Tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 concentrations in cerebrospinal fluid predict ventriculoperitoneal shunt infection

OBJECTIVE: To determine the diagnostic value of cerebrospinal fluid tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and IL-6 released into the cerebrospinal fluid of patients with ventriculoperitoneal shunt infection. DESIGN: Prospective, observational study. SETTING: University teaching hospital. PATIENTS: Sixty-four patients requiring cerebrospinal fluid aspiration for suspected ventriculoperitoneal shunt malfunction. INTERVENTIONS: Cerebrospinal fluid samples were obtained by shunt aspiration at the time of patient presentation. MEASUREMENTS AND MAIN RESULTS: TNF-alpha and IL-1 beta concentrations were measured by enzyme-linked immunosorbent assay, and IL-6 activity by bioassay. The sensitivity, specificity, predictive values, and overall efficiency for each cytokine were determined based on the cerebrospinal fluid culture results. Ten patients had positive cerebrospinal fluid cultures, eight of which yielded Staphylococcus species, and one each Acinetobacter and Pseudomonas. Cerebrospinal fluid TNF-alpha, IL-1 beta, IL-6, protein, and leukocyte concentrations were significantly increased in patients with shunt infection. Cerebrospinal fluid IL-6 activity had the highest diagnostic accuracy of the cytokines evaluated, with sensitivity of 80% and specificity of 98%. CONCLUSIONS: The presence of cerebrospinal fluid inflammatory cytokines strongly suggests ventriculoperitoneal shunt infection. Detection of these cytokines in the cerebrospinal fluid could be used for earlier diagnosis of bacterial infection.     

Do low vancomycine serum levels predict failures of vancomycine therapy in neutropenic cancer patients?

Vancomycine serum levels were measured in 198 cancer patients with documented grampositive bacteremia and twenty two failed. Failures were analyzed for risk factors of therapy failure. Only 8 of 22 showed low serum peak or through vancomycin levels. One patient was treated less than 7 days, 9 had persisting and 4 catheter associated bacteremia. Bacteremias due to VAN resistant strains were excluded. In 14 out of 22 patients, multiple or one risk factor could be determined, but in 8 patients, no risk factor was found. Hence the, case control study was conducted to compare the group of failures in 22 patients with a group of patients with underlying disease and neutropenia treated successfully within the same period and same antibiotic policy at the same cancer center, by VAN for gram-positive bacteremia. Persisting, catheter associated and enterococcal bacteremias were the only statistical significant risk factors predicting a therapy failure in cancer patients. Neither Vancomycine serum peak nor through levels predicted the outcome: failure or cure of gram-positive bacteremia in cancer patients. (Tab. 1, Ref. 5.).     

Elevated interleukin-8 serum concentrations in beta-thalassemia and graft-versus-host disease

Neutrophil chemotactic and functional defects occur in beta-thalassemia and in patients after bone marrow transplantation (BMT). Interleukin-8 (IL-8) is a novel chemotactic and activating peptide for neutrophils and can be detected in the circulation. IL-8 serum concentrations were evaluated in 30 beta-thalassemic patients before and after BMT. Serial samples from 16 patients were also studied. Fourteen sera from healthy children, 43 patients with chronic viral hepatitis, 16 patients on chronic transfusion treatment for various hematologic disorders, and 28 healthy adults were studied as controls. IL-8 was evaluated by an enzyme-linked immunosorbent assay. Patients with beta-thalassemia had higher IL-8 concentrations than did normal controls, patients with liver disease, and patients on chronic transfusion. beta-Thalassemic patients with severe liver siderosis and fibrosis had the highest IL-8 concentrations. After BMT in patients with successful engraftment, IL-8 concentrations decreased significantly. In contrast, in patients with acute graft-versus-host disease (GVHD), IL-8 concentrations were not statistically different from the concentrations found before BMT and were higher than in patients with no complications and patients with graft rejection. IL-8 may play a part in the immune dysregulation that occurs in beta-thalassemia and may be involved in the immune mechanisms leading to GVHD.     

