IL-8, IL-12, and anti-inflammatory IL-10 have been found to be correlated with increased Acute Physiology and Chronic Health Evaluation (APACHE) II and III scores and mortality, despite discrepancies in results of studies regarding the prognostic significance of IL-1 and interferon (IFN) levels.4-7 However, the relationship between the absolute plasma levels of cytokines and sepsis appears to be inconsistent and variable. The short plasma half-life of these cytokines, such as IL-1, with a rapid disappearance, and increased plasma levels of cytokine inhibitors such as soluble TNF receptors I and II, IL-1 receptor antagonists, or soluble IL-1 receptors may result in discrepancies among previous reports describing the incidence and kinetics of cytokine blood levels during sepsis.8-11 The reticuloendothelial system, consisting of Kupffer cells (liver), alveolar macrophages (lung), etc, also plays an important role in sepsis as a potential source of cytokines.12-13 As a consequence, plasma levels of cytokines represent the "tip of the iceberg," and investigations at the cellular level can provide more relevant information.14
Therefore, peripheral-blood leukocyte–associated cytokines have been investigated in sepsis in the past decade, and contradictory results have been obtained in these studies. High levels of leukocyte-associated IL-8 were observed in septic patients,15 while reduced TNF- and IL-6 expression was reported in sepsis by Ertel et al.16 However, the prognostic significance of these intracytoplasmic cytokine expressions remains to be answered. In the present study, we investigated the prognostic value of spontaneous expression of the monocyte-associated (TNF-, IL-6, IL-8, and IL-12) and T-lymphocyte–associated (IL-2, IFN-, TNF-, IL-6, and IL-10) proinflammatory and anti-inflammatory cytokines and also their serum levels in addition to procalcitonin (PCT) and C-reactive protein (CRP) levels as the main acute-phase proteins.
PATIENTS AND METHODS
PATIENT SELECTION
Between November 1, 1998, and December 31, 1999, 16 patients with sepsis syndrome, severe sepsis, or septic shock in the surgical intensive care units of the Departments of Anesthesiology and General Surgery, Istanbul Faculty of Medicine, University of Istanbul, Istanbul, Turkey, were eligible for this study, according to criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference.17 Sepsis syndrome was defined by fever or hypothermia (temperature >38°C or <36°C, respectively), tachycardia (>90 beats per minute in the absence of -blockade), and tachypnea (respiratory rate >20 breaths per minute or the requirement of mechanical ventilation). Severe sepsis or septic shock was defined as clinical diagnosis of sepsis syndrome plus organ dysfunction, hypoperfusion, or hypotension (systolic blood pressure <90 mm Hg or a 40–mm Hg decrease below baseline systolic blood pressure), or the use of vasopressor drugs to maintain blood pressure; and/or by clinical signs of altered organ perfusion resulting in mental disorientation, oliguria, or elevated lactate levels. Patients who were younger than 18 years or older than 70 years, and with any immunologic disorder, pregnancy, any organ transplantation, or any immunosupressive therapy (eg, use of corticosteroids) were excluded.
Six patients were considered to have early sepsis or septic shock and 10 patients to have late sepsis or septic shock, with early and late sepsis or septic shock defined as symptoms earlier or later than 72 hours. All patients underwent mechanical ventilation for respiratory problems and were also invasively monitored and followed up to study completion at day 28 or death. A blood sample was obtained from each patient on day 1, 2, or 3 after admission to the intensive care unit. Patients were categorized as having low or high multiple organ dysfunction (MOD) and Sepsis-related Organ Failure Assessment (SOFA) scores,18-19 with low scores defined as those less than the median value and high scores as those equal to or more than the median value, and as survivors and nonsurvivors according to the 28-day all-cause mortality.
BLOOD AND CULTURE SAMPLES
After assessment of the APACHE II,20 MOD, and SOFA scores, 20 mL of peripheral blood was collected for immunologic, hematologic, and biochemical analysis. Blood samples for determination of the specific cytokine, CRP, and PCT levels were spun at 3000 rpm for 10 minutes, and serum was frozen at -80°C. Blood, tracheal, and urine cultures and cultures from the suspected source of infection (eg, incisions and abdominal drains) were also obtained.
