Naim Ouldali, Corinne Levy, Emmanuelle Varon, Stéphane Bonacorsi, Stéphane Béchet, Robert Cohen, François Angoulvant, The French Pediatric Meningitis Network

The early effect of PCV13 implementation greatly reduced the incidence of pneumococcal meningitis in children less than 15 years old. However, a sharp rebound in incidence linked to the emergence of serotype 24F compromised the long-term PCV efficacy. If confirmed in future studies and in other countries, pneumococcal meningitis incidence rebound and 24F emergence should be considered when developing next-generation PCVs.

Dian, S., Yunivita, V., Ganiem, A. R., Pramaesya, T., Chaidir, L., Wahyudi, K., Achmad, T. H., Colbers, A., te Brake, L., van Crevel, R., Ruslami, R., Aarnoutse, R.

High doses of rifampicin may help tuberculous meningitis (TBM) patients to survive. Pharmacokinetic-pharmacodynamic evaluations suggested that rifampicin doses higher than 13 mg/kg intravenously or 20 mg/kg orally (as previously studied) are warranted to maximize treatment response. In a double-blinded, randomised, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg or 1350 mg (10, 20 and 30 mg/kg) oral rifampicin combined with other TB drugs for 30 days. Endpoints included pharmacokinetic measures, adverse events and survival. A double and triple dose of oral rifampicin led to three and five-fold higher geometric mean total exposures in plasma in the critical early days (2±1) of treatment (AUC0-24h: 53·5 mg.h/L vs 170·6 mg.h/L vs. 293·5 mg.h/L, p

Sabine. L. van Elsland , Remco Peters , Maarten O. Kok , Ronald van Toorn , Priscilla Springer , Mark F. Cotton , Cornelis J. Grobbelaar , Rob Aarnoutse , A. Marceline van Furth

Abstract Objectives To evaluate a paediatric treatment‐support intervention for home‐based treatment of HIV infection or tuberculous meningitis (TBM). Methods A randomized‐controlled study comparing local standard care (controls) with standard care plus intervention (combining adherence education, reinforcement and monitoring) in children aged 0‐14 years. We recorded adherence measures (self‐report, pill‐count, drug‐assays for isoniazid and rifampicin in urine and pyrazinamide in saliva), difficulties administering medication and PedsQL™ questionnaires for health‐related quality‐of‐life (HRQoL) and family impact. Results In the HIV group (6‐months follow‐up, n=195), more children had above‐median HRQoL‐scores in the intervention group than in the control group (p=0.009). Problems reported administering medication declined between baseline and follow‐up for controls (p=0.043). Disclosure of HIV status to the child increased between baseline and follow‐up in both groups (intervention p

Ansdell, Vernon; Wattanagoon, Yupaporn

Purpose of review Angiostrongylus cantonensis eosinophilic meningitis is a neglected, yet important emerging disease, which has been increasingly recognized in travelers. In this review, we describe the occurrence of the disease in travelers, sources of infection, clinical manifestations, diagnosis, and currently recommended treatment. Recent findings Various intermediate hosts and/or paratenic hosts can be the source of infection in humans. Serological tests for antibody may be negative early in the course of the disease but PCR for antigen detection in the CSF has recently been developed and may help to make the diagnosis at an earlier stage. High-dose corticosteroids (e.g. prednisolone 60 mg per day for at least 1–2 weeks) are currently the recommended treatment. Efficacy and safety of antihelminthic drugs for treatment remains controversial because of theoretical concerns that they may worsen the inflammatory response to dead and dying worms. Previous clinical trials were conducted with small numbers of participants and were underpowered. Further well designed clinical trials are urgently needed. Summary Awareness about increasing numbers of A. cantonensis eosinophilic meningitis in travelers is very important. Travelers should be advised about possible sources of infection. Diagnosis should be confirmed by antigen or antibody detection in blood or CSF. High-dose corticosteroids are the recommended treatment. The efficacy of various antihelminthic drugs is unproven. A large-scale, double-blind, randomized, controlled trial of antihelminthic drug involving antihelminthic drugs such as albendazole is necessary to prove the efficacy before formally advocating their use on a regular basis Correspondence to Yupaporn Wattanagoon, MBBS, DTM&H, Dip Thai Board Internal Med, Faculty of Tropical Medicine, Mahidol University, Ratchathewi, Bangkok, Thailand. Tel: +66 23549168; e-mail: yupaporn.wat@mahidol.ac.th Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Yoon H, Nakouzi A, Chang C, et al.