Blood transfusion and postoperative serum interleukin-6 levels in colorectal cancer patients

BACKGROUND/AIMS: Postoperative cytokine response affects various factors. However, excessive stress responses are deleterious as increased serum concentration of cytokines may induce tissue injury and an impaired immune system. METHODOLOGY: We determined serum IL-6 levels in 35 patients who had undergone resection of colorectal carcinoma. Eleven patients had a blood transfusion before or during the operation (transfused group) but 24 patients had received no blood transfusion (control group). Serum IL-6 levels were determined before the operation, and at the end of operation,POD-1, 3, and 7. RESULTS: There was no significant difference of preoperative mean levels of IL-6 between these two groups (p=0.20). Postoperative serum IL-6 levels were significantly elevated. Mean serum levels of IL-6 were significantly higher at the end of operation in the transfused group than in the control group (131.7 pg/ml in control group and 269.8 pg/ml in transfused group; p=0.02). CONCLUSION: The present study suggested that perioperative allogeneic blood transfusion can induce an excessive cytokine response and may be deleterious.     

Variations in interleukin-2 and interleukin-6 due to surgical trauma in cancer patients

Inflammatory response after surgical trauma, which is necessary for infection control and tissue repairing, can actually produce some cytokines suppressive of the antitumoral immunity response. In this study the authors evaluate pre- and post-operative IL-2 (antitumor response activator) and IL-6 (lymphocytic response inhibitor and tumor growth factor) levels in 26 cancer patients undergoing resective surgery. Analysis of the results showed a significative IL-6 increase and a tendency to IL-2 decrease in the post-operative period. It is thus confirmed, even on the basis of the cytokines, the meaningful immunosuppressive effect of the surgical trauma on neoplastic growth control.     

Molecular epidemiological analysis of quinolone-resistant Escherichia coli causing bacteremia in neutropenic patients with leukemia in Korea

We analyzed an outbreak of Escherichia coli bacteremia in eight patients with leukemia in a hematology-oncology unit from July to September 1994. The antibiograms and genotypic patterns of the isolates were different, thus suggesting that the outbreak did not originate from a single clone. However, all the isolates were resistant to quinolones, which led us to examine the microbiological records from 1992 to 1994. The incidence of quinolone-resistant E. coli bacteremia in the hematology-oncology unit ranged from 81.8% to 94.6% during this period. We then analyzed 36 more isolates recovered from late 1994 to 1995. Field inversion gel electrophoresis patterns of these isolates were also different. Analysis of the quinolone resistance determining region in gyrA revealed that all the isolates had a double mutation in gyrA. In conclusion, quinolone-resistant E. coli could be an emerging threat to neutropenic patients with leukemia who receive a quinolone prophylactically, and attention must be paid to this trend of resistance.     

Increased serum concentrations of interleukin-10 in patients with hepatosplenic candidiasis

Hepatosplenic candidiasis (HSC) becomes clinically overt in cancer patients upon recovery from neutropenia. HSC may be a consequence of a Th1-Th2 imbalance, characterized by increased serum levels of one or more cytokines. Serum levels of two immunosuppressive cytokines, markers of the Th2 pathway, interleukin (IL)-4 and IL-10 were measured by ELISA in 10 patients with HSC (22 samples) and compared with 19 healthy blood donors, 13 patients with cancer but no infection (23 samples), and 11 patients with cancer and various bacterial infections (17 samples). IL-4 was undetectable in all controls and patients. By contrast, levels of IL-10 were increased in HSC patients compared with levels in healthy donors and cancer patients without infection (P < .001) or with bacterial infections (P < .01). These findings indicate that IL-10 but not IL-4 is increased in patients with HSC and suggest that IL-10 plays a role in the pathogenesis of this infection.     

