| Section One Predictive Value of DcR3 and sTREM-1 in Nosocomial Bacterial Meningitis【Background】Despite emergence of antibiotics and improvement of clinical techniques, nosocomial bacterial meningitis (NBM) continues to be a significant cause of mortality. The incidence rate of NBM can range from 0.8% to 17% following different neurosurgical procedures, while its mortality is up to 34% or even higher. Early diagnosis and appropriate antibiotic treatment can significantly reduce mortality of NBM. However, it is a challenge for clinicians to make an accurate and rapid diagnosis of bacterial meningitis.Firstly, classic symptoms of bacterial meningitis, such as fever, headache, neck stiffness and mental status alteration are not specific. Secondly, clinical laboratory tests are not satisfactory. Cerebrospinal fluid culture is specific but lacks sensitivity, especially with previous use of antibiotics and it usually takes at least 24 - 48 h to yield results and may lead to delayed treatment. Based on the above reasons, it is important to identify desirable indicators for the rapid diagnosis of bacterial meningitis.Decoy receptor 3 (DcR3) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) are elevated under some infectious conditions. DcR3 is abundant in human cerebrospinal fluid. However, the diagnostic value of DcR3 in bacterial meningitis is not well evaluated. Although sTREM-1 is valuable for the diagnosis of bacterial meningitis. Clinical application of sTREM-1 in bacterial meningitis still requires more evidences.The present study was performed for two purposes. The first aim of this study was to evaluate the individual value of DcR3 and sTREM-1 for the diagnosis of NBM; the second objective was to estimate the combined predictive accuracy of the above mentioned biomarkers.【Methods】According to the features of cerebrospinal fluid and the results of cerebrospinal fluid culture,123 patients were enrolled in present study, among them 80 patients being diagnosed with bacterial meningitis and 43 patients with non-bacterial meningitis. All the cerebrospinal fluid samples were frozen at -80℃ ultra low temperature freezer until assay. Enzyme linked immunosorbent assay (ELISA) was used to detected the levels of DcR3 and sTREM-1.【Results】The mean age of the 123 patients was 43.15 years. 39 patients had received treatment of glucocorticosteroid, among them 27 patients with bacterial meningitis and 12 patients with non-bacterial meningitis. The rate of receiving steroid >24 h before cerebrospinal fluid sampling was not significantly different between the groups of bacterial meningitis and non-bacterial meningitis. The rate of receiving antibiotic>24 h before cerebrospinal fluid sampling in bacterial meningitis was much higher than that of non-bacterial meningitis (p< 0.001). The former rate was as high as 48.75%. Cerebrospinal fluid white cell count in the patients with bacterial meningitis were significantly higher than those with non-bacterial meningitis (765.00 (265.25-1976.00) ×106/L vs. 4.00 (2.00-36.00)×106/L,p< 0.001). Cerebrospinal fluid glucose, protein and lactate levels were also statistically significant between the two groups.Concentrations of DcR3 in the patients with bacterial meningitis were significantly higher than those with non-bacterial meningitis (0.646 (0.229-1.514) ng/mL vs. 0 (0-0.192) ng/mL, p< 0.001). Levels of sTREM-1 were also significantly different between the two groups. Levels of sTREM-1 in the patients with bacterial meningitis were significantly higher than those with non-bacterial meningitis (19.017 (0-60.256) pg/mL vs. 0 (0-0) pg/mL, p< 0.001). Levels of DcR3 and sTREM-1 did not differentiate patients with Gram-positive bacteria infection from those with Gram negative bacteria infection. DcR3 and sTREM-1 values were also not associated with treatment of antibiotic/steroid>24 h.Receiver operating characteristic curve (ROC) and area under the ROC curve (AUC) were performed to determine the discriminative accuracy of DcR3 and sTREM-1 in cerebrospinal fluid. DcR3 had a better discriminative value than sTREM-1. The AUC of DcR3 and sTREM-1 for the diagnosis of bacterial meningitis was 0.831(95% confidence interval (CI) 0.752-0.911; p< 0.001) and 0.756 (95% CI 0.673-0.839;p< 