Derivation of a metabolic signature associated with bacterial meningitis in infants.

BACKGROUND: Diagnosis of bacterial meningitis (BM) is challenging in newborn infants. Presently, biomarkers of BM have limited diagnostic accuracy. Analysis of cerebrospinal fluid (CSF) metabolites may be a useful diagnostic tool in BM. METHODS: In a nested case-control study, we examined >400 metabolites in CSF of uninfected infants and infants with culture-confirmed BM using gas and liquid chromatography mass spectrometry. Preterm and full-term infants in a Level III or IV Neonatal Intensive Care Unit were prospectively enrolled when evaluated for serious bacterial infection. RESULTS: Over 200 CSF metabolites significantly differed in uninfected infants and infants with BM. Using machine learning, we found that as few as 6 metabolites distinguished infants with BM from uninfected infants in this pilot cohort. Further analysis demonstrated three metabolites associated with Group B Streptococcal meningitis. CONCLUSIONS: We report the first comprehensive metabolic analysis of CSF in infants with BM. In our pilot cohort, we derived a metabolic signature that predicted the presence or absence of BM, irrespective of gestational age, postnatal age, sex, race and ethnicity, presence of neurosurgical hardware, white blood cell count in CSF, and red blood cell contamination in CSF. Metabolic analysis may aid diagnosis of BM and facilitate clinical decision-making in infants. IMPACT: In a pilot cohort, metabolites in cerebrospinal fluid distinguished infants with bacterial meningitis from uninfected infants.We report the first comprehensive metabolic analysis of cerebrospinal fluid in infants with bacterial meningitis.Our findings may be used to improve diagnosis of bacterial meningitis and to offer mechanistic insights into the pathophysiology of bacterial meningitis in infants.

The Influence of Gender and Underrepresented Minority Status on Medical Student Ranking of Residency Programs.

BACKGROUND: Physician diversity is linked to improved quality of care of diverse patient populations. The transition from medical school to residency is an opportunity to improve and increase workforce diversity in all specialties. However, there is limited published literature on the factors contributing to the ranking of residency programs on women and underrepresented minorities (URMs). OBJECTIVE: To characterize factors medical students used to rank residency programs and describe any differences based on race/ethnicity or gender. METHODS: A mixed-methods study consisting of a web-based survey and semi-structured interviews with National Resident Matching Program (NRMP) participating graduates over a two-year period. The survey assessed demographics and a 6-point Likert scale rating of various factors used to rank residency programs. Unpaired student t-tests were used to compare means. A subset of students was interviewed and a modified grounded theory approach identified decision-making themes as well as the role of gender and URM status. RESULTS: Out of a total of 316 invitations sent, 148 completed the survey (46.8% response rate), of which 21% of respondents self-identified as URMs. The majority of respondents graduated in 2014 (53%), and were male (51%). Participants ranked program atmosphere, reputation, location, and proximity to family the highest. URM students ranked patient population (p < 0.01), revisit opportunities (p = 0.04), gender diversity (p < 0.01), and ethnic diversity (p < 0.01) significantly higher than non-URM students. Female students ranked patient population (p < 0.01) and gender diversity (p < 0.01) significantly higher than males. Qualitative findings revealed differences in perceptions by URMs and non-URMs of patient population, revisit opportunities, gender diversity, and ethnic diversity. CONCLUSIONS: While all students prioritized pragmatic factors, women and URM students assess and weigh additional factors related to culture, inclusion, and diversity more than others. By tailoring recruitment strategies to meet the expectations of women and URMs, residency programs can better meet goals in becoming more diverse and inclusive.

Elevations of novel cytokines in bacterial meningitis in infants.