FLOW CYTOMETRIC ANALYSIS
Peripheral-blood mononuclear cells were isolated by standard Ficoll-Hypaque density gradient centrifugation and washed twice in phosphate-buffered saline. A cell fixation/permeabilization kit (Cytofix/Cytoperm; Pharmingen, San Diego, Calif) was used in the intracytoplasmic cytokine determination. Aliquots of the cell suspensions (100 µL) were first incubated with 5 µL of anti–CD2–fluorescein isothiocyanate (FITC) (DAKO Diagnostika GmbH, Hamburg, Germany) and anti–CD14-FITC (DAKO Diagnostika GmbH) monoclonal antibodies (mAbs) for the phycoerythrin-labeled cytokines and anti–CD3-phycoerythrin (DAKO Diagnostika GmbH) and anti–CD14-FITC mAbs (DAKO Diagnostika GmbH) for the FITC-labeled cytokines or corresponding isotypic control antibodies (DAKO Diagnostika GmbH) for 30 minutes at room temperature in the dark. After being washed twice in staining buffer, the cells were incubated in 100 µL of Permeafix (Pharmingen) (phosphate buffered saline containing 4% paraformaldehyde and 0.1% saponin) for 20 minutes at 4°C and washed 2 times in Permwash solution (Pharmingen) (phosphate buffered saline containing 0.1% saponin). The pellets were suspended in 50 µL of Permwash solution and incubated with pretitrated amounts of cytokine-specific mAbs and corresponding control antibodies for 20 minutes at 4°C (anti–IFN-, anti–IL-6, anti–IL-8, and anti–IL-12 mAbs were FITC-labeled and anti–IL-10, anti–TNF-, and anti–IL-2 mAbs were phycoerythrin-labeled [all antibodies were purchased from Pharmingen]). The cells were washed twice in Permwash solution and stored after suspension in staining buffer containing 2% paraformaldehyde at 4°C in the dark before analysis.
List mode data were acquired on a flow cytometer (FACS Calibur; Becton Dickinson Immunocytometry Systems, San Jose, Calif) and analyzed by means of CellQuest software (Becton Dickinson Immunocytometry Systems). After appropriate instrument settings and spectral compensations were achieved, the instrument settings were not changed and a minimum of 10 000 events were acquired in the gating window computed in list mode by means of log-amplified fluorescence signals and linearly amplified side scatter and forward scatter signals. Two-parameter dot plots showing cytokine staining were created according to lymphocyte and monocyte gates, respectively, and quadrants were then placed according to the staining of negative controls. Estimated median values were presented as positive net percentages in the figures.
CYTOKINE CONCENTRATIONS
Commercially available enzyme-linked immunosorbent assay kits were used for the measurement of IFN-, TNF-, and IL-2 (ELISA kits; Immunotech, Marseille, France); IL-10 and IL-12 (Medgenix Combo IL-10/IL-12 kit, BioSource Europe SA, Nivelles, Belgium); and IL-6 and IL-8 (CLB PeliKine Compact Human ELISA kits; CLB, Amsterdam, the Netherlands) cytokine levels. The sensitivity, defined as the lowest concentration significantly different from the zero standard with a probability of 95%, was 0.08 IU/mL for IFN- and 5 pg/mL for TNF- and IL-2, whereas the sensitivity of IL-6, IL-8, and IL-10, defined as the mean calculated zero signal + 3 SDs, was 0.2 pg/mL for IL-6 and 1 pg/mL for both IL-8 and IL-10. Furthermore, the minimum detectable concentration, defined as the IL-10 and IL-12 concentrations corresponding to the average optic density of 20 replicates of the zero standard + 2 SDs, was estimated as 3 pg/mL for both IL-10 and IL-12.