AbstractBackgroundInitiation of antiretroviral therapy (ART) in HIV-infected individuals with cryptococcal meningitis places them at risk for Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS). The relationship between antibody immunity and C-IRIS risk has not been investigated.MethodsWe compared plasma levels of immunoglobulins, Cryptococcus neoformans (CN) glucuronoxylomannan (GXM) capsule-specific and (Lam)inarin-binding IgM and IgG, and percentages of peripheral blood total and memory B cells between 27 HIV-infected patients with CM who developed C-IRIS and 63 who did not and evaluated associations of these parameters with risk of C-IRIS.ResultsPrior to initiation of ART, plasma IgM, Lam-binding IgM (Lam-IgM), Lam-IgG, and GXM-IgM levels were significantly lower in patients who developed C-IRIS than those who did not. Multivariate analysis revealed significant inverse associations between C-IRIS and IgM (P=0.0003), Lam-IgM (P=0.0005), Lam-IgG (P=0.002), and GXM-IgM (P=0.002) independent of age, sex, HIV viral load, CD4+ T cell count and cerebrospinal fluid fungal burden. There were no associations between C-IRIS and total or memory B cells.DiscussionAntibody profiles that include plasma IgM, Lam-IgM, Lam-IgG, and/or GXM-IgM, may have value in furthering our understanding of C-IRIS pathogenesis and hold promise as candidate biomarkers of C-IRIS risk.

Abstract Background Bacterial meningitis is a life-threatening infection that remains a public health concern. Bacterial meningitis is commonly caused by the following species: Neisseria meningitidis, Streptococcus pneumoniae, Listeria monocytogenes, Haemophilus influenzae and Escherichia coli. Here, we describe BMScan (Bacterial Meningitis Scan), a whole-genome analysis tool for the species identification of bacterial meningitis-causing and closely-related pathogens, an essential step for case management and disease surveillance. BMScan relies on a reference collection that contains genomes for 17 focal species to scan against to identify a given species. We established this reference collection by supplementing publically available genomes from RefSeq with genomes from the isolate collections of the Centers for Disease Control Bacterial Meningitis Laboratory and the Minnesota Department of Health Public Health Laboratory, and then filtered them down to a representative set of genomes which capture the diversity for each species. Using this reference collection, we evaluated two genomic comparison algorithms, Mash and Average Nucleotide Identity, for their ability to accurately and rapidly identify our focal species. Results We found that the results of Mash were strongly correlated with the results of ANI for species identification, while providing a significant reduction in run-time. This drastic difference in run-time enabled the rapid scanning of large reference genome collections, which, when combined with species-specific threshold values, facilitated the development of BMScan. Using a validation set of 15,503 genomes of our species of interest, BMScan accurately identified 99.97% of the species within 16 min 47 s. Conclusions Identification of the bacterial meningitis pathogenic species is a critical step for case confirmation and further strain characterization. BMScan employs species-specific thresholds for previously-validated, genome-wide similarity statistics compiled from a curated reference genome collection to rapidly and accurately identify the species of uncharacterized bacterial meningitis pathogens and closely related pathogens. BMScan will facilitate the transition in public health laboratories from traditional phenotypic detection methods to whole genome sequencing based methods for species identification.

Marlène Amara, Nathalie Zappella, Emilie Bruneel, Camille Courboulès, Nithiya Ung, Perrine Bayle, Esther Gydé, Fabrice Bruneel, Jean-Pierre Bédos, Béatrice Pangon

A 60-year-old man presented at the emergency department with a typical meningeal syndrome with anisocoria, after a flu-like episode. He had a medical history of ischemic cardiopathy and excessive alcohol consumption. Empiric antibiotherapy by ceftriaxone 1 g was initiated, associated with dexamethasone 10 mg.CSF was turbid, showing 390 leukocytes per μl (87% neutrophils), protein 4.15 g/L, glucose 0 g/L and lactate level 15 mmol/L. The Gram stain revealed a high number of long and thin Gram-negative rods (GNR) (Figure 1A).

Liu R, Wu C, Li L, et al.

