Cerebrospinal fluid levels of extracellular heat shock protein 72: A potential biomarker for bacterial meningitis in children

Extracellular heat shock protein 72 (Hsp72) is an endogenous danger signal and potential biomarker for critical illness in children. We hypothesized that elevated levels of extracellular Hsp72 in the cerebrospinal fluid (CSF) of children with suspected meningitis could predict bacterial meningitis. We measured extracellular Hsp72 levels in the CSF of 31 critically ill children with suspected meningitis via a commercially available enzyme-linked immunosorbent assay. Fourteen had bacterial meningitis based on CSF pleocytosis and bacterial growth in either blood or CSF culture. Seventeen children with negative cultures comprised the control group. CSF Hsp72 was significantly elevated in children with bacterial meningitis compared to controls. Importantly, CSF Hsp72 levels did not correlate with the CSF white blood cell count. On receiver operator characteristic analysis, using a cut-off of 8.1 ng/mL, CSF Hsp72 has a sensitivity of 79% and a specificity of 94% for predicting bacterial meningitis. We therefore conclude that CSF extracellular Hsp72 levels are elevated in critically ill children with bacterial meningitis versus controls. Hsp72 potentially offers clinicians improved diagnostic information in distinguishing bacterial meningitis from other processes

From the microbiome to the central nervous system, an update on the epidemiology and pathogenesis of bacterial meningitis in childhood [version 1; referees: 3 approved]

In the past century, advances in antibiotics and vaccination have dramatically altered the incidence and clinical outcomes of bacterial meningitis. We review the shifting epidemiology of meningitis in children, including after the implementation of vaccines that target common meningitic pathogens and the introduction of intrapartum antibiotic prophylaxis offered to mothers colonized with Streptococcus agalactiae. We also discuss what is currently known about the pathogenesis of meningitis. Recent studies of the human microbiome have illustrated dynamic relationships of bacterial and viral populations with the host, which may potentiate the risk of bacterial meningitis

Unbiased Metagenomic Sequencing for Pediatric Meningitis in Bangladesh Reveals Neuroinvasive Chikungunya Virus Outbreak and Other Unrealized Pathogens.

The burden of meningitis in low-and-middle-income countries remains significant, but the infectious causes remain largely unknown, impeding institution of evidence-based treatment and prevention decisions. We conducted a validation and application study of unbiased metagenomic next-generation sequencing (mNGS) to elucidate etiologies of meningitis in Bangladesh. This RNA mNGS study was performed on cerebrospinal fluid (CSF) specimens from patients admitted in the largest pediatric hospital, a World Health Organization sentinel site, with known neurologic infections (n = 36), with idiopathic meningitis (n = 25), and with no infection (n = 30), and six environmental samples, collected between 2012 and 2018. We used the IDseq bioinformatics pipeline and machine learning to identify potentially pathogenic microbes, which we then confirmed orthogonally and followed up through phone/home visits. In samples with known etiology and without infections, there was 83% concordance between mNGS and conventional testing. In idiopathic cases, mNGS identified a potential bacterial or viral etiology in 40%. There were three instances of neuroinvasive Chikungunya virus (CHIKV), whose genomes were >99% identical to each other and to a Bangladeshi strain only previously recognized to cause febrile illness in 2017. CHIKV-specific qPCR of all remaining stored CSF samples from children who presented with idiopathic meningitis in 2017 (n = 472) revealed 17 additional CHIKV meningitis cases, exposing an unrecognized meningitis outbreak. Orthogonal molecular confirmation, case-based clinical data, and patient follow-up substantiated the findings. Case-control CSF mNGS surveys can complement conventional diagnostic methods to identify etiologies of meningitis, conduct surveillance, and predict outbreaks. The improved patient- and population-level data can inform evidence-based policy decisions.IMPORTANCE Globally, there are an estimated 10.6 million cases of meningitis and 288,000 deaths every year, with the vast majority occurring in low- and middle-income countries. In addition, many survivors suffer from long-term neurological sequelae. Most laboratories assay only for common bacterial etiologies using culture and directed PCR, and the majority of meningitis cases lack microbiological diagnoses, impeding institution of evidence-based treatment and prevention strategies. We report here the results of a validation and application study of using unbiased metagenomic sequencing to determine etiologies of idiopathic (of unknown cause) cases. This included CSF from patients with known neurologic infections, with idiopathic meningitis, and without infection admitted in the largest children's hospital of Bangladesh and environmental samples. Using mNGS and machine learning, we identified and confirmed an etiology (viral or bacterial) in 40% of idiopathic cases. We detected three instances of Chikungunya virus (CHIKV) that were >99% identical to each other and to a strain previously recognized to cause systemic illness only in 2017. CHIKV qPCR of all remaining stored 472 CSF samples from children who presented with idiopathic meningitis in 2017 at the same hospital uncovered an unrecognized CHIKV meningitis outbreak. CSF mNGS can complement conventional diagnostic methods to identify etiologies of meningitis, and the improved patient- and population-level data can inform better policy decisions