CRP AND PCT LEVELS
For the determination of CRP levels, we used a kit (Dade Behring, Marburg, Germany) with a lower detection limit of 2.5 mg/L. Levels of PCT were determined by an immunoluminometric assay (LUMI test PCT, BRAHMS Diagnostica GmbH, Berlin, Germany). The PCT sequence consists of 3 segments: katacalcin, calcitonin, and an N-terminal residue. In this test, the PCT molecule is sandwiched between 2 mAbs, 1 of which has a luminescent label. The test ultimately produces a luminescence signal directly proportional to the PCT concentration of the serum. The functional assay sensitivity (ie, the lowest value measured with a precision of 20% maximum interassay variation) is approximately 0.3 ng/mL. The analytic assay sensitivity (which is the value that can be discriminated from 0 with a 95% confidence interval) is 0.1 ng/mL.
STATISTICAL ANALYSIS
The SPSS 10.1 software package (SPSS Inc, Chicago, Ill) was used for statistical analysis. The Mann-Whitney test was used to evaluate differences between groups according to the low and high MOD and SOFA scores and the 28-day all-cause mortality. Furthermore, the relationships between the variables were assessed by Spearman correlation test. All analyses are 2-tailed, and P .05 was considered significant.
RESULTS
The median age of the patients was 58.5 years (range, 33-70 years); 10 patients (62%) were male. Patient characteristics and clinical outcome are shown in Table 1. The 28-day all-cause mortality rate was 56.3%.
|
|
|
|
Table 1. Patient Characteristics and Clinical Course*
|
|
|
CHANGES IN CYTOKINE, CRP, AND PCT LEVELS ACCORDING TO 28-DAY ALL-CAUSE MORTALITY ANALYSIS
Nonsurvivors were found to have higher CRP and PCT levels than survivors (P = .048 and P = .05, respectively). In contrast, nonsurvivors had decreased percentages of lymphocyte-associated IL-2, IL-6, IL-10, and TNF- (P = .05, P = .02, P = .03, and P = .009, respectively) and monocyte-associated IL-10 and TNF- (P = .048 and P = .03, respectively) compared with the survivors, as shown in Figure 1.
|
|
|
|
Figure 1. Intracytoplasmic cytokine profile of unstimulated monocytes (A) and lymphocytes (B) and serum levels of cytokines, procalcitonin (PCT), and C-reactive protein (CRP) (C) from survivors (S; n = 7) and nonsurvivors (NS; n = 9) according to the 28-day all-cause mortality analysis. Results showing the median values were compared with the Mann-Whitney test. Asterisk indicates statistically significant changes (P<.05). Procalcitonin values are in nanograms per milliliter. IL indicates interleukin; TNF, tumor necrosis factor; and IFN, interferon.
|
|
|
CHANGES IN CYTOKINE, CRP, AND PCT LEVELS ACCORDING TO MOD AND SOFA SCORES
The median APACHE II score of the patients was 21 (range, 11-31), whereas the median MOD and SOFA scores were 8 (3-14) and 10.5 (4-16), respectively. Accordingly, all of the immunologic measures were analyzed according to low (<8) and high ( 8) MOD scores and low (<11) and high (11) SOFA scores. In patients with high MOD and SOFA scores, serum levels of CRP (P = .18 and P = .009, respectively), PCT (P = .06 and P = .10, respectively), IL-6 (P = .009 and P = .007, respectively), and IL-8 (P = .002 and P = .02, respectively) were found to be increased. However, lymphocyte-associated IL-6 (P = .03 and P = .08, respectively) and TNF- (P = .04 and P = .03, respectively) and monocyte-associated IL-10 (P = .04 and P = .13, respectively) and IL-12 (P = .10 and P = .03, respectively) proportions were determined to be decreased, as shown in Figure 2 and Figure 3.
|
|
|
|
Figure 2. Intracytoplasmic cytokine profile of unstimulated monocytes (A) and lymphocytes (B) and serum levels of cytokines, procalcitonin (PCT), and C-reactive protein (CRP) (C) of patients with severe sepsis (n = 16) according to low (n = 7) and high (n = 9) multiple organ dysfunction scores. Results showing the median values were compared with the Mann-Whitney test. Asterisk indicates statistically significant changes (P<.05). Procalcitonin values are in nanograms per milliliter. IL indicates interleukin; TNF, tumor necrosis factor; and IFN, interferon.
