Cerebrospinal Fluid WBC Research Articles

Safety and effectiveness of dual channels vancomycin administration in the treatment of intracranial infection after severe brain injury surgery.

To observe the clinical efficacy and safety of vancomycin intravenous drip combined with vancomycin intrathecal injection in the treatment of intracranial infection after severe brain injury surgery. From January 2020 to June 2022, 80 patients with intracranial infection after severe brain injury surgery were selected and randomly divided into 2 subgroups; there were 40 patients in each subgroup. All patients were treated with vancomycin. The control subgroup was medicated with intravenous drip, and the observation subgroup was treated through 2 channels (intravenous drip + intrathecal injection), with a course of 7 days. The clinical efficacy, intracranial pressure, infection control time, routine indexes of cerebrospinal fluid (white blood cell count [WBC], glucose content [Glu], and total protein content [Pro]) and the incidence of adverse reactions were contrasted between the 2 subgroups. Versus the control subgroup, the total effective rate in the observation subgroup was notably higher (95.00% vs 77.50%). After treatment, aiming at the intracranial pressure and infection control time, versus the control subgroup (146.20 ± 22.37) mmH2O and (9.86 ± 1.62) days, the observation subgroup were (125.43 ± 18.5) mmH2O and (7.35 ± 1.57) days respectively, which were notably lower. After treatment, versus the control subgroup, the concentrations of WBC and Pro in cerebrospinal fluid in the observation subgroup were lower, and the content of Glu was higher. There was no statistical distinction in the incidence of adverse reactions between the 2 subgroups (17.50% vs 10.00%). Two-channel administration of vancomycin can improve the clinical efficacy of internal infection after severe craniocerebral injury, reduce intracranial pressure, and cerebrospinal fluid WBC and Pro levels, and has high safety.

Cerebrospinal Fluid IL-6 Plus IL-10 As Effective Diagnostic Biomarkers for Secondary Central Nervous System Lymphoma

Background : Secondary central nervous system lymphoma (SCNSL) characterized by the involvement of the CNS at initial diagnosis of systemic lymphoma or in the setting of relapse. Accurate diagnosis and therapeutic response of SCNSL are particular challenges, which need to be improved. We aimed to evaluate the diagnostic and the post-therapeutic prognostic value of cerebrospinal fluid (CSF) cytokine in patients with SCNSL. Methods: In this retrospective study involving 234 NHL patients and 53 other CNS patients, the NHL patients was divided into two sub-groups based on with and without CNS involvement: SCNSL (n=57) and non-SCNSL (n=177). The CSF cytokine profiles (interleukin (IL)-2, -4, -6, and -10, tumor necrosis factor-α, interferon-γ, and IL-17A) of these patients were measured by cytometric bead assay and evaluated the ability of CSF cytokine levels as diagnostic, therapeutic and prognostic biomarkers for SCNSL. Results: CSF IL-6 and IL-10 levels were significantly higher in SCNSL patients than non-SCNSL and other CNS patients. CSF levels of IL-6 and IL-10 were significantly higher in patients with an stage at Ⅲ and Ⅳ, CSF WBC counts>5/µL, CSF protein ≥0.45g/L.Using a CSF IL-6 cut-off value of 10.13 pg/ml yielded a diagnostic sensitivity and specificity was 62.34% and 87.57%, respectively (AUC, 0.7798; 95% CI, 0.7083 to 0.8514); For a CSF IL-10 cutoff value of 7.82, the sensitivity was 76.23%, and the specificity was 98.31% (AUC, 0.8164; 95% CI, 0.7466 to 0.8862). Combined CSF IL-6 and IL-10 significantly improved the diagnostic effect of SCNSL (AUC, 0.8959; 95% CI, 0.8371 to 0.9547). The levels of IL-6 and IL-10 in cerebrospinal fluid of SCNSL patients who responded to intrathecal chemotherapy were significantly decreased during follow-up, while the levels of these two cytokines showed fluctuating changes in patients with progressive SCNSL. Moreover, poor Progression free survival (PFS) for patients with SCNSL was associated with the increased CSF IL-10 level at diagnosis with CNS involvement (P=0.035), but not with the increased CSF IL-6 level. Conclusion: Our study confirmed CSF level of IL-6 and IL-10 were potentially effective diagnostic biomarkers for SCNSL, and poor progression free survival (PFS) for patients with SCNSL was associated with the increased CSF IL-10 level.