0.001) respectively. Youden index was used to acquire a cut-off point for each cytokine. DcR3 had a better sensitivity than that of sTREM-1 and had a lower specificity than that of sTREM-1. A cut-off value of 0.201 ng/mL for DcR3 had a sensitivity of 78.75% (95% CI 67.89%-86.79%), a specificity of 81.40% (95% CI 66.08% - 91.08%). A cut-off value of 11.515pg/mL for sTREM-1 had a sensitivity of 60.00% (95%CI 48.42% - 70.61%), a specificity of 88.37% (95% CI 74.12% 95.64%).Compared with other markers in predicting bacterial meningitis, such as cerebrospinal fluid leucocyte count, glucose, protein and lactate, cerebrospinal fluid leucocyte count yielded the best discriminative value with an AUC of 0.928 (95% CI 0.872 - 0.984; p< 0.001), followed by DcR3, sTREM-1, lactate, glucose and protein. Multiple stepwise logistic regression analysis testified that only DcR3 and sTREM-1 were the independently risk factors with bacterial meningitis (odds ratio (OR) = 3.325, 95% CI = 1.185-9.334, p = 0.023 for DcR3; OR = 1.059,95% CI = 1.015-1.106,p = 0.008 for sTREM-1).The AUC for the combined bioscore was 0.842 (95% CI 0.770-0.914; p< 0.001). When the bioscore was entered into the multivariate stepwise logistic regression model, the bioscore was also proved to be a significant factor for bacterial meningitis (OR,7.007, 95% CI 3.576-13.730;p< 0.001). The possibility of being infected by bacteria grew with the increasing bioscore. The rate of bacterial meningitis ranged from 28.89% for a bioscore of 0 to 95.65% for a bioscore of 2.[Conclusions]1. Concentrations of DcR3 and sTREM-1 in the patients with bacterial meningitis were much higher than those with non-bacterial meningitis2. The application of antibiotics and steroid did not affect the levels of cerebrospinal fluid DcR3 and sTREM-1.3. Detecting the cerebrospinal fluid values of DcR3 and sTREM-1 was useful for the diagnosis of NBM.4. Combination of DcR3 and sTREM-1 in cerebrospinal fluid could yielded a better diagnostic value for NBM than that of each biomarker.Section Two Clinical Analysis of 80 Patients with Nosocomial Bacterial Meningitis[Background]Nosocomial bacterial meningitis (NBM) is a significant problem among hospitalized patients, which threatens patients’ lives, extends their stay in hospital and increases the medical costs, sometimes even results in doctor-patient conflicts. Compared with community-acquired bacterial meningitis, NBM has a more insidious onset, prolonged clinical course and is likely to be caused by resistant microorganisms. With the development of craniocerebral operation, application of medical device and broad-spectrum antibiotics, distribution of pathogenic bacteria causing NBM has changed in recent years. So it is important for clinicians to understand the clinical characteristics of NBM, distribution of pathogenic bacteria and characteristics of drug-resistance bacteria, which can guide the clinicians to rapidly diagnose and timely treat this disease. And it is of great significance for improving the prognosis and survival rate of patients.[Methods]Eighty patients being diagnosed with NBM were enrolled in Qilu Hospital of Shandong University between November 2012 and October 2013.The clinical features and laboratory data of each patient were included as follows: age, gender, underlying disease, predisposing factors, clinical symptoms and signs, tracheotomy, ventilator, ASA score, type of neurosurgery, emergency operation, history of neurosurgery, duration of operation, operator, cerebrospinal fluid white blood cell count, glucose, protein and lactate, pressure of cerebrospinal fluid, clinical application of antibiotics and glucocorticosteroid, blood transfusion, prognosis and outcome, isolated microorganisms, results of antimicrobial susceptibility, etc. All statistical analyses were performed with SPSS, version 20.0.【Results】Among the 80 patients recruited in this study,57 patients were males and 23 patients were females. The mean age (mean±SD) was 43.75±16.46 years and the main of those patients fell in the age group of 15-59 years, accounting for 76.25%. 