BACKGROUND: Bacterial meningitis is challenging to diagnose in infants, especially in the common setting of antibiotic pre-treatment, which diminishes yield of cerebrospinal fluid (CSF) cultures. Prior studies of diagnostic markers have not demonstrated sufficient accuracy. Interleukin-23 (IL-23), interleukin-18 (IL-18) and soluble receptor for advanced glycation end products (sRAGE) possess biologic plausibility, and may be useful as diagnostic markers in bacterial meningitis. METHODS: In a prospective cohort study, we measured IL-23, IL-18 and sRAGE levels in CSF. We compared differences between infected and non-infected infants, and conducted receiver operating characteristic (ROC) analyses to identify individual markers and combinations of markers with the best diagnostic accuracy. RESULTS: 189 infants <6 months, including 8 with bacterial meningitis, 30 without meningitis, and 151 with indeterminate diagnosis (due to antibiotic pretreatment) were included. CSF IL-23, IL-18 and sRAGE levels were significantly elevated in infants with culture proven meningitis. Among individual markers, IL-23 possessed the greatest accuracy for diagnosis of bacterial meningitis (area under the curve (AUC) 0.9698). The combination of all three markers had an AUC of 1. CONCLUSIONS: IL-23, alone and in combination with IL-18 and sRAGE, identified bacterial meningitis with excellent accuracy. Following validation, these markers could aid clinicians in diagnosis of bacterial meningitis and decision-making regarding prolongation of antibiotic therapy.

Cerebrospinal fluid cytokines in the diagnosis of bacterial meningitis in infants.

BACKGROUND: Bacterial meningitis poses diagnostic challenges in infants. Antibiotic pretreatment and low bacterial density diminish cerebrospinal fluid (CSF) culture yield, while laboratory parameters do not reliably identify bacterial meningitis. Pro and anti-inflammatory cytokines are elevated in bacterial meningitis and may be useful diagnostic adjuncts when CSF cultures are negative. METHODS: In a prospective cohort study of infants, we used cytometric bead arrays to measure tumor necrosis factor alpha (TNF-α), interleukin 1 (IL-1), IL-6, IL-8, IL-10, and IL-12 in CSF. Receiver operating characteristic (ROC) analyses and Principal component analysis (PCA) were used to determine cytokine combinations that identified bacterial meningitis. RESULTS: Six hundred and eighty four infants < 6 mo were included; 11 had culture-proven bacterial meningitis. IL-6 and IL-10 were the individual cytokines possessing greatest accuracy in diagnosis of culture proven bacterial meningitis (ROC analyses; area under the concentration-time curve (AUC) 0.91; 0.9103 respectively), and performed as well as, or better than combinations identified using ROC and PCA. CSF cytokines were highly correlated with each other and with CSF white blood cell count (WBC) counts in infants with meningitis. A subset of antibiotic pretreated culture-negative subjects demonstrated cytokine patterns similar to culture positive subjects. CONCLUSION: CSF cytokine levels may aid diagnosis of bacterial meningitis, and facilitate decision-making regarding treatment for culture negative meningitis.

Risk factors associated with laboratory-confirmed bloodstream infections in a tertiary neonatal intensive care unit.

BACKGROUND: Bloodstream infections (BSI) remain a leading cause of morbidity and mortality among infants admitted to neonatal intensive care units (NICUs). At the time of evaluation for suspected BSI, presenting signs may be nonspecific. We sought to determine the clinical signs and risk factors associated with laboratory-confirmed BSI among infants evaluated for late-onset sepsis in a tertiary NICU. METHODS: This prospective cohort study included infants >3 days of age admitted to a level 4 NICU from July 2006 to October 2009 for whom a blood culture was drawn for suspected sepsis. Clinicians documented presenting signs at the time of culture. Laboratory-confirmed BSI was defined as per the National Healthcare Safety Network. Multivariate analyses were performed using a logistic regression random effects model. RESULTS: Six-hundred and eighty eligible episodes of suspected BSI were recorded in 409 infants. Enteral contrast within the preceding 48 hours was the most significant risk factor for laboratory-confirmed BSI [Odds Ratio: 9.58 (95% confidence interval: 2.03-45.19)] followed by presence of a central venous catheter. Apnea and hypotension were the most strongly associated presenting signs. CONCLUSION: Among infants evaluated in a tertiary NICU, recent exposure to enteral contrast was associated with increased odds of developing BSI. Apnea and hypotension were the most strongly associated clinical signs of infection.