1027. Cerebrospinal Fluid Findings of Solid Organ Transplant Recipients with West Nile Virus Infections

Abstract Background In the solid organ transplant (SOT) population, West Nile virus (WNV) neuroinvasive disease can have significant morbidity and mortality. We evaluated cerebrospinal fluid (CSF) findings in neuroinvasive WNv infections among SOT recipients. Methods We retrospectively reviewed medical records of all SOT recipients at our institution with WNv neuroinvasive disease (meningitis, encephalitis, meningo-encephalitis) from 2010 to 2018. Descriptive statistics were examined on key variables. Results Eight transplant patients with mean age 54.47 years (12.79) were included: 5 kidney transplants, 1 in each kidney-pancreas, liver and lung transplants. Median time from transplant to infection was 49.8 months (2.7-175.4) and mean time-to-diagnosis 2 days (1.31) . On admission, mean total CSF WBC count was 134.57 cells/mm3 (150.82), mean lymphocyte count 56.29 cells/mm3 (32.32), mean neutrophil count 27.14 cells/mm3 (34.34), and mean CSF protein 95.4 mg/dL (40.52mg/dL). West Nile virus CSF IgG at the time of diagnosis was negative in 7 patients, and not performed on 1 patient. WNv diagnosis is depicted below. Serum and CSF WNV Antibodies in Neuroinvasive Disease in SOT Recipients WNV CSF and serum IgG was negative at the time of diagnosis in 7/8 patients. Initial CSF IgM was positive in 3 out of 7 patients. Conclusion WNv infection produces a CSF pleocytosis with neutrophilic predominance, though we noted more lymphocytic predominance among SOT recipients. CSF IgM and IgG are important diagnostics in neuroinvasive WNv. Disclosures Diana F. Florescu, MD, AlloVir: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|NobelPharma: Grant/Research Support|Novavax: Grant/Research Support|Regeneron: Grant/Research Support|SymBio: Grant/Research Support|Takeda: Advisor/Consultant|Takeda: Grant/Research Support.

Risk Factors and Outcomes of Central Nervous System Infection After Spinal Surgery: A Retrospective Cohort Study

To investigate the risk factor associated with central nervous system infection, a rare and dire complication after spinal surgery. Univariate and multivariate logistic regression analyses were performed to screen for the independent risk factors. According to the different administration methods of antibiotics, patients were divided into intravenous and intrathecal groups. The differences in time needed for body temperature, white blood cells (WBC), and C-reactive protein (CRP) to return to normal and the time of antibiotic application were compared between the 2 groups. In addition, the differences in WBC, neutrophil ratio, CRP, procalcitonin in blood, and WBC in cerebrospinal fluid were compared before intrathecal injection, after the first one, and the last one. The incidence of complications in the 2 groups was observed. Dural tears, laminectomy, and operation time >3 hours were identified as independent risk factors. The time needed for body temperature, WBC, and CRP to return to normal and the antibiotic application time were significantly different between the 2 groups (all P < 0.05). Before and after the first intrathecal injection and after the last intrathecal injection, the differences in WBCs, neutrophil ratios, CRP, procalcitonin in blood, and cerebrospinal fluid-WBC were statistically significant in overall and pairwise comparisons (P < 0.05). Complications occurred in 2 and 14 cases, respectively. The independent risk factors for central nervous system infection after spinal surgery were a dural tear, laminectomy, and operation time > 3 hours. Combined intravenous and intrathecal injections of antibiotics led to a better effect than intravenous injection alone; however, this approach was associated with more complications.

Reference range for cerebrospinal fluid values in neonates: 5-year retrospective study

Background Cerebro spinal fluid (CSF) parameters (white blood cell count, protein, glucose) in the diagnosis of neonatal bacterial meningitis Objectives To report the reference range of CSF parameters (white blood cell count, protein, glucose) in both term and preterm infants. Methods This was a single center retrospective study over a period of 5 years (2015–2020). We included infants aged 0–3 months admitted to the neonatal unit and infants ≤28 days attending pediatric acute care and who underwent Lumbar Puncture. We excluded infants with evidence of CSF bacteremia, viral infection and traumatic lumbar puncture defined as CSF Red Blood Cell >500 cells/µL. Clinical, demographic, and microbiological data were collected from the hospital database. The study was approved by ethics committee. Results We identified a total of 518 CSF samples, with 232 CSF samples available for final analysis. 54% of excluded samples were traumatic. Median birth gestation and birth weight of the study cohort were 38 (IQR 35–40) weeks and 3030 (IQR 1965–3565) grams respectively. Median RBC, WBC count, protein and glucose were 15 (IQR 3–85)/µL, 3(IQR 0–8.5)/µL, 0.72 (0.53–1.06) g/L and 2.8 (2.4–3.3) mmol/L respectively. There was no difference in CSF WBC cell count between preterm and term infants. Higher CSF protein content was noted in preterm infants and infants in the first 7 days of life. Use of antibiotics prior to LP was associated with higher CSF protein. Presence of any CSF RBC (including <500 cells/µL) influenced the CSF WBC count and protein content. Conclusion We have provided a reference range of CSF parameters in neonates without meningitis. CSF WBC count between preterm and term infants were similar with higher CSF protein content in preterm infants and for infants in the first seven days of life. Presence of any CSF RBC influenced CSF parameters.

Recurrence of Symptoms Following Cryptococcal Meningitis: Characterizing a Diagnostic Conundrum With Multiple Etiologies.