|
|
|
|
|
|
|
Figure 3. Intracytoplasmic cytokine profile of unstimulated monocytes (A) and lymphocytes (B) and serum levels of cytokines, procalcitonin (PCT), and C-reactive protein (CRP) (C) of patients with severe sepsis (n = 16) according to low (n = 7) and high (n = 9) sepsis-related organ failure assessment scores. Results showing the median values were compared with the Mann-Whitney test. Asterisk indicates statistically significant changes (P<.05). Procalcitonin values are in nanograms per milliliter. IL indicates interleukin; TNF, tumor necrosis factor; and IFN, interferon.
|
|
|
CORRELATION ANALYSIS
The statistically significant Spearman correlation coefficients are presented in Table 2 to show the relationship of serum levels of acute-phase proteins, cytokines, and leukocyte-associated cytokine percentages with MOD and SOFA scores. Serum PCT, IL-6, and IL-8 levels positively correlated with MOD and SOFA scores by different P values, while a reverse correlation was found between MOD and SOFA scores and both lymphocyte-associated IL-6 and TNF- and monocyte-associated IL-10, IL-12, and TNF- percentages.
|
|
|
|
Table 2. Correlations Between Immunologic Variables and MOD and SOFA Scores*
|
|
|
COMMENT
Activation of inflammatory pathways, including the cytokine network, is considered to play a major role in the pathogenesis of sepsis. The particular type of immune response is determined by the differentiation of naive helper T (TH0) cells into TH1 and TH2 cells, which can be induced to express the TH1 phenotype by exposure to the cytokine IL-12, whereas exposure to IL-4 induces the TH2 phenotype.3 Interleukin 12 is produced predominantly by monocytes and macrophages. The TH1 cells predominantly produce IFN-, IL-2, and TNF-, and are responsible for both humoral and cell-mediated responses. The TH2 cells produce predominantly IL-4, as well as IL-5, IL-6, IL-10, and IL-13, and provide help for humoral responses, including IgE isotypes and mucosal immunity. Several other proteins are secreted both by TH1 and TH2 cells, including IL-3, TNF-, and granulocyte-macrophage colony-stimulating factor. Furthermore, IL-6, IL-10, and TNF- are also major monocyte products. The cytokine network produced by these effector cells is proinflammatory, which are mainly TNF-, IL-1, IL-12, IFN-, or IL-6 with both proinflammatory and anti-inflammatory properties, or anti-inflammatory, which are IL-4, IL-10, and IL-13. Both types of TH cells regulate the immune responses through these different cytokines with antagonistic interactions in septic patients.
Numerous studies1-11 have been published on serum or plasma concentrations of cytokines in patients with sepsis. In general, proinflammatory cytokines can be detected only in a subset of patients, whereas anti-inflammatory cytokines and soluble inhibitors can be found in the vast majority of patients with sepsis. However, the results regarding the relationship between circulating cytokines and APACHE II and III scores and mortality are showing great variability. In comparison with other cytokines, IL-6 (a mixed proinflammatory and anti-inflammatory cytokine) was most consistently reported in the circulation of septic patients, showing a positive correlation with mortality.21 These discrepancies may be due to patients having different stages or severity of sepsis syndrome, timing of samples relative to the onset of sepsis or septic shock, high interindividual variation, and methods.22 Our results also did not show any difference in the circulating cytokine levels in terms of 28-day all-cause mortality analysis, while CRP and PCT levels were found to be significantly elevated in patients with poor prognosis. However, there was a significant positive correlation between MOD and SOFA scores and serum IL-6, IL-8, and PCT levels in concordance with some reports,23-25 while CRP levels did not show any significant correlation. Rau et al26 also reported higher levels of IL-8 and PCT in patients with infected pancreatic necrosis than in those with sterile necrosis, whereas there was no difference in levels of CRP. Furthermore, PCT was found to be increased earlier and returned to the normal range more quickly than was CRP in children with infectious disease, and also was a more specific and sensitive marker of IL-6 and TNF- secretion than was CRP in septic patients.27-28 However, additional large studies are needed to determine whether PCT is superior to CRP in differentiating between inflammation of infectious and noninfectious origin and also in evaluating the severity of sepsis or multiple organ dysfunction.