Traumatic lumbar punctures in infants hospitalized in the neonatal intensive care unit.

Traumatic lumbar punctures occur frequently in the neonatal intensive care unit, making the interpretation of cerebrospinal fluid values difficult. We report correction factors for cerebrospinal fluid protein and white blood cells in the face of red blood cell contamination. These correction factors should facilitate the diagnosis of bacterial meningitis in highrisk hospitalized infants.

Lumbar puncture in the neonate: challenges in decision making and interpretation.

Multiple studies have provided normative ranges for cerebrospinal fluid (CSF) parameters in term and preterm infants and described changes with advancing postnatal age, as well as in special circumstances, such as traumatic lumbar puncture (LP), previous antibiotic administration, seizures, and concomitant infections at other sites. Although guidelines exist for the interpretation of CSF parameters in neonates, there appears to be no single combination of parameters that conclusively excludes meningitis. It remains important for clinicians to perform LPs early in the course of illness, ideally before the administration of antibiotic therapy. This review presents currently available literature on the indications for LP as well as guidelines for the interpretation of CSF parameters in neonates.

Can broad-range 16S ribosomal ribonucleic acid gene polymerase chain reactions improve the diagnosis of bacterial meningitis? A systematic review and meta-analysis.

STUDY OBJECTIVE: We aim to evaluate the accuracy of the broad-range 16S polymerase chain reaction test in the diagnosis of bacterial meningitis through a systematic review and meta-analysis. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Registry, using the Medical Subject Headings terms "polymerase chain reaction," "RNA, ribosomal, 16S," and "bacterial meningitis." For our primary analysis, we examined the 16S polymerase chain reaction in culture-proven bacterial meningitis. In ancillary observations, we included studies of culture-negative presumed bacterial meningitis, in which there was high clinical suspicion for bacterial meningitis despite negative cerebrospinal fluid culture results. We extracted information necessary to calculate sensitivity and specificity and used bivariate hierarchic modeling meta-analysis methods to obtain pooled statistics. We also estimated potential sources of error and bias such as between-study heterogeneity and publication bias. RESULTS: Fourteen of 299 studies met inclusion criteria for culture-proven bacterial meningitis; 448 (16.1%) of 2,780 subjects had positive cerebrospinal fluid culture results. Pooled analysis demonstrated a sensitivity of 92% (95% confidence interval [CI] 75% to 98%), specificity of 94% (95% CI 90% to 97%), positive likelihood ratio of 16.26 (95% CI 9.07 to 29.14), and negative likelihood ratio of 0.09 (95% CI 0.03 to 0.28) for culture-proven bacterial meningitis. The polymerase chain reaction test result was also positive in 30% of cases of culture-negative presumed bacterial meningitis. There was significant heterogeneity between studies. CONCLUSION: This meta-analysis supports the role of 16S ribosomal ribonucleic acid polymerase chain reaction as a diagnostic tool in bacterial meningitis. With further refinements in technology, the polymerase chain reaction test has the potential to become a useful adjunct in the diagnosis of bacterial meningitis in the emergency department.

Cerebrospinal fluid reference ranges in term and preterm infants in the neonatal intensive care unit.