Cryptococcal meningitis is a common cause of AIDS-related mortality. Although symptom recurrence after initial treatment is common, the etiology is often difficult to decipher. We sought to summarize characteristics, etiologies, and outcomes among persons with second-episode symptomatic recurrence. We prospectively enrolled Ugandans with cryptococcal meningitis and obtained patient characteristics, antiretroviral therapy (ART) and cryptococcosis histories, clinical outcomes, and cerebrospinal fluid (CSF) analysis results. We independently adjudicated cases of second-episode meningitis to categorize patients as (1) microbiological relapse, (2) paradoxical immune reconstitution inflammatory syndrome (IRIS), (3) persistent elevated intracranial pressure (ICP) only, or (4) persistent symptoms only, along with controls of primary cryptococcal meningitis. We compared groups with chi-square or Kruskal-Wallis tests as appropriate. 724 participants were included (n = 607 primary episode, 81 relapse, 28 paradoxical IRIS, 2 persistently elevated ICP, 6 persistent symptoms). Participants with culture-positive relapse had lower CD4 (25 cells/μL; IQR: 9-76) and lower CSF white blood cell (WBC; 4 cells/μL; IQR: 4-85) counts than paradoxical IRIS (CD4: 78 cells/μL; IQR: 47-142; WBC: 45 cells/μL; IQR: 8-128). Among those with CSF WBC <5 cells/μL, 86% (43/50) had relapse. Among those with CD4 counts <50 cells/μL, 91% (39/43) had relapse. Eighteen-week mortality (from current symptom onset) was 47% among first episodes of cryptococcal meningitis, 31% in culture-positive relapses, and 14% in paradoxical IRIS. Poor immune reconstitution was noted more often in relapse than IRIS as evidenced by lower CSF WBC and blood CD4 counts. These easily obtained laboratory values should prompt initiation of antifungal treatment while awaiting culture results. NCT01802385.

Association of Cerebrospinal Fluid Parameters and Neurofilament Light Chain With Retinal Nerve Fiber Layer Thickness in Multiple Sclerosis.

IntroductionMultiple sclerosis (MS) pathophysiology comprises both inflammatory and neurodegenerative characteristics. Cerebrospinal fluid (CSF) analysis allows for assessment of inflammation while neurofilament light chain can indicate neuroaxonal damage. Retinal thinning is a robust prognostic biomarker for neurodegeneration in MS. To date, an association between CSF parameters upon MS diagnosis and retinal thinning has not been investigated.Aims and ObjectivesWe aimed to determine whether CSF parameters are associated with the evolution of retinal layer thinning in people with MS (pwMS).MethodsFor this longitudinal observational study, we investigated pwMS from the Vienna MS database (VMSD), who had undergone (1) a diagnostic lumbar puncture (LP) between 2015 and 2020, and (2) simultaneous optical coherence tomography (OCT) and/or (3) a follow-up OCT scan. Linear stepwise regression models were calculated with OCT parameters (peripapillary retinal nerve fiber layer [pRNFL] thickness at LP and at follow-up, annualized loss of pRNFL thickness [aLpRNFL]) as a dependent variable, and CSF parameters (white blood cell [WBC] count, total protein [CSFTP], CSF/serum albumin ratio [Qalb], intrathecal synthesis of immunoglobulins, neurofilament light chain [NfL] in both CSF and serum [CSFNfL/sNfL]) as independent variables adjusted for age, sex, and disease duration.ResultsWe analyzed 61 pwMS (median age 30.0 years [interquartile range 25.5–35.0], 57.4% female, median disease duration 1.0 month [IQR 0–2.0] before LP, median follow-up 1.9 years [IQR 1.1–3.5]). CSFNfL and sNfL measurements were available in 26 and 31 pwMS, respectively. pRNFL thickness at LP was inversely associated with the CSF WBC count (β = −0.36; 95% CI −0.51, −0.08; p = 0.008). We did not find any association between other CSF parameters, including CSFNfL, sNfL, and aLpRNFL.ConclusionsIncreased WBC count as an indicator of acute inflammation and blood-brain-barrier breakdown seems to be associated with the amount of retinal thickness already lost at the time of LP. However, neither routine CSF parameters nor a singular NfL measurement allows the prediction of future retinal thinning.

Effect of antiretroviral treatment on blood-brain barrier integrity in HIV-1 infection

BackgroundBlood-brain barrier (BBB) injury is prevalent in patients with HIV-associated dementia (HAD) and is a frequent feature of HIV encephalitis. Signs of BBB damage are also sometimes found in neuroasymptomatic HIV-infected individuals without antiretroviral therapy (ART). The aim of this study was to investigate the integrity of the BBB before and after initiation of ART in both neuroasymptomatic HIV infection and in patients with HAD.MethodsWe determined BBB integrity by measuring cerebrospinal fluid (CSF)/plasma albumin ratios in archived CSF samples prior to and after initiation of ART in longitudinally-followed neuroasymptomatic HIV-1-infected individuals and patients with HAD. We also analyzed HIV RNA in blood and CSF, IgG Index, CSF WBC counts, and CSF concentrations of β2-micoglobulin, neopterin, and neurofilament light chain protein (NfL).ResultsWe included 159 HIV-infected participants; 82 neuroasymptomatic individuals and 77 with HAD. All neuroasymptomatic individuals (82/82), and 10/77 individuals with HAD, were longitudinally followed with a median (interquartile range, IQR) follow-up of 758 (230–1752) days for the neuroasymptomatic individuals, and a median (IQR) follow-up of 241 (50–994) days for the individuals with HAD. Twelve percent (10/82) of the neuroasymptomatic individuals and 80% (8/10) of the longitudinally-followed individuals with HAD had elevated albumin ratios at baseline. At the last follow-up, 9% (7/82) of the neuroasymptomatic individuals and 20% (2/10) of the individuals with HAD had elevated albumin ratios. ART significantly decreased albumin ratios in both neuroasymptomatic individuals and in patients with HAD.ConclusionThese findings indicate that ART improves and possibly normalizes BBB integrity in both neuroasymptomatic HIV-infected individuals and in patients with HAD.