Serum levels of cytokines in patients with colorectal cancer: possible involvement of interleukin-6 and interleukin-8 in hematogenous metastasis

Serum levels of interleukin-1 (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor (TNF-alpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured preoperatively in 24 patients with colorectal cancer. IL-1 beta was not elevated, IL-6 and IL-8 were markedly elevated, and GM-CSF was slightly elevated. TNF-alpha was not detected in most patients. Serum IL-6 levels correlated closely with serum IL-8 levels and with serum carbohydrate antigen (CA) 19-9 levels. Serum IL-6 levels were significantly higher in patients whose tumors exceeding 5.0 cm in diameter or spreading circumferentially. Serum IL-8 levels showed significant differences according to histological type, being lower in well differentiated adenocarcinoma compared to other types. Serum levels of IL-6 and IL-8 were significantly higher in patients with liver metastasis than in those without liver metastasis and serum levels of both these cytokines were also significantly higher in patients with lung metastasis than in those without lung metastasis. These results suggest that IL-6 and IL-8 may play an important role in the hematogenous metastasis of colorectal cancer.     

Serum soluble IL-6 receptor concentrations correlate with stages of multiple myeloma defined by serum beta 2-microglobulin and C-reactive protein

Serum soluble interleukin-6 receptor (sIL-6R) concentrations were measured in 52 patients with multiple myeloma (MM) and 24 normal controls, using a commercially available immunoenzymatic assay kit. Patients were staged according to the Bataille et al. myeloma staging system based on the levels of patients' serum beta 2-microglobulin and C-reactive protein. Twenty-one patients were at stage A of disease, 19 at stage B and 12 at stage C at the time of serum collection for sIL-6R determination. Serum sIL-6R concentrations ranged from 15 to 176 ng/ml with a mean of 64.8 +/- 35.9 ng/ml and a median of 58 ng/ml in the entire group of patients studied. These values were significantly higher than those of 34.4 +/- 13.4 ng/ml found in the controls (P < or = 0.001). Patients of stage C had higher sIL-6R levels (94.8 + 41.2 ng/ml) than patients of stage B (67.7 +/- 31.0 ng/ml) (P < 0.01), and markedly higher than patients of stage A (45.0 +/- 23.1 ng/ml) (P < 0.001). Serum levels of sIL-6R in patients with stage A disease did not differ statistically from those of the controls. A linear positive correlation was observed between serum levels of the receptor and the stage of MM (r = 0.539, P < 0.001). These data strongly suggest that serum sIL-6R concentrations correlate with the stages of MM and may be used as an indicator of the activity of the disease.     

Tumor necrosis factor-alpha, interleukin-6, and interleukin-8 secretion and the acute-phase response in patients with bacterial and tuberculous osteomyelitis

Osteomyelitis, or bone infection, is a major worldwide cause of morbidity. Treatment is frequently unsatisfactory, yet little is known about pathogenesis of infection. Plasma tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 concentrations were measured before and after lipopolysaccharide stimulation of whole blood from patients with bacterial and tuberculous osteomyelitis and from controls. Patients with bacterial and tuberculous osteomyelitis mounted an acute-phase response and were anemic and febrile. However, plasma IL-6 concentrations were significantly elevated in only tuberculous osteomyelitis patients (vs. controls, P < .05). IL-6 concentrations correlated with erythrocyte sedimentation rate, C-reactive protein level, and plasma albumin concentration, all acute-phase markers. There were no other correlations between cytokine concentrations and clinical data. Following ex vivo stimulation, TNF, IL-6, and IL-8 were secreted equally by patients and controls. In summary, tuberculous osteomyelitis is characterized by elevated systemic IL-6 concentrations associated with an acute-phase response. For further insight into immunopathology of osteomyelitis, studies on infected bone are required.     