Measuring cytokine levels in the circulation should be viewed as an inadequate exploration of the tip of the iceberg. Short plasma half-life of circulating cytokines, soluble cytokine receptors or inhibitors, and peripheral-blood cells such as erythrocytes or leukocytes trapping excessive exogenous cytokines via their specific receptors can cause a reduction of these individual cytokines, resulting in misleading results. Erythrocytes were shown to bind to IL-8 and other chemokines via the Duffy antigen.29-30 It was also observed that a larger amount of IL-8 could be found in cell-associated form in comparison with its plasma levels after activation of leukocytes including monocytes and polymorphonuclear neutrophils of septic patients, as determined in cell lysates by enzyme-linked immunosorbent assay technique.31-33
Taking these findings into consideration, there has been a tendency to investigate leukocyte intracytoplasmic cytokines separately from their corresponding serum levels. With a recently developed technology for intracellular detection of cytokine synthesis on a single-cell level, a powerful diagnostic tool has become available to discriminate a shift of functionality in T-cell subsets via their individual cytokine profiles by performing flow cytometric analysis.34 In this study, we used this flow cytometric approach, which allows for the determination of the functional potential of T cells and also monocytes for mediator synthesis to evaluate the participation of these subsets in the immune response of patients with severe sepsis in terms of MOD and SOFA scores and survival analysis. In the study design, we aimed to investigate the unstimulated spontaneous cytokine expression in the peripheral-blood lymphocytes and monocytes under the influence of septic conditions, comparing the results with their corresponding serum levels and also CRP and PCT. It was previously reported that intracytoplasmic cytokines were almost undetectable within unstimulated cells in healthy volunteers.35 However, in the present study, we demonstrated higher percentages of lymphocyte-associated TNF-, IL-2, IL-6, and IL-10 and monocyte-associated TNF-, IL-10, and IL-12 in septic patients with a better prognosis. Our results suggest that both TH1- and TH2-cell responses are necessary for the survival of the septic patients, most of who have intra-abdominal sepsis after major visceral surgery. However, diminished or absent TH1 and TH2 responses characterized by immunologic anergy resulted in poor clinical outcome.
The term anergy is defined as a state of nonresponsiveness to antigen, and it is used in the clinical literature to describe a condition characterized by the lack of delayed-type hypersensitivity response to skin-test antigens. In concordance with our results, Puyana et al36 reported a higher mortality rate in anergic patients after trauma, whereas a significant inverse correlation was found between T-cell proliferation and APACHE III or MOD scores. There was a global reduction of T-cell lymphokine production, including IL-2, IFN-, IL-10, and IL-4 secreted by TH1 and TH2 cells, and a significant direct correlation between depressed IL-4 and IFN- levels in anergic patients. These findings are also in concordance with previous studies reporting strongly reduced TNF- and IL-6 messenger RNA expression in peripheral-blood mononuclear cells harvested from lipopolysaccharide-stimulated whole blood of patients with severe sepsis16 and decreased T-cell proliferation and production of IL-2 and TNF in patients with lethal intra-abdominal infection as compared with survivors and healthy controls.37 In contrast, persisting levels of unstimulated monocyte-associated TNF- were determined in surviving septic patients.38 In addition to "T-cell anergy," monocytic deactivation was found to be associated with a higher mortality.39 These monocytes were characterized by a markedly reduced HLA-DR expression, a loss of antigen-presenting capacity, and a profound reduction of their ability to produce lipopolysaccharide-induced TNF-, IL-10, and IL-12 in vitro.39-41 Nevertheless, a recent study demonstrated that postoperative sepsis was associated with immediate monocyte defects that affected both proinflammatory and anti-inflammatory cytokine secretion, and sepsis survival correlated with the recovery of the proinflammatory, but not anti-inflammatory, response.42 Our findings regarding the inverse correlation between MOD and SOFA scores and monocyte-associated higher percentages of proinflammatory and anti-inflammatory cytokines, including IL-10, IL-12, and TNF-, support the necessity of adequate monocytic capacity with a predominance of proinflammatory cytokine expression for immunologic surveillance in sepsis. Furthermore, IL-12 therapy significantly increased survival in mice with intra-abdominal sepsis induced by cecal ligation and puncture by enhancing TNF- and IFN- production.41
In conclusion, the development of both types of TH-cell response with a predominance of proinflammatory cytokine expression, especially by monocytes, is suggested to play a major role in survival of severely septic patients. Nevertheless, both T-cell and monocyte anergy characterized by low intracytoplasmic cytokine expression in this study is found to be a poor prognostic factor. Immunomodulatory agents like IL-12 that might correct this immunologic dysfunction are to be further studied in severe sepsis.