50. Evaluation of Discordant Results Between Filmarray Meningitis/encephalitis Panel and Conventional Testing in Pediatric Patients: A Multi-site Retrospective Cohort Study

BackgroundFilmArray Meningitis/Encephalitis Panel (ME panel) has a 11% false positive and 2.2% false negative rate compared to conventional testing. We aim to describe characteristics, treatment decisions and outcomes in pediatric patients with discordant results between ME panel and conventional testing.MethodsWe conducted a multisite (n=4) retrospective review of patients < 18 years with positive cerebrospinal fluid (CSF) results by ME panel or conventional testing (CSF culture, Herpes Simplex Virus [HSV] and enterovirus [EV] PCR) from time of local ME panel implementation to February 2019. We excluded CSF obtained for non-infectious reasons. Demographic and clinical data were extracted from electronic medical records. Comparison between concordant and discordant results were made using Mann-Whitney test for continuous and Fisher’s exact test for categorical variables.ResultsA total of 355 patients had at least 1 positive result. Baseline characteristics and pathogens are shown in Table 1 and 2. Of the 53 bacterial pathogens identifiable by ME panel, 31 (58%) had discordant results – 29 positive by ME panel only and 2 by culture only (both E.coli). Patients with bacterial pathogens identified by ME panel only had lower CSF WBC and protein but higher CSF glucose (Table 3). Five patients with bacteria identified on ME panel only were not treated as meningitis given lack of pleocytosis, no antibiotic pretreatment and negative repeat cultures. Of these, 4 recovered without complications but one had hypoxic encephalopathy.Two patients had HSV noted in ME panel but individual PCR negative. The first was a 13-day-old with typical skin lesions and positive surface swab. The other was a 6-day old only with CSF pleocytosis. Both had abnormal neuroimaging and were treated as true cases. Of 24 who had both EV PCR and ME panel, 7 were positive by ME panel only and 3 by PCR only.Table 1: Baseline Characteristics of the Study Population Table 2: Pathogens identified via CSF Culture, ME panel or Conventional PCR Table 3: Characteristics of Discordant Results for Bacterial Pathogens Tested in ME panel ConclusionMore than half of bacterial pathogens identified by ME panel did not have a corresponding positive CSF culture. No difference was noted by antibiotic pretreatment. Treatment decisions based on positive ME panel should be made in the appropriate clinical context. Likewise, a negative ME panel does not rule out infection especially when atypical organisms are suspected.Disclosures Krow Ampofo, MBChB, Merck (Grant/Research Support)

74 MULTICENTER VALIDATION OF CORRECTION FACTORS FOR CEREBROSPINAL FLUID LABORATORY VALUES IN YOUNG INFANTS WITH A TRAUMATIC LUMBAR PUNCTURE

Abstract Background The evaluation of fever among infants in the first months of life remains one of the most common problems in pediatric healthcare. Approximately 10% harbor potentially life-threatening infections including bacterial meningitis, frequently necessitating invasive cerebrospinal fluid (CSF) testing by lumbar puncture (LP). LPs are often traumatic leading to uninterpretable results and consequently, broad-spectrum antibiotic exposure and prolonged hospitalization. Several strategies have been proposed to identify low-risk infants with traumatic LPs, including recently-derived correction factors, however studies validating the safety and diagnostic utility of such approaches are lacking. Objectives To evaluate the test characteristics and misclassification rates of recently described ratio-based correction methods for the interpretation of CSF results among young infants with traumatic LPs. Design/Methods We undertook a multicenter cohort study of infants aged ≤60 days with a traumatic LP performed at two urban tertiary Pediatric hospitals from 2006 to 2018. Traumatic LPs were defined as CSF specimens with ≥10,000 RBCs/mm3, and for infants aged ≤28 days and 29-60 days, pleocytosis was defined as ≥20 and ≥10 WBC/mm3, respectively, and abnormal protein ≥1.15 and ≥0.89 g/L, respectively. CSF WBCs and protein were adjusted downward for traumatic LPs using RBC ratio-based correction methods (newly derived 877:1, commonly used 500 and 1000:1, peripheral RBC:WBC ratio, and newly derived 1000 RBCs:0.011g/L protein). Descriptive statistics are presented with sensitivity, specificity, and negative predictive values of unadjusted and adjusted CSF for predicting culture-proven bacterial meningitis. Results Of 4,912 LPs meeting inclusion criteria, 437 (8.9%) were traumatic, among which 4 (0.9%) were positive for bacterial meningitis. Compared to uncorrected CSF WBC counts, both 877 and 1000 correction factors classified fewer infants with pleocytosis (38.0% and 42.6% vs 81.7%). These correction factors both maintained 100% sensitivity and 100% negative predictive value, and performed with greater specificity for bacterial meningitis than the uncorrected WBC count (62.6% and 58.0% vs 18.5%). No infants with bacterial meningitis were misclassified using either 877 or 1000:1 correction factors. CSF 500:1 and peripheral RBC:WBC correction ratios performed with the lowest sensitivity and negative predictive values and both misclassified 1 infant with bacterial meningitis. Corrected CSF protein outperformed uncorrected protein in specificity (66.8% vs 33.9%), but did not add diagnostic value when used in combination with WBC correction ratios. Conclusion Correction of the CSF WBC count substantially reduced the number of infants classified with CSF pleocytosis. The newly-derived 877:1 correction factor performed with the best test characteristics, safely reclassifying nearly half of all infants with a traumatic LP. It may be appropriate to use a correction factor in the evaluation of CSF cell counts in traumatic LPs in order to more effectively risk-stratify febrile young infants, reduce antibiotic exposure and admission duration.