Interleukin-6 and acute-phase protein concentrations in surgical intensive care unit patients: diagnostic signs in nosocomial infection

OBJECTIVE: To determine the value of serum concentrations of interleukin-6 (IL-6), C-reactive protein, and glycosylation of alpha 1-acid glycoprotein as tools for diagnosing nosocomial infection in surgical intensive care unit (ICU) patients. DESIGN: Prospective, consecutive entry study of patients with an anticipated stay of at least 24 hrs in a surgical ICU. SETTING: University hospital, a major provider of acute surgical care. PATIENTS: One hundred four consecutive patients admitted to the surgical ICU between March and June 1990. MEASUREMENTS: Concentrations of IL-6, C-reactive protein, and glycosylation of alpha 1-acid glycoprotein were measured on days 1 and 6 after ICU admission. Clinical evaluation for infection was performed daily in a blinded fashion, i.e., without knowing the results of the acute-phase parameters. MAIN RESULTS: On day 6 after surgery or trauma, nosocomial infection could be ascertained in 13 cases. The clinical parameter of fever > 38 degrees C had a sensitivity of 54% and a specificity of 90% to demonstrate nosocomial infection. Infected patients showed increased concentrations of IL-6 (p < .001), C-reactive protein (p < .001), and increased reactivity of alpha 1-acid glycoprotein to concanavalin A (p < .001) compared with patients without infections. By choosing appropriate cutoff values, IL-6 determinations had the highest specificity (97%), and C-reactive protein values had the highest sensitivity (85%) for diagnosing nosocomial infections. In uninfected patients, 81% of the IL-6 values, but only 29% of the C-reactive protein values, were back to the normal range on day 6 after injury. CONCLUSION: Due to the rapid normalization after trauma, a single measurement of the serum IL-6 concentration may be useful to support or refute the clinical suspicion of nosocomial infection.     

Bacillus Calmette-Guérin potentiates monocyte responses to lipopolysaccharide-induced tumor necrosis factor and interleukin-1, but not interleukin-6 in bladder cancer patients

During the past decade, particular attention has been focused on treatment of bladder cancer patients with the bacterial agent bacillus Calmette-Guérin (BCG). In these studies, bladder cancer patients were instilled with BCG (75 mg/50 ml) once per week for 6 weeks, 1-2 weeks following trans-urethral resection of the bladder. Cystoscopy was performed after 6 weeks and, unless tumor progression was present, monthly treatments were given for 1 year. Blood was drawn 2 h after the last instillation, and monocytes were isolated (5 x 10(6) cells/ml) and treated, or not, with lipopolysaccharide (LPS) (20 microgram/ml) for tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha) and interleukin-6 (IL-6) release. The levels of monokines were determined by a monokine-specific enzyme-linked immunosorbent assay. Our results clearly show that, after 18 h incubation, macrophages from BCG-treated bladder cancer patients produced from 2.8- to 1.9-fold and from 2.0- to 1.3-fold greater amounts of TNF alpha and IL-1 alpha respectively, compared to macrophages from healthy controls, 5-fold higher than bladder cancer patients not treated with BCG. IL-6 was not affected. In another set of experiments macrophages (5 x 10(6) cells/ml) from healthy subjects were pretreated, or not, with BCG (100 micrograms/ml) overnight and treated, or not, with LPS 20 microgram/ml alone and in combination with interleukin-1 receptor antagonist (IL-1ra) 250 ng/ml. Macrophages treated with BCG had a strong stimulatory effect on IL-1 alpha release (9.45 ng/ml) while LPS was less effective (3.59 ng/ml). The combination of BCG plus LPS produced an additive effect on IL-1 alpha release (13.71 ng/ml) compared to the effect of the compound alone. The addition of IL-1ra (250 ng/ml) to BCG was not effective, while when IL-1ra was added to BCG plus LPS only a partial inhibition of IL-1 alpha release was found (9.83 ng/ml), compared to BCG plus LPS without IL-1ra (13.71 ng/ml). These effects seem to be related to the inhibition of IL-1 alpha stimulated with LPS, but not BCG. The priming effect of BCG exerted on LPS-stimulated monocyte production of TNF alpha and IL-1 alpha from bladder cancer patients led us to study the possible modulation of fibrinogen and C-reactive protein in the serum of BCG-treated cancer patients. The plasma levels of fibrinogen and C-reactive protein were higher (approximately twice) in BCG-treated patients compared to values obtained in untreated patients or healthy controls. We conclude that the beneficial immunotherapeutic effects of BCG in bladder cancer patients are related to its capacity to prime macrophages to enhance the release of TNF alpha and IL-1 alpha, but not IL-6 in response to physiological secondary stimuli, or through the direct stimulation of BCG on IL-1 alpha or TNF alpha, which are directly involved in the killing of cancer cells.(ABSTRACT TRUNCATED AT 400 WORDS)     