AUTHOR INFORMATION
This study was supported by the Research Fund of the University of Istanbul, Istanbul, Turkey (project No. G-1117/010598).
This study was presented at the 14th European Immunology Meeting, European Federation of Immunological Societies 2000, September 25, 2000, Poznan, Poland.
Corresponding author and reprints: Neslihan Cabioglu, MD, PhD, Departments of Cancer Biology and Surgical Oncology, Box 173, The University of Texas M. D. Anderson Cancer Center, Holcombe Boulevard, Houston, TX 77030-4095 (e-mail: ncabiogl{at}mdanderson.org or neslicab{at}yahoo.com).
From the Departments of Surgery (Drs Cabioglu and Gunay), Medical Biology (Dr Seyhun), and Anesthesiology (Dr Esen), Istanbul Faculty of Medicine, and the Division of Immunology, Institute of Experimental and Medical Research (Drs Cabioglu, Deniz, and Turna and Mss Bilgic and Aktas), University of Istanbul, Istanbul, Turkey. Dr Cabioglu is now with the Departments of Cancer Biology and Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston.
REFERENCES
| |
1. Damas P, Canivet JL, de Groote D, et al. Sepsis and serum cytokine concentrations. Crit Care Med. 1997;25:405-412.
FULL TEXT
|
ISI
| PUBMED
2. Blackwell TS, Christman JW. Sepsis and cytokines: current status. Br J Anaesth. 1996;77:110-117.
FREE FULL TEXT
3. Pinsky MR, Vincent JL, Deviere J, Alegre M, Kahn RJ, Dupont E. Serum cytokine levels in human septic shock: relation to multiple-system organ failure and mortality. Chest. 1993;103:565-575.
FREE FULL TEXT
4. Damas P, Ledoux D, Nys M, et al. Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg. 1992;215:356-362.
ISI
| PUBMED
5. Rogy MA, Oldenburg HSA, Coyle S, Trousdale R, Moldawer LL, Lowry SF. Correlation between Acute Physiology and Chronic Health Evaluation (APACHE) III score and immunological parameters in critically ill patients with sepsis. Br J Surg. 1996;83:396-400.
ISI
| PUBMED
6. Friedland JS, Porter JC, Daryanani S, et al. Plasma proinflammatory cytokine concentrations, Acute Physiology and Chronic Health Evaluation (APACHE) III scores and survival in patients in an intensive care unit. Crit Care Med. 1996;24:1775-1781.
FULL TEXT
|
ISI
| PUBMED
7. Patel RT, Deen KI, Youngs D, Warwick J, Keighley MRB. Interleukin 6 is a prognostic indicator of outcome in severe intra-abdominal sepsis. Br J Surg. 1994;81:1306-1308.
ISI
| PUBMED
8. Van Deuren M. Kinetics of tumour necrosis factor-alpha, soluble tumour necrosis factor receptors, interleukin 1-beta and its receptor antagonist during serious infections. Eur J Clin Microbiol Infect Dis. 1994;13(suppl 1):12-16.
9. Goldie AS, Fearon KC, Ross JA, et al for the Sepsis Intervention Group. Natural cytokine antagonists and endogenous antiendotoxin core antibodies in sepsis syndrome. JAMA. 1995;274:172-177.