23. RETROSPECTIVE REVIEW OF ADULT PATIENTS WITH LEPTOMENINGEAL DISEASE SECONDARY TO MELANOMA AT MOFFITT CANCER CENTER: DIAGNOSIS, TREATMENT AND OUTCOMES

BACKGROUNDNearly 5–8% of solid cancers present with leptomeningeal disease (LMD). Patients with LMD have a dismal prognosis with survival measured in weeks-to-months. The pathophysiology of this devastating disease remains unknown.METHODSA retrospective chart review was performed of twenty-five adult patients with LMD due to melanoma who were enrolled in the MCC 50172 clinical trial between 05/26/2015 and 07/17/2018.RESULTSPatients had a median age 63 years (31–80) at diagnosis with LMD. Sixteen had confirmed LMD and five did not meet criteria for LMD, but had positive cerebrospinal fluid (CSF)-circulating tumor cells (CTC’s). Those with LMD had a median KPS of 70 (30–90) at presentation, and symptoms most commonly included altered mentation n=6 (37%), headaches n=4 (25%), focal weakness n=3 (19%), and paresthesia n=2 (12%). Eleven patients were diagnosed by MRI. Ten patients (62%) had positive CSF cytology on first attempt and fourteen (87%) on first-two attempts. Lumbar puncture mean OP was 29.4 cmH2O (18–65), with CSF WBC 21.8/cumm (SD 25.6), RBC 2942.5/cumm (SD 9056.1), and protein 187.6 mg/dL (SD 166.1). CSF-CTC’s CellSearch analysis had a sensitivity of 0.75 (12[12 + 4]) and specificity of 0.44 (4[4 + 5]); PPV 0.71 and NPV 0.50. Twelve patients with LMD had positive CSF-CTC’s. Prior to LMD diagnosis, patients were treated with immune checkpoint inhibitors (ICI’s) n=9 (56%), BRAF+/-MEK inhibitors n=5 (31%), and/or RT n=5 (31%). Patients with LMD were treated with Ommaya n=13 +VPS n=3, WBRT n=7, ICI’s n=5, BRAF+MEK inhibitors n=4, and IT topotecan. LMD patients had a median survival 3.27 months after diagnosis (0.30–39). Two patients outlived their counterparts by 21.1 and 39.0 months. The 2 long-term survivors were treated with WBRT and either ICI, pembrolizumab or ipilimumab+nivolumab.CONCLUSIONClinical studies in LMD can provide critical insights and help to develop improved guidelines and current therapies.

Comparison of Ventricular and Lumbar Cerebrospinal Fluid Composition.

ObjectiveCerebrospinal fluid (CSF) analysis is a common diagnostic tool used to evaluate diseases of the central nervous system (CNS). We sought to determine whether there is a difference between the composition of CSF sampled from an external ventricular drain (EVD) and lumbar drain (LD) and whether this made a difference in guiding therapeutic decisions.Patients and MethodsThis study was a retrospective analysis from a single neurosurgery service between the dates of January 2011 and April 2019. A total of 12,134 patients were screened. Inclusion criteria were ages 18-80 and the presence of both an EVD and LD. Exclusion criteria were not having both routes of CSF sampling and the inability to determine which samples originated from which compartment.ResultsSix patients underwent simultaneous spinal and ventricular routine CSF sampling <24 hours apart and were analyzed for their compositions. There were 42 samples, but only 20 paired EVD-LD samples that could be analyzed. When comparing the EVD and LD sample compositions, there were statistically significant differences in white blood cells (WBCs; p = 0.040), total protein (p = 0.042), and glucose (p = 0.043). Red blood cells (RBCs; p = 0.104) and polymorphonuclear leukocytes (PMN; p = 0.544) were not statistically significant. We found a statistically significant correlation between cranial and spinal CSF WBC (r = 0.944, p < 0.001), protein (r = 0.679, p = 0.001), and glucose (r = 0.805, p < 0.001). We also found that there was a significant correlation between CSF and serum glucose (r = 0.502, p = 0.040). There was no statistically significant correlation between RBCs (r = 0.276, p = 0.252).ConclusionOur results demonstrate a correlation between the cranial and spinal CSF samples, except for RBCs, with statistically significant differences in WBC, glucose, and protein values between the two sites. This confirms that sampling CSF via lumbar puncture, which carries less risk than a ventriculostomy and provides accurate data to help establish a diagnosis for intracranial pathologies.