Interleukin-8 expression in normal nasal epithelium and its modulation by infection with respiratory syncytial virus and cytokines tumor necrosis factor, interleukin-1, and interleukin-6

Inflammation in nasal and airway tissue caused by allergens, microbial infection, and air pollution are likely to be regulated by inflammatory mediators produced by airway epithelial cells. We have therefore investigated the baseline expression of a number of cytokine genes known to be important inducers and modulators of inflammation, in freshly isolated human nasal epithelium. Cells were obtained by superficial scraping of turbinate tissue, and cDNA for polymerase chain reaction (PCR) amplification was reverse-transcribed directly from lysates of 3 x 10(3) to 5 x 10(3) epithelial cells using random hexamers. Constitutive expression of relatively high levels of interleukin-8 (IL-8) mRNA but undetectable levels (< 1 mRNA copy/cell) of granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-6, IL-1, or tumor necrosis factor (TNF) mRNA were found after PCR amplification of the cDNA. IL-8 protein, but not IL-6, was identified in the nasal epithelial cells by immunocytochemistry. Infection with respiratory syncytial virus (RSV) or stimulation of nasal epithelium for 4 h with TNF or IL-1 in vitro resulted in a 4- to 10-fold increase in IL-8 mRNA expression but not in the expression of detectable levels of mRNA for the other cytokines. IL-8 was secreted by RSV-, IL-1-, and TNF-stimulated as well as unstimulated nasal epithelial cells after 6 to 20 h of culture. Neither IL-6, GM-CSF, nor TNF activity/immunoreactivity was detectable in the culture supernatants. Thus, it appears that IL-8 is a major cytokine of human nasal epithelium, constitutively expressed and readily secreted upon virus infection or stimulation with IL-1 and TNF.     

Serial measurement of interleukin-6, transforming growth factor-beta, and S-100 protein in patients with acute stroke

BACKGROUND AND PURPOSE: Cytokine changes in patients with acute stroke have been insufficiently studied. The purpose of this study was to delineate the characteristics of serial changes of serum interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) in patients with cerebral infarction and intracerebral hemorrhage. METHODS: We serially (within 24 hours, at day 3, and at day 7) measured the serum levels of IL-6 and TGF-beta in 29 patients with acute stroke (10 with large cortical cerebral infarction, 9 with subcortical small infarction, and 10 with intracerebral hemorrhage). As an index of brain damage. S-100 protein was also measured. Twelve age-matched healthy subjects were tested as a control. RESULTS: S-100 protein was detected in only 11 patients with large infarction or intracerebral hemorrhage. Its level peaked at day 3 in patients with infarction, whereas it peaked within 24 hours in those with intracerebral hemorrhage. The level of IL-6 was most markedly elevated at day 1, which tended to decrease thereafter. However, its level remained significantly elevated compared with that of the control group even at day 7. The level of TGF-beta was significantly decreased at day 1 and day 3 and tended to return toward the control value thereafter. The levels of both cytokines were not significantly different among the three different stroke subtypes and were not correlated with the number of blood leukocytes and platelets. CONCLUSIONS: The alteration of IL-6 and TGF-beta levels, which occurs rapidly after acute stroke regardless of the subtype, may reflect the changing immunological-inflammatory status of these patients and does not appear to reflect merely the consequence of the brain damage.     