Vaccine implementation: Alaska 2017

Bacterial meningitis is a serious disease that causes permanent dysfunction or death; adolescents and young adults carry the greatest risk. The national Advisory Committee on Immunization Practices (ACIP) has released vaccine recommendations that include incorporation of meningitis vaccine in to the mandatory school vaccine schedule. Throughout the nation, much of legislative policy has made meningitis vaccination a requirement for public school attendance. Alaska does not have such policy; the purpose of the project was to address this policy need. A secondary project goal was to increase community awareness of bacterial meningitis. Project actions were divided into policy advocacy and community awareness. Policy advocacy included the development of a Policy Brief to Persuade designed for the Alaska legislative health care committee members. A legislative survey to assess willingness to incorporate a required meningitis vaccine schedule into existing Alaska vaccine policy was sent electronically with the policy brief. Community awareness interventions included the development of a Meningitis Education Bundle for healthcare professionals and a Protect Alaska’s Future campaign. The education bundle was distributed to local health establishments on Prince of Wales Island and the campaign information was distributed at the 2017 Prince of Wales Community Health Fair. Project outcomes demonstrated a lack of response to the policy survey. Efforts must continue over time with a deliberate plan to gain legislative support for the incorporation of a meningitis vaccination schedule into existing Alaska vaccine policy, as recommended by the ACIP. Community awareness activities at the health fair were successful and should continue

A Systematic Review of Cases of Meningitis in the Absence of Cerebrospinal Fluid Pleocytosis on Lumbar Puncture

Background: Definitive diagnosis of meningitis is made by analysis of cerebrospinal fluid (CSF) culture or polymerase chain reaction (PCR) obtained from a lumbar puncture (LP), which may take days. A timelier diagnostic clue of meningitis is pleocytosis on CSF analysis. However, meningitis may occur in the absence of pleocytosis on CSF. Areas of Uncertainty: A diagnosis of meningitis seems less likely without pleocytosis on CSF, leading clinicians to prematurely exclude this. Further, there is little available literature on the subject.Methods: Ovid/Medline and Google Scholar search was conducted for cases of CSF culture-confirmed meningitis with lack of pleocytosis. Inclusion criterion was reported cases of CSF culture-positive or PCR positive meningitis in the absence of pleocytosis on LP. Exclusion criteria were pleocytosis on CSF, cases in which CSF cultures/PCR were not performed, and articles that did not include CSF laboratory values.Results: A total of 124 cases from 51 articles were included. Causative organisms were primarily bacterial (99 cases). Outcome was reported in 86 cases, 27 of which died and 59 survived. Mortality in viral, fungal and bacterial organisms was 0, 56 and 31%, respectively. The overall percentage of positive initial CSF PCR/culture for viral, fungal and bacterial organisms was 100, 89 and 82%, respectively. Blood cultures were performed in 79 of the 124 cases, 56 (71%) of which ultimately cultured the causative organism. In addition to bacteremia, concomitant sources of infection occurred in 17 cases.Conclusions: Meningitis in the absence of pleocytosis on CSF is rare. If this occurs, causative organism is likely bacterial. We recommend ordering blood cultures as an adjunct, and, if clinically relevant, concomitant sources of infection should be sought. If meningitis is suspected, empiric antibiotics/antifungals should be administered regardless of initial WBC count on lumbar puncture

Cryptococcal Meningitis Diagnostics and Screening in the Era of Point-of-Care Laboratory Testing.