Clinical application and evaluation of metagenomic next-generation sequencing in suspected adult central nervous system infection

BackgroundAccurate etiology diagnosis is crucial for central nervous system infections (CNS infections). The diagnostic value of metagenomic next-generation sequencing (mNGS), an emerging powerful platform, remains to be studied in CNS infections.MethodsWe conducted a single-center prospective cohort study to compare mNGS with conventional methods including culture, smear and etc. 248 suspected CNS infectious patients were enrolled and clinical data were recorded.ResultsmNGS reported a 90.00% (9/10) sensitivity in culture-positive patients without empirical treatment and 66.67% (6/9) in empirically-treated patients. Detected an extra of 48 bacteria and fungi in culture-negative patients, mNGS provided a higher detection rate compared to culture in patients with (34.45% vs. 7.56%, McNemar test, p < 0.0083) or without empirical therapy (50.00% vs. 25.00%, McNemar test, p > 0.0083). Compared to conventional methods, positive percent agreement and negative percent agreement was 75.00% and 69.11% separately. mNGS detection rate was significantly higher in patients with cerebrospinal fluid (CSF) WBC > 300 * 106/L, CSF protein > 500 mg/L or glucose ratio ≤ 0.3. mNGS sequencing read is correlated with CSF WBC, glucose ratio levels and clinical disease progression.ConclusionmNGS showed a satisfying diagnostic performance in CNS infections and had an overall superior detection rate to culture. mNGS may held diagnostic advantages especially in empirically treated patients. CSF laboratory results were statistically relevant to mNGS detection rate, and mNGS could dynamically monitor disease progression.

Performance of the Modified Boston and Philadelphia Criteria for Invasive Bacterial Infections.

The ability of the decades-old Boston and Philadelphia criteria to accurately identify infants at low risk for serious bacterial infections has not been recently reevaluated. We assembled a multicenter cohort of infants 29 to 60 days of age who had cerebrospinal fluid (CSF) and blood cultures obtained. We report the performance of the modified Boston criteria (peripheral white blood cell count [WBC] ≥20 000 cells per mm3, CSF WBC ≥10 cells per mm3, and urinalysis with >10 WBC per high-power field or positive urine dip result) and modified Philadelphia criteria (peripheral WBC ≥15 000 cells per mm3, CSF WBC ≥8 cells per mm3, positive CSF Gram-stain result, and urinalysis with >10 WBC per high-power field or positive urine dip result) for the identification of invasive bacterial infections (IBIs). We defined IBI as bacterial meningitis (growth of pathogenic bacteria from CSF culture) or bacteremia (growth from blood culture). We applied the modified Boston criteria to 8344 infants and the modified Philadelphia criteria to 8131 infants. The modified Boston criteria identified 133 of the 212 infants with IBI (sensitivity 62.7% [95% confidence interval (CI) 55.9% to 69.3%] and specificity 59.2% [95% CI 58.1% to 60.2%]), and the modified Philadelphia criteria identified 157 of the 219 infants with IBI (sensitivity 71.7% [95% CI 65.2% to 77.6%] and specificity 46.1% [95% CI 45.0% to 47.2%]). The modified Boston and Philadelphia criteria misclassified 17 of 53 (32.1%) and 13 of 56 (23.3%) infants with bacterial meningitis, respectively. The modified Boston and Philadelphia criteria misclassified a substantial number of infants 29 to 60 days old with IBI, including those with bacterial meningitis.

Cerebrospinal Fluid Profiles of Infants ≤60 Days of Age With Bacterial Meningitis.

We aimed to describe the cerebrospinal fluid (CSF) profiles of infants ≤60 days old with bacterial meningitis and the characteristics of infants with bacterial meningitis who did not have CSF abnormalities. We included infants ≤60 days old with culture-positive bacterial meningitis who were evaluated in the emergency departments of 11 children's hospitals between July 1, 2011, and June 30, 2016. From medical records, we abstracted clinical and laboratory data. For infants with traumatic lumbar punctures (CSF red blood cell count of ≥10 000 cells per mm3), we used a red blood cell count/white blood cell (WBC) count correction factor of 1000:1 to determine the corrected CSF WBC count. We calculated the sensitivity for bacterial meningitis of a CSF Gram-stain and corrected CSF pleocytosis (≥16 WBCs per mm3 for infants ≤28 days old and ≥10 WBCs per mm3 for infants 29-60 days old). Among 66 infants with bacterial meningitis, the sensitivity of a CSF Gram-stain was 71.9% (95% confidence interval [CI]: 59.2-82.4), and the sensitivity of corrected CSF pleocytosis was 80.3% (95% CI: 68.7-89.1). The sensitivity of combining positive Gram-stain results with corrected CSF pleocytosis was 86.4% (95% CI: 75.7-93.6). Of 9 infants with meningitis who had a negative Gram-stain result and no corrected CSF pleocytosis, 8 (88.9%) had either an abnormal peripheral WBC count (>15 000 or <5000 cells per μL) or bandemia >10%. Most infants ≤60 days old with bacterial meningitis have CSF pleocytosis or a positive Gram-stain result. Infants with no CSF pleocytosis and a negative Gram-stain result are unlikely to have bacterial meningitis in the absence of other laboratory abnormalities.