FREE FULL TEXT
10. Pruitt JH, Welborn MB, Edwards PD, et al. Increased soluble interleukin-1 type II receptor concentrations in postoperative patients and in patients with sepsis syndrome. Blood. 1996;87:3282-3288.
FREE FULL TEXT
11. van der Poll T, de Waal Malefyt R, Coyle SM, Lowry SF. Antiinflammatory cytokine responses during clinical sepsis and experimental endotoxemia: sequential measurements of plasma soluble interleukin (IL)–1 receptor type II, IL-10, and IL-13. J Infect Dis. 1997;175:118-122.
ISI
| PUBMED
12. Emmanuilidis K, Weighardt H, Maier S, et al. Critical role of Kupffer cell–derived IL-10 for host defense in septic peritonitis. J Immunol. 2001;167:3919-3927.
FREE FULL TEXT
13. Reddy RC, Chen GH, Newstead MW, et al. Alveolar macrophage deactivation in murine septic peritonitis: role of interleukin 10. Infect Immun. 2001;69:1394-1401.
FREE FULL TEXT
14. Cavaillon JM, Marie C, Pitton C, Fitting C. The production of TNF alpha and IL-8 in whole blood assays are differently regulated upon activation by LPS. Prog Clin Biol Res. 1995;392:433-439.
PUBMED
15. Marie C, Fitting C, Cheval C, et al. Presence of high levels of leukocyte-associated interleukin-8 upon cell activation and in patients with sepsis syndrome. Infect Immun. 1997;65:865-871.
ABSTRACT
16. Ertel W, Kremer JP, Kenney J, et al. Downregulation of proinflammatory cytokine release in whole blood from septic patients. Blood. 1995;85:1341-1347.
FREE FULL TEXT
17. Bone RC, Balk RA, Cerra FB, et al. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864-874.
ISI
| PUBMED
18. Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med. 1995;23:1638-1652.
FULL TEXT
|
ISI
| PUBMED
19. Vincent JL, Moreno R, Takala J, et al for the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med. 1996;22:707-710.
ISI
| PUBMED
20. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818-829.
ISI
| PUBMED
21. Rodriguez-Gaspar M, Santolaria F, Jarque-Lopez A, et al. Prognostic value of cytokines in SIRS general medical patients. Cytokine. 2001;15:232-236.
FULL TEXT
|
ISI
| PUBMED
22. Wray GM, Hinds CJ. Determinants of outcome from sepsis and septic shock. In: Vincent JL, ed. Yearbook of Intensive Care and Emergency Medicine. Berlin, Germany: Springer-Verlag; 1997:168-179.
23. Meisner M, Tschaikowsky K, Palmaers T, Schmidt J. Comparison of procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations at different SOFA scores during the course of sepsis and MODS. Crit Care. 1999;3:45-50.
FULL TEXT
|
ISI
| PUBMED
24. Wanner GA, Keel M, Steckholzer U, Beier W, Stocker R, Ertel W. Relationship between procalcitonin plasma levels and severity of injury, sepsis, organ failure, and mortality in injured patients. Crit Care Med. 2000;28:950-957.
FULL TEXT
|
ISI
| PUBMED
25. Hatherill M, Tibby SM, Turner C, Ratnavel N, Murdoch IA. Procalcitonin and cytokine levels: relationship to organ failure and mortality in pediatric septic shock. Crit Care Med. 2000;28:2591-2594.
FULL TEXT
|
ISI
| PUBMED
26. Rau B, Steinbach G, Gansauge F, Mayer JM, Grünert A, Beger HG. The potential role of procalcitonin and interleukin-8 in the prediction of infected necrosis in acute pancreatitis. Gut. 1997;41:832-840.
FREE FULL TEXT
27. Monneret G, Labaune JM, Isaac C, Bienvenu F, Putet G, Bienvenu J. Procalcitonin and C-reactive protein levels in neonatal infections. Acta Paediatr. 1997;86:209-212.
ISI
| PUBMED
28. Oberhoffer M, Karzai W, Meier-Hellmann A, Bögel D, Fassbinder J, Reinhart K. Sensitivity and specificity of various markers of inflammation for the prediction of tumor necrosis factor– and interleukin-6 in patients with sepsis. Crit Care Med. 1999;27:1814-1818.