22 (27.50%) patients were with underlying disease, of which 16 patients with hypertension, 6 patients with diabetes and one patient with coronary heart disease. All the 80 patients underwent neurosurgical operation, of which 73 patients underwent neurosurgical procedure in our hospital and 7 patients were with operation at other hospitals. The predisposing factors associated with this study were as follows: neurosurgical operation, a distant focus of infection (pneumonia), immunocompromise (diabetes), etc.12 patients had a distant focus of infection or immunocompromise. The most common predisposing factor was neurosurgery operation, followed by implanted medical device. The highest proportion of neurosurgery type was intracranial tumor operation, accounting for 55.00%.A high proportion of patients were present with headache and fever (headache in 71.25% and fever in 78.75%), the rates of disturbance of consciousness and nuchal rigidity were low and the typical triad of bacterial meningitis-fever, stiff neck and disorder of consciousness was present in only 10 patients (12.50%). Cerebrospinal fluid white cell count was 765.00 (265.25-1976.00)×106/L. Cerebrospinal fluid white blood cell count was concentrated in the group of 100-10000×106/L. One patient was with normal white blood cell count. Cerebrospinal fluid glucose, protein and lactate were 1.59 (0.72-2.58) mmol/L, 0.82 (0.37-1.80) g/L and 3.23 (1.87-6.42) mmol/L respectively. Cerebrospinal fluid pressure was detected in 22 patients.3 of the 22 patients were with cerebrospinal fluid pressure higher than 300 mmH2O.In this study, 67 strains of Gram positive bacteria were isolated, 12 strains of Gram negative bacteria and one mixed strains with Gram positive bacteria and Gram negative bacteria. Plus the mixed strains, 63 strains of coagulase negative Staphylococcus were isolated, along with 4 strains of Staphylococcus aureus and 1 strain of Pediococcus pentosaceus. Methicillin resistance was found in 51 strains of Staphylococcus and all the methicillin resistant strains were coagulase negative Staphylococci. The drug resistance rate was as high as 80.95% (51/63). Most of the coagulase negative Staphylococci were Staphylococcus epidermidis and 33 strains of Staphylococcus epidermidis were isolated. Gram negative bacteria were isolated as follows:3 strains of Enterobacter cloacae, 2 strains of Pseudomonas aeruginosa, 2 strains of Klebsiella pneumoniae, 2 strains of Escherichia coli, one strain of Bacillus typhi suis, one strain of Acinetobacter baumannii and one strain of Pseudomonas oryzihabitans. One of the two strains of Escherichia coli was extended spectrum beta lactamases (ESBLs) producing strain.Gram positive bacteria isolated were sensitive to vancomycin, linezolid, daptomycin and tigecycline and the rate of susceptibility was 100%. The rate of susceptibility to rifampicin was 95.52% and the rate of susceptibility to ampicillin was only 4.00%. The rate of susceptibility of Gram negative bacteria to meropenem, cefepime and ceftazidime was 85.71%,69.23% and 76.92% respectively.Among the 73 patients operated in our hospital, the rate of prophylactic antibiotics and glucocorticoid in peroperative period were 57.53% and 42.47% respectively. And 57.53% of the patients were with adjuvant corticosteroids after neurosurgery. 73 patients (91.25%) were treated with empirical antibiotics before cerebrospinal fluid culture results came out. The empirical application of glycopeptide antibiotics was carried out in 34 patients. Only one patient was with intrathecal treatment.One patient died of respiratory and circulatory failure, 9 patients were at automatic discharge and the other 70 patients were cured or improved at discharge. The mortality rate was 1.25%.【Conclusions】1. All the patients had predisposing factors of NBM and neurosurgical interventions were the major predisposing conditions.2. The onset of NBM was insidious and the clinical manifestation was not typical.3. Coagulase negative Staphylococci were the mainly isolated bacteria of NBM which constituted majorly by methicillin-resistant coagulase negative Staphylococci.4. The drug resistance rate of coagulase negative Staphylococci was high. The susceptibility to vancomycin, linezolid, daptomycin and tigecycline was satisfactory and no drug resistance was found.5. The choice of empirical antibiotics was vancomycin plus meropenem. |
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