Implementation of an Algorithmic Approach to Molecular Infectious Disease Laboratory Testing on Cerebrospinal Fluid Samples

Abstract Rapid turnaround time for infectious disease laboratory testing is critical for the encephalitic/meningitic patient. Clinicians and emergency medicine providers often will bundle cerebrospinal fluid (CSF) studies (cell counts, glucose, protein) with molecular infectious disease laboratory (MIDL) assays, up front, to expedite clinical decision making about antimicrobial therapy and hospital admission. Many patients, however, ultimately do not have CSF pleocytosis and, predictably, have negative MIDL results. We quantified patients who had MIDL testing ordered, without concurrent CSF pleocytosis, to justify a mandated algorithm for CSF MIDL testing. Four months of MIDL CSF results were reviewed (viral monoplex PCRs); 274 patients were identified. Forty-seven percent of patients (128/274) were neonates (&lt;2 months old) and thus may not have had the immunologic capacity to mount a pleocytosis to CNS infection. Of the remaining 53% of patients (&gt;2 months old), who would have been expected to generate a CSF pleocytosis, 55% (81/146) had one or more MIDL studies ordered without CSF pleocytosis; 3.4% of these patients (5/146) did not have CSF cell counts ordered. Among all patients, 7.7% (21/274) had positive MIDL results (1 HSV1; 2 HSV2; 18 enterovirus). Seventeen patients had CSF pleocytosis; the 4 patients without CSF pleocytosis were neonates (3) or had no cell counts ordered (1). A ratio of 700 RBC to 1 WBC was used to approximate the expected number of CSF WBC in bloody taps (10%; 28/274). We show that over half of patients &gt;2 months old had MIDL studies ordered without CSF pleocytosis; all patients with positive MIDL results had CSF pleocytosis or were neonates or had no cell counts ordered. An algorithm will be implemented in which all neonates with concern for CNS infection will have CSF MIDL tests ordered; among nonneonates, only those with documented CSF pleocytosis may have MIDL assays ordered (with rare exceptions; eg, leukopenia).

Utility of chemokines CCL2, CXCL8, 10 and 13 and interleukin 6 in the pediatric cohort for the recognition of neuroinflammation and in the context of traditional cerebrospinal fluid neuroinflammatory biomarkers.

BackgroundThe recognition of active inflammation in the central nervous system (CNS) in the absence of infectious agents is challenging. The present study aimed to determine the diagnostic relevance of five selected chemo/cytokines in the recognition of CNS inflammation and in the context of traditional cerebrospinal fluid (CSF) biomarkers (white blood cell [WBC] counts, oligoclonal bands, protein levels, CSF/serum albumin ratios) and clinical diagnoses.MethodsC-C and C-X-C motif ligands (CCL2, CXCL8, 10 and 13) and interleukin (IL) 6 levels in the CSF and serum from 37 control and 87 symptomatic children with ten different (mostly noninfectious) inflammatory CNS disorders (16 of which had follow-up samples after recovery) were determined using Luminex multiple bead technology and software. Nonparametric tests were used; p < 0.05 was considered statistically significant. Receiver operating characteristic curves were constructed to analyze controls and 1) all symptomatic samples or 2) symptomatic samples without CSF pleocytosis.ResultsCompared with the control CSF samples, levels of all investigated chemo/cytokines were increased in symptomatic CSF samples, and only IL-6 remained elevated in recovery samples (p ≤ 0.001). CSF CXCL-13 levels (> 10.9 pg/mL) were the best individual discriminatory criterion to differentiate neuroinflammation (specificity/sensitivity: 97/72% and 97/61% for samples without pleocytosis), followed by CSF WBC counts (specificity/sensitivity: 97/62%). The clinical utility of the remaining CSF chemo/cytokine levels was determined in descending order of sensitivities corresponding to thresholds that ensured 97% specificity for neuroinflammation in samples without pleocytosis (pg/mL; sensitivity %): IL-6 (3.8; 34), CXCL8 (32; 26), CXCL10 (317; 24) and CCL2 (387; 10). Different diagnosis-related patterns of CSF chemo/cytokines were observed.ConclusionsThe increased CSF level of CXCL13 was the marker with the greatest predictive utility for the general recognition of neuroinflammation among all of the individually investigated biomarkers. The potential clinical utility of chemo/cytokines in the differential diagnosis of neuroinflammatory diseases was identified.

Human adenovirus meningoencephalitis: a 3-years' overview.

Human adenovirus (HAdV) has been recognized as a significant viral pathogen implicated in neurological diseases, particularly in immunocompromised patients. However, its involvement in meningoencephalitis remains unclear. The aim of this study was to investigate HAdV and other viral co-infections in the cerebrospinal fluid (CSF) of patients suspected of having either meningoencephalitis or encephalitis. A total of 373 CSF samples from patients under clinical suspicion of neurological viral infection were included in this study. HAdV was investigated by conventional or multiplex real-time PCR, for different time periods. The frequency of HAdV central nervous system (CNS) infection was 1.08%, predominating in female patients with a predisposing condition, and presented with HAdV encephalitis. HAdV CNS infection was found to occur during the months of autumn and winter. The frequency of HAdV detected in CSF positive samples increased after the change in the diagnostic method from conventional to multiplex real-time PCR. There were no specific NMRI or EEG characteristics and two CSF samples with HAdV encephalitis had normal CSF WBC count. There were two cases of co-infection with HIV; no other co-infections with enterovirus or herpes family viruses were detected. All patients had good outcome. Although HAdV is rarely observable in CNS infectious syndromes, it must be investigated particularly in immunocompromised patients.