AbstractFimH-mediated bacterial invasion and polymorphonuclear neutrophil (PMN) transmigration across human brain microvascular endothelial cells (HBMEC) are required for the pathogenesis of Escherichia coli meningitis. However, the underlying mechanism remains unclear. This study demonstrated that the TnphoA mutant (22A33) and FimH-knockout mutant (ΔFimH )of Escherichia coli strain E44, which resulted in inactivation of FimH, were less invasive and less effective in promoting PMN transmigration than their wildtype strain. FimH protein induced PMN transmigration, while calmodulin inhibitor significantly blocked this effect. Moreover, immunofluorescence and co-immunoprecipitation analysis indicated that co-localized CD48 and α7 nAChR formed a complex on the surface of HBMEC that is associated with increased cofilin dephosphorylation, which could be remarkably enhanced by FimH+ E44. Our study concluded that FimH-induced E. coli K1 invasion and PMN migration across HBMEC may be mediated by the CD48-α7nAChR complex in lipid rafts of HBMEC via Ca2+ signaling and cofilin dephosphorylation.

Alcides Moniz Munguambe, António Eugénio Castro Cardoso de Almeida, Aquino Albino Nhantumbo, Charlotte Elizabeth Come, Tomás Francisco Zimba, José Paulo Langa, Ivano de Filippis, Eduardo Samo Gudo

by Alcides Moniz Munguambe, António Eugénio Castro Cardoso de Almeida, Aquino Albino Nhantumbo, Charlotte Elizabeth Come, Tomás Francisco Zimba, José Paulo Langa, Ivano de Filippis, Eduardo Samo Gudo Introduction In sub Saharan Africa, the epidemiology, including the distribution of serogroups of strains of N. meningitidis is poorly investigated in countries outside “the meningitis belt”. This study was conducted with the aim to determine the distribution of serogroups of strains of N. meningitidis causing meningococcal meningitis in children and adults in Mozambique. Methods A total of 106 PCR confirmed Neisseria meningitidis Cerebrospinal Fluid (CSF) samples or isolates were obtained from the biobank of acute bacterial meningitis (ABM) surveillance being implemented by the National Institute of Health, at three central hospitals in Mozambique, from January to December 2014. Serogroups of N. meningitidis were determined using conventional PCR, targeting siaD gene for Neisseria meningitidis. Outer Membrane Proteins (OMP) Genotyping was performed by amplifying porA gene in nine samples. Results Of the 106 PCR confirmed Neisseria meningitidis samples, the most frequent serotype was A (50.0%, 53/106), followed by W/Y (18.9%, 20/106), C (8.5%, 9/106), X (7.5%, 8/106) and B (0.9%, 1/106). We found non-groupable strains in a total of 15 (14.2%) samples. PorA genotypes from nine strains showed expected patterns with the exception of two serogroup C strains with P1.19,15,36 and P1.19–36,15 and one serogroup X with P1.19,15,36, variants frequently associated to serogroup B. Conclusion Our data shows that the number of cases of meningococcal meningitis routinely reported in central hospitals in Mozambique is significant and the most dominant serogroup is A. In conclusion, although serogroup A has almost been eliminated from the “meningitis belt”, this serogroup remains a major concern in countries outside the belt such as Mozambique.

Friedrich MJ.

The deaths of children in developing countries from the leading bacterial causes of pneumonia and meningitis—Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae type b (Hib)—declined between 2000 and 2015, according to a recent report in the Lancet Global Health.

Abstract Background Sepsis-like illness with suspected meningitis or encephalitis is a common reason for using empiric antimicrobial therapy in infants and children. However, in cases of viral meningitis not covered by these antimicrobials, this management is ineffective and due to side effects potentially harmful. Methods A retrospective analysis of cerebrospinal fluid (CSF) multiplex PCRs (Biofire FilmArray®) in children with clinical suspicion of meningitis, encephalitis or sepsis-like illness was performed over the period of 1 year. Subsequently, a subgroup of children (age of 8–84 days of life) diagnosed with viral meningitis (enterovirus, HHV-6, human parechovirus) was compared to an age-matched control group. Results During the study period, the multiplex PCR panel was performed on 187 individual CSF samples that met the inclusion criteria. About half of the patients (92/187) were less than 1 year of age. In 27 cases (14.4%), the PCR yielded a positive result with the majority (12/27) being indicative of an enteroviral infection. In the age group of 8–84 days of life, 36.4% of the patients had a positive result. When the patients with a PCR positive for a viral agent were compared to an age-matched group of patients, no differences were observed regarding symptoms and laboratory parameters. However, the duration of antimicrobial therapy could be significantly reduced through the use of multiplex PCR. Conclusion The use of on-site diagnostic multiplex PCR was able to reduce the use of antimicrobials in selected cases. This test can guide clinical decisions earlier during the course of medical care compared to standard diagnostics.