Plasma and synovial fluid interleukin-1, interleukin-6 and substance P concentrations in rheumatoid arthritis patients: effect of the nonsteroidal anti inflammatory drugs indomethacin, diclofenac and naproxen

We performed an open, between patients, placebo controlled study in order to evaluate the effect of the treatment with the non steroidal anti inflammatory drugs indomethacin, diclofenac and naproxen on the concentrations of the cytokines IL-1 beta and IL-6 and of the neuropeptide substance P in plasma and synovial fluid of 24 rheumatoid arthritis patients. All patients had high synovial fluid cytokine and substance P levels, and high plasma cytokine levels at the beginning of the study. The treatment with the non steroidal anti inflammatory drugs significantly decreased both plasma and synovial fluid IL-6 and synovial fluid substance P in comparison to placebo, but did not affect IL-1 beta concentrations. This effect can participate in the therapeutic effect of non steroidal anti inflammatory drugs in rheumatoid arthritis.     

Bacteremic pneumonia in neutropenic patients with cancer: causes, empirical antibiotic therapy, and outcome

BACKGROUND: Bacteremic pneumonia is a major cause of death among neutropenic patients with cancer. METHODS: We analyzed the causes, empirical antibiotic therapy, and outcome of 40 consecutive cases of bacteremic pneumonia identified among 408 episodes of bacteremia in adult neutropenic patients with cancer, prospectively documented from 1986 to 1995. RESULTS: The most frequent causative organisms were Pseudomonas aeruginosa (17 cases), Streptococcus pneumoniae (12 cases), Escherichia coli (5 cases), and Streptococcus mitis (3 cases). Overall, P. aeruginosa and S. pneumoniae caused 72.5% of all episodes of bacteremic pneumonia, compared with 11.4% of bacteremic episodes from other sources (P< .001). Thirty patients received ceftazidime and 10 patients received imipenem as the beta-lactam component of the initial empirical treatment. All strains of P. aeruginosa were susceptible to both agents. Forty-seven percent of streptococcal strains were penicillin resistant and showed a decreased susceptibility to ceftazidime (minimum inhibitory concentration ranged from 1 to 64 microg/mL). Five patients (12.5%) were considered to have received inappropriate empirical antibiotic therapy. Attributable mortality in patients with bacteremic pneumonia was higher than in patients with bacteremia from other sources; 22 (55%) of the 40 patients with bacteremic pneumonia died, whereas 39 (10.6%) of the 368 patients with bacteremia from other sources died (P<.001). CONCLUSIONS: Our data suggest that bacteremic pneumonia in neutropenic cancer patients is associated with a poor outcome and that empirical antibiotic therapy for neutropenic patients with pneumonia should include agents active against both P. aeruginosa and cephalosporin-resistant streptococci.     

Peritoneal fluid concentrations of interleukin-8 in women with endometriosis: relationship to stage of disease

There is increasing evidence that immunological mechanisms play a role in the pathogenesis and pathophysiology of endometriosis. It was therefore of interest to study interleukin-8 (IL-8), a chemokine, in the peritoneal fluid and peripheral blood of women undergoing laparoscopic procedures. The presence and concentrations of IL-8 in relation to endometriosis, infertility and abdominal pain were evaluated. Samples of peritoneal fluid (n = 49) and peripheral blood (n = 50) were obtained from 50 consecutive patients undergoing laparoscopic surgery for various gynaecological indications (abdominal pain, infertility, sterilization). IL-8 was present in the peritoneal fluid of most women (87%). The concentration of IL-8 in the peritoneal fluid was higher in women with endometriosis compared to women without (P = 0.02). This difference was more pronounced in early (stage 1) endometriosis (P = 0.001). IL-8 concentrations in the peritoneal fluid were also higher in women with early endometriosis compared to women with later stages of the disease (P = 0.003). Peripheral blood concentrations did not correlate with peritoneal fluid concentrations of IL-8 and/or the presence of endometriosis. We conclude that IL-8 is an important factor that may contribute to the pathogenesis of endometriosis possibly by promoting neovascularization. This information can be a guide in the development of new therapeutic approaches for the treatment of endometriosis.