Abstract TP258: Clinical and Radiographic Features of Stroke in Cryptococcal Meningoencephalitis in a US Cohort Study

Background: Cryptococcal meningitis can present with small vessel vasculitis and ischemic stroke. Acute and chronic infection carry a high mortality in both immunocompetent and immunocompromised patients. Among the survivors, multiple neurological deficit cause marked disability. Predictors of poor outcome and stroke recurrence remain unrecognized. Methods: We aim to describe clinical and radiographic features of stroke in a prospectively collected cohort of patients with Cryptococcal meningitis. A retrospective analysis of neuroimaging studies, cerebrospinal fluid(CSF) and clinical presentation was performed at the University of Colorado Hospital between 2000-2018. A multivariable logistic regression model was constructed to explore associations between dichotomous variables and informed as risk ratios. A T-Test and Wilcoxon test were applied to means of continuous variables. Fisher's exact test and contingency tables were used. Results: A total of 42 patients had cryptococcal meningitis, of which 31 had available imaging. Ischemic stroke was present in 8 patients (26%). Most strokes were acute (75%), lacunar (100%), multiple (88%), bilateral (63%) and localized in the basal ganglia (75%). Hyponatremia carried a RR: 5.7 (95% CI, 1.7-34.1) p=0.005. Other variables such malignancy, basal exudates, cryptococcoma, meningeal enhancement, hydrocephalus and CSF WBC did not seem to increase or reduce the risk of stroke. Anemia and hyponatremia were associated with presence of stroke, p=0.02 and p=0.03, respectively. Every unit decrease in hemoglobin is associated with 0.26 times the risk of ischemic stroke, (95% CI, 1.7-34.1) p=0.0312. Cryptococcal meningitis lead to death in 13 patients (30%) and 3 (14%) in patients with pulmonary manifestations only. Conclusion: Cryptococcal meningitis carries a high risk of neurologic complications, including lacunar stroke, particularly in the basal ganglia. Predisposing risk factors include anemia and hyponatremia regardless of the immune status of the patients. We report a mortality comparable to developing countries in the setting of a center of reference. The most common radiographic features of cryptococcal vasculitic infection may play a role in the high mortality of the population.

Disease Detection Methodologies in Acute Lymphoblastic Leukemia (ALL): Opportunities for Improvement

Background Minimal residual disease (MRD) is highly prognostic for outcomes in ALL, particularly prior to HCT. New methods for MRD determination in bone marrow (BM) increase the sensitivity of disease detection but remain dependent on the quality of the specimen obtained. Residual disease testing in the cerebrospinal fluid (CSF) is rarely performed. With the dual objectives to identify the role of BM biopsy in conjunction with BM aspirate and flow cytometry (FC), and also the role of CSF FC alongside cytopathology (CP), we evaluated the frequency and degree of discrepancies in disease detection based on methodologies of BM and CSF disease assessments. Design In this retrospective study of children and young adults with relapsed ALL who were enrolled on one or more phase I/II trials at the NCI between 2012 and 2018, we systematically analyzed all BM and CSF assessments that were performed. All CSF analyses included cell count, CP, and frequently FC. BM samples needed to have a biopsy, aspirate, and FC results to be included in the study. BM and CNS status were classified based on established definitions. For BM samples, a discrepancy was defined as any difference in marrow status (M1, M2, or M3). For CSF, a discrepancy was noted if the CP and the FC were discordant. BM specimens were further analyzed by extent of hemodilution and cellularity with MRD threshold set at Results From 98 patients, a total of 410 BM samples were analyzed, amongst which 61 (14.8%) samples had at least one discordant result (Figure 1). This included 26 discrepancies between biopsy and aspirate, 47 between biopsy and FC, and 39 between aspirate and FC. From these, 26 (6.3%) were deemed clinically relevant, defined as changing the assessment from a morphologic remission to more extensive involvement, and had a median discrepancy of 30.5% blasts (range, 7-91%). In 17 of these cases, the biopsy was essential to determine the full extent of disease. In 35 cases, the aspirate was reported as poor quality and in 30% the flow specimen had hemodilution deemed to be clinically significant. 351 of 418 CSF samples had a concurrent FC analysis of which, 32 (9.1%) had disease discrepancies; all cases demonstrated FC positivity with a negative CP report, with the highest discrepancy at 60% blasts (CSF WBC: 2). Conclusion MRD testing in ALL is critical, however, assessing the depth of remission is dependent on the quality of the sample acquired. This retrospective analysis highlights the frequency and degree of discrepancies observed between traditional histopathologic methods of disease assessment and FC. While the incorporation of highly-sensitive MRD testing will increase disease detection, these data support expanding methodologies for complimentary quantitation of BM and CNS involvement in patients with ALL.