Kunling Shen, Matthew Wasserman, Dongdong Liu, Yong-Hong Yang, Junfeng Yang, Greg F. Guzauskas, Bruce C. M. Wang, Betsy Hilton, Raymond Farkouh

by Kunling Shen, Matthew Wasserman, Dongdong Liu, Yong-Hong Yang, Junfeng Yang, Greg F. Guzauskas, Bruce C. M. Wang, Betsy Hilton, Raymond Farkouh Background The burden of pneumococcal disease in China is high, and a 13-valent pneumococcal conjugate vaccine (PCV13) recently received regulatory approval and is available to Chinese infants. PCV13 protects against the most prevalent serotypes causing invasive pneumococcal disease (IPD) in China, but will not provide full societal benefits until made broadly available through a national immunization program (NIP). Objective To estimate clinical and economic benefits of introducing PCV13 into a NIP in China using local cost estimates and accounting for variability in vaccine uptake and indirect (herd protection) effects. Methods We developed a population model to estimate the effect of PCV13 introduction in China. Modeled health states included meningitis, bacteremia, pneumonia (PNE), acute otitis media, death and sequelae, and no disease. Direct healthcare costs and disease incidence data for IPD and PNE were derived from the China Health Insurance and Research Association database; all other parameters were derived from published literature. We estimated total disease cases and associated costs, quality-adjusted life years (QALYs), and deaths for three scenarios from a Chinese Payer Perspective: (1) direct effects only, (2) direct+indirect effects for IPD only, and (3) direct+indirect effects for IPD and inpatient PNE. Results Scenario (1) resulted in 370.3 thousand QALYs gained and 12.8 thousand deaths avoided versus no vaccination. In scenarios (2) and (3), the PCV13 NIP gained 383.2 thousand and 3,580 thousand QALYs, and avoided 13.1 thousand and 147.5 thousand deaths versus no vaccination, respectively. In all three scenarios, the vaccination cost was offset by cost reductions from prevented disease yielding net costs of ¥29,362.32 million, ¥29,334.29 million, and ¥13,524.72 million, respectively. All resulting incremental cost-effectiveness ratios fell below a 2x China GDP cost-effectiveness threshold across a range of potential vaccine prices. Discussion Initiation of a PCV13 NIP in China incurs large upfront costs but is good value for money, and is likely to prevent substantial cases of disease among children and non-vaccinated individuals.

Abstract Background With a prevalence of 4.7–13% in Danish Ixodes ricinus ticks, Rickettsia helvetica is one of the most frequently detected tick-borne organisms in Denmark. Most reports of human exposure have described asymptomatic seroconversion or a mild, self-limiting flu-like illness but it has also been implicated as a cause of subacute lymphocytic meningitis. Because Borrelia burgdorferi sensu lato (Bbsl) and R. helvetica are both found in the same tick species, potential co-transmission is a possibility. We examined 1) the seroprevalence of anti-rickettsia antibodies in patients investigated for Lyme neuroborreliosis (LNB), and 2) the cerebrospinal fluid (CSF) and sera of same patients for the presence of Rickettsia DNA. Methods Ninety-nine sera and 87 CSF samples from patients with intrathecal synthesis of anti-Borrelia antibodies and 101 sera and 103 CSF samples from patients with no detectable intrathecal synthesis were retrospectively examined for this study. Sera were analyzed for antibodies against spotted fever group (SFG) rickettsiae and both the CSF and sera were tested for Rickettsia DNA using a genus-specific real-time PCR. Results Of the patients tested for LNB, 32% (64/200) had IgG antibodies against SFG rickettsiae. Among patients with confirmed intrathecal synthesis of Borrelia-specific antibodies, 38% (38/99) exhibited IgG antibodies. None of these values were statistically significant when compared with sera from healthy blood donors (p = 0.7 and 0.19). Rickettsia DNA was found in the CSF of 4% (8/190) of patients. Conclusion No statistically significant difference was found in the seroprevalence of anti-rickettsia antibodies in patients tested for LNB and healthy blood donors, indicative of a low rate of exposure in this group of patients. Eight patients showed evidence of Rickettsia DNA in the CSF, five of whom had LNB. However, cycle threshold (Ct) values were high, indicating low concentrations of DNA, and no apparent alteration in the clinical manifestations of LNB were noted in the medical records of these patients.