FULL TEXT
|
ISI
| PUBMED
29. Neote K, Darbonne W, Ogez J, Horuk R, Schall TJ. Identification of a promiscuous inflammatory peptide receptor on the surface of red blood cells. J Biol Chem. 1993;268:12247-12249.
FREE FULL TEXT
30. Horuk R, Chitnis CE, Darbonne WC, et al. A receptor for the malarial parasite Plasmodium vivax: the erythrocyte chemokine receptor. Science. 1993;261:1182-1184.
FREE FULL TEXT
31. Kuhns DB, Gallin JI. Increased cell-associated IL-8 in human exudative and A23187-treated peripheral blood neutrophils. J Immunol. 1995;154:6556-6562.
ABSTRACT
32. Fujishima SH, Nakamura H, Waki Y, et al. Cell-associated IL-8 in human blood monocytes: analysis by flow cytometry. Cytometry. 1996;24:382-389.
FULL TEXT
|
ISI
| PUBMED
33. Nakamura H, Fujishima S, Waki Y, et al. Priming of alveolar macrophages for interleukin-8 production in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1995;152:1579-1586.
ABSTRACT
34. Jung T, Schauer U, Heusser C, Neumann C, Rieger C. Detection of intracellular cytokines by flow cytometry. J Immunol Methods. 1993;159:197-207.
FULL TEXT
|
ISI
| PUBMED
35. Rostaing L, Tkaczuk J, Durand M, et al. Kinetics of intracytoplasmic Th1 and Th2 cytokine production assessed by flow cytometry following in vitro activation of peripheral blood mononuclear cells. Cytometry. 1999;35:318-328.
FULL TEXT
|
ISI
| PUBMED
36. Puyana JC, Pellegrini JD, De AK, Kodys K, Silva WE, Miller CL. Both T-helper-1– and T-helper-2–type lymphokines are depressed in posttrauma anergy. J Trauma. 1998;44:1037-1046.
ISI
| PUBMED
37. Heidecke CD, Hensler T, Weighardt H, et al. Selective defects of T lymphocyte function in patients with lethal intraabdominal infection. Am J Surg. 1999;178:288-292.
FULL TEXT
|
ISI
| PUBMED
38. Munoz C, Misset B, Fitting C, Bleriot JP, Carlet J, Cavaillon JM. Dissociation between plasma and monocyte-associated cytokines during sepsis. Eur J Immunol. 1991;21:2177-2184.
ISI
| PUBMED
39. Döcke WD, Randow F, Syrbe U, et al. Monocyte deactivation in septic patients: restoration by IFN- treatment. Nat Med. 1997;3:678-681.
FULL TEXT
|
ISI
| PUBMED
40. Heidecke CD, Weighardt H, Hensler T, Bartels H, Holzmann B. Immunparalyse von T-lymphocyten and Monocyten in der postoperativen abdominellen Sepsis. Chirurg. 2000;71:159-165.
FULL TEXT
|
ISI
| PUBMED
41. Göebel A, Kavanagh E, Lyons A, et al. Injury induces deficient interleukin-12 production, but interleukin-12 therapy after injury restores resistance to infection. Ann Surg. 2000;231:253-261.
FULL TEXT
|
ISI
| PUBMED
42. Weighardt H, Heidecke CD, Emmanuilidis K, et al. Sepsis after major visceral surgery is associated with sustained and interferon-–resistant defects of monocyte cytokine production. Surgery. 2000;127:309-315.
FULL TEXT
|
ISI
| PUBMED
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
RELATED ARTICLE
Invited Critique
Stephen F. Lowry
Arch Surg. 2002;137(9):1043.
EXTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Mediators or Markers of Injury, Inflammation, and Infection (Harbingers of Doom or Predictors of Disaster) and Biologic Puzzles or Ambiguities
Baue
Arch Surg 2007;142:89-93.
FULL TEXT
What Is New in Cytokine Research Related to Trauma/Critical Care
Jawa et al.
J Intensive Care Med 2006;21:63-85.
ABSTRACT
|