OBJECTIVE: To determine reference ranges of cerebrospinal fluid (CSF) laboratory findings in term and preterm infants in the neonatal intensive care unit. STUDY DESIGN: Data were collected prospectively as part of a multisite study of infants aged <6 months undergoing lumbar puncture for evaluation of suspected sepsis. Infants with a red blood cell count >500 cells/µL or a known cause of CSF pleocytosis were excluded from the analysis. RESULTS: A total of 318 infants met the inclusion criteria. Of these, 148 infants (47%) were preterm, and 229 (72%) received antibiotics before undergoing lumbar puncture. The upper reference limit of the CSF white blood cell (WBC) count was 12 cells/µL in preterm infants and 14 cells/µL in term infants. CSF protein levels were significantly higher in preterm infants (upper reference limit, 209 mg/dL vs 159 mg/dL in term infants; P < .001), and declined with advancing postnatal age in both groups (preterm, P = .008; term, P < .001). CSF glucose levels did not differ in term and preterm infants. Antibiotic exposure did not significantly affect CSF WBC, protein, or glucose values. CONCLUSIONS: CSF WBC counts are not significantly different in preterm and term infants. CSF protein levels are higher and decline more slowly with postnatal age in preterm infants compared with term infants. This study provides CSF reference ranges for hospitalized preterm and term infants, particularly in the first month of life.

New technologies for the rapid diagnosis of neonatal sepsis.

PURPOSE OF REVIEW: To present recent literature on novel diagnostic tests in neonatal sepsis. RECENT FINDINGS: Our review of technologies for the rapid diagnosis of neonatal sepsis includes new adaptations of time-honored tests as well as advances on the forefront of medicine. A recent study demonstrates that age-specific likelihood values for the complete blood count may determine risk of infection. Systematic reviews of procalcitonin, mannose-binding lectin and molecular amplification techniques provide summary data from accumulated literature on these tests. Proteomics-based and genomics-based exploratory researches suggest new combinations of markers as important signals of sepsis, whereas damage-associated molecular patterns, a class of inflammatory mediators now viewed as key players in the inflammatory cascade, may be useful predictors of disease progression and severity. Heart rate variability monitoring has also been suggested as a way to reduce mortality in very low birth weight neonates. Finally, molecular techniques are rapidly advancing in sophistication and may soon be useful as adjunctive bacterial identification tests. SUMMARY: Several novel tests show promise in the early detection of sepsis. Highlights include new combinations of biomarkers unearthed by proteomics-based research and identification of sepsis based on gene expression profiling. Future research should focus on validation of these findings and further refinement of molecular techniques.

Broad-range bacterial polymerase chain reaction in the microbiologic diagnosis of complicated pneumonia.

BACKGROUND: A bacterial cause is not frequently identified in children with pneumonia complicated by parapneumonic effusion (ie, complicated pneumonia). OBJECTIVES: To determine the frequency of positive blood and pleural fluid cultures in children with complicated pneumonia and to determine whether broad-range 16S rRNA polymerase chain reaction (PCR) improves identification of a microbiologic cause. METHODS: This prospective cohort study included children 1-18 years of age hospitalized with complicated pneumonia. RESULTS: Pleural fluid drainage was performed in 64 (51.6%) of 124 children with complicated pneumonia. A microbiologic cause was identified in 11 of 64 patients (17.2%; 95% confidence interval [CI]: 8.9%-28.7%). Bacteria were isolated from pleural fluid culture in 6 of 64 patients (9.4 %; 95% CI: 3.5%-19.3%) undergoing pleural drainage; the causative bacteria were Staphylococcus aureus (n = 5) and Streptococcus pneumoniae (n = 1). Blood culture identified a bacterial cause in 3 of 44 cases (6.8%; 95% CI: 1.4%-18.7%) undergoing pleural fluid drainage; S. pneumoniae (n = 1), Haemophilus influenzae (n = 1), and S. aureus (n = 1) were isolated. Only 3 of the 19 pleural fluid samples (15.8%; 95% CI: 3.4%-39.6%) analyzed with 16S rRNA PCR were positive. S. pneumoniae was the only organism detected in all three samples; two of these three had negative pleural fluid cultures and absence of bacteria on Gram stain. S. aureus was isolated from pleural fluid culture in one patient with a negative 16S rRNA PCR test. CONCLUSIONS: Causative bacteria were infrequently identified in children with complicated pneumonia. Broad-range 16S rRNA PCR only modestly improved the microbiologic yield over conventional culture methods.