Bongyoung Kim, Shinje Moon, Geun-Ryang Bae, Hyungmin Lee, Hyunjoo Pai, Sung Hee Oh

by Bongyoung Kim, Shinje Moon, Geun-Ryang Bae, Hyungmin Lee, Hyunjoo Pai, Sung Hee Oh Background In 2009, a nationwide sentinel surveillance for hand-foot-mouth disease (HFMD) and herpangina (HA) with neurologic complications was initiated in South Korea. We used this surveillance system to investigate the clinical characteristics of patients with either HFMD or HA with neurologic complications, with the aim of determining risk factors for severe neurologic complications. Methods A retrospective review of medical records was conducted on all cases of HFMD and HA with neurologic complications that were reported in the national system between April 1, 2009 and December 31, 2014. A severe case was defined as having HFMD or HA with encephalitis, polio-like syndrome, or cardiopulmonary failure, and less-severe cases were defined as having HFMD or HA with aseptic meningitis. Results A total of 138 cases (less-severe: 90/138, 65.2%; severe: 48/138, 24.8%) were included from 28 hospitals; 28 ineligible cases were excluded. Of 48 severe cases, 27 (56.2%) had encephalitis; 14 (29.2%) had polio-like syndrome; and seven (14.6%) had cardiopulmonary syndrome. The median patient age was 36 months (IQR: 18–60) and 63 (45.7%) patients were female. Most patients completely recovered, except for seven cases that were fatal or resulted in long-term symptoms (5.1%, 3 patients with neurologic sequelae and 4 deaths). In a multivariable logistic regression analysis, lethargy (OR = 4.67, 95% CI: 1.37–15.96, P = 0.014), female sex (OR = 3.51, 95% CI: 1.17–10.50, P = 0.025), and enterovirus A71 (OR = 3.55, 95% CI: 1.09–11.57, P = 0.035) were significantly associated with severe neurologic complications in HFMD and HA patients. Conclusion In patients with HFMD and HA, lethargy, female, and enterovirus A71 may predict severe neurologic complications.

C. Chaves et al.

Depledge D, Cudini J, Kundu S, et al.

AbstractBackgroundVaricella zoster virus (VZV) may cause encephalitis, both with and without rash. Here we investigate whether viruses recovered from the central nervous system (CNS; encephalitis or meningitis) differ genetically from those recovered from non-CNS samples.MethodsEnrichment-based deep sequencing of 45 VZV genomes from cerebral spinal fluid (CSF), plasma, bronchoalveolar lavage (BAL), and vesicles was carried out with samples collected from 34 patients with and without VZV infection of the CNS.ResultsViral sequences from multiple sites in the same patient were identical at the consensus level. Virus from vesicle fluid and CSF in cases of meningitis showed low-level diversity. By contrast, plasma, BAL, and encephalitis had higher numbers of variant alleles. Two CSF-encephalitis samples had high genetic diversity, with variant frequency patterns typical of mixed infections with different clades.ConclusionsLow viral genetic diversity in vesicle fluid is compatible with previous observations that VZV skin lesions arise from single or low numbers of virions. A similar result was observed in VZV from cases of VZV meningitis, a generally self-limiting infection. CSF from cases of encephalitis had higher diversity with evidence for mixed clade infections in 2 cases. We hypothesize that reactivation from multiple neurons may contribute to the pathogenesis of VZV encephalitis.

Wiederhold, N. P., Xu, X., Wang, A., Najvar, L. K., Garvey, E. P., Ottinger, E. A., Alimardanov, A., Cradock, J., Behnke, M., Hoekstra, W. J., Brand, S. R., Schotzinger, R. J., Jaramillo, R., Olivo, M., Kirkpatrick, W. R., Patterson, T. F.