Over the past ten years, standard diagnostics for cryptococcal meningitis in HIV-infected persons have evolved from culture to India ink to detection of cryptococcal antigen (CrAg), with the recent development and distribution of a point-of-care lateral flow assay. This assay is highly sensitive and specific in cerebrospinal fluid (CSF), but is also sensitive in the blood to detect CrAg prior to meningitis symptoms. CrAg screening of HIV-infected persons in the blood prior to development of fulminant meningitis and preemptive treatment for CrAg-positive persons are recommended by the World Health Organization and many national HIV guidelines. Thus, CrAg testing is occurring more widely, especially in resource-limited laboratory settings. CrAg titer predicts meningitis and death and could be used in the future to customize therapy according to burden of infection

Rheumatoid meningitis sine arthritis.

Rheumatoid meningitis is a rare and very serious extra-articular manifestation of rheumatoid arthritis. We present a case of a 7()year-old female with no history of arthritis who developed stroke-like symptoms, seizures, psychosis and compulsive behavior. Serial brain magnetic resonance images (MRI) over four months demonstrated progressive interhemispheric meningeal thickening. She had mild lymphocytic pleocytosis on the cerebrospinal fluid analysis and serum anti-cyclic citrullinated peptide antibodies resulted positive in high titers. She underwent a brain biopsy showing necrotizing granulomas consistent with rheumatoid meningitis. Her symptoms resolved with treatment with glucocorticoids and cyclophosphamide. She has not been diagnosed with rheumatoid arthritis even after 1 year of follow up. Clinicians should be aware of the possibility of rheumatoid meningitis without rheumatoid arthritis and keep it on the differential for patients with aseptic meningitis and otherwise negative work up

Detection of (1,3)-β-d-Glucan in Cerebrospinal Fluid in Histoplasma Meningitis

The diagnosis of central nervous system (CNS) histoplasmosis is often difficult. Although cerebrospinal fluid (CSF) (1,3)-β-d-glucan (BDG) is available as a biological marker for the diagnosis of fungal meningitis, there are limited data on its use for the diagnosis of Histoplasma meningitis. We evaluated CSF BDG detection, using the Fungitell assay, in patients with CNS histoplasmosis and controls. A total of 47 cases and 153 controls were identified. The control group included 13 patients with a CNS fungal infection other than histoplasmosis. Forty-nine percent of patients with CNS histoplasmosis and 43.8% of controls were immunocompromised. The median CSF BDG level was 85 pg/ml for cases, compared to <31 pg/ml for all controls (P < 0.05) and 82 pg/ml for controls with other causes of fungal meningitis (P = 0.27). The sensitivity for detection of BDG in CSF was 53.2%, whereas the specificity was 86.9% versus all controls and 46% versus other CNS fungal infections. CSF BDG levels of ≥80 pg/ml are neither sensitive nor specific to support a diagnosis of Histoplasma meningitis

Aseptic meningitis in a patient taking etanercept for rheumatoid arthritis: a case report

Background \ud We report a case of a 53 year old lady recently commenced on etanercept, an anti-TNF (tumour necrosis factor) therapy for rheumatoid arthritis presenting with \ud confusion, pyrexia and an erythematous rash. \ud \ud Case presentation \ud A lumbar puncture was highly suggestive of bacterial meningitis, but CSF cultures produced no growth, and polymerase chain reactions (PCR) for all previously reported bacterial, fungal and viral causes of meningitis were negative. \ud \ud Conclusions \ud This case report describes aseptic meningitis as a previously unreported complication of etanercept therapy, and serves as a reminder of the rare but potentially lifethreatening risk of serious infections in patients taking anti-TNF therapy for a variety of conditions

Draft genome sequence of a meningitic isolate of Cronobacter sakazakii clonal complex 4, strain 8399

The Cronobacter sakazakii clonal lineage defined as clonal complex 4 (CC4), composed of nine sequence types, is associated with severe cases of neonatal meningitis. To date, only closely related C. sakazakii sequence type 4 (ST4) strains have been sequenced. C. sakazakii strain 8399, isolated from a case of neonatal meningitis, was sequenced as the first non-ST4 C. sakazakii strain