VT-1129 is a novel fungal-specific Cyp51 inhibitor with potent cryptococcal activity. Because of its long half-life (>6 days in mice) and the desire to quickly reach potent efficacy, we evaluated a VT-1129 loading dose-maintenance dose (LD-MD) strategy against cryptococcal meningitis. VT-1129 plasma and brain pharmacokinetics were first studied in healthy mice, and these data were used to model LD-MD doses to generate different steady-state concentrations. Mice were inoculated intracranially with C. neoformans, and oral treatment began 1 day later. Treatment consisted of placebo, three VT-1129 LD-MD groups: LD of 1, 3, or 30 mg/kg on day 1, followed by MD of 0.15, 0.5, or 5 mg/kg once daily, respectively. In the fungal burden arm, therapy continued for 14 days, and brains were collected on day 15 for fungal burden assessment. In the survival arm, treatment continued for 10 days after which mice were monitored off-therapy until day 30. VT-1129 plasma and brain concentrations were also measured. Each VT-1129 dose significantly improved survival and reduced fungal burden compared to placebo. VT-1129 plasma and brain levels correlated with fungal burden reductions (R2 = 0.72 and 0.67, respectively), with plasma concentration of 1 μg/mL yielding a reduction of ~5 log10 CFU/g. With the highest LD-MD dose, fungal burden was undetectable in half of the mice in the fungal burden arm, and in a quarter of the mice in the survival arm, 20 days after final dose. These data support an LD-MD strategy for quickly reaching highly efficacious VT-1129 concentrations in treating cryptococcal meningitis.

Hui Jiang, Yang Huai, Hui Chen, Timothy M. Uyeki, Maoyi Chen, Xuhua Guan, Shali Liu, Youxing Peng, Hui Yang, Jun Luo, Jiandong Zheng, Jigui Huang, Zhibin Peng, Nijuan Xiang, Yuzhi Zhang, John D. Klena, Dale J. Hu, Jeanette J. Rainey, Xixiang Huo, Lin Xiao, Xuesen Xing, Faxian Zhan, Hongjie Yu, Jay K. Varma

by Hui Jiang, Yang Huai, Hui Chen, Timothy M. Uyeki, Maoyi Chen, Xuhua Guan, Shali Liu, Youxing Peng, Hui Yang, Jun Luo, Jiandong Zheng, Jigui Huang, Zhibin Peng, Nijuan Xiang, Yuzhi Zhang, John D. Klena, Dale J. Hu, Jeanette J. Rainey, Xixiang Huo, Lin Xiao, Xuesen Xing, Faxian Zhan, Hongjie Yu, Jay K. Varma Background Streptococcus pneumoniae (Sp) is a leading cause of bacterial pneumonia, meningitis, and sepsis and a major source of morbidity and mortality worldwide. Invasive pneumococcal disease (IPD) is defined as isolation of Sp from a normally sterile site, including blood or cerebrospinal fluid. The aim of this study is to describe outcomes as well as clinical and epidemiological characteristics of hospitalized IPD case patients in central China. Methods We conducted surveillance for IPD among children and adults from April 5, 2010 to September 30, 2012, in four major hospitals in Jingzhou City, Hubei Province. We collected demographic, clinical, and outcome data for all enrolled hospitalized patients with severe acute respiratory infection (SARI) or meningitis, and collected blood, urine, and cerebrospinal fluid (CSF) for laboratory testing for Sp infections. Collected data were entered into Epidata software and imported into SPSS for analysis. Results We enrolled 22,375 patients, including 22,202 (99%) with SARI and 173 (1%) with meningitis. One hundred and eighteen (118, 3%) with either SARI or meningitis were Sp positive, 32 (0.8%) from blood/CSF culture, and 87 (5%) from urine antigen testing. Of those 118 patients, 57% were aged ≥65 years and nearly 100% received antibiotics during hospitalization. None were previously vaccinated with 7-valent pneumococcal conjugate vaccine (PCV 7), 23-valent pneumococcal polysaccharide vaccine, or seasonal influenza vaccine. The main serotypes identified were 14, 12, 3, 1, 19F, 4, 5, 9V, 15 and 18C, corresponding to serotype coverage rates of 42%, 63%, and 77% for PCV7, PCV10, and PCV13, respectively. Conclusions Further work is needed to expand access to pneumococcal vaccination in China, both among children and potentially among the elderly, and inappropriate use of antibiotics is a widespread and serious problem in China.

Ming Zhang , Yilin Zhao , Haihao Zhang , Keqin Lin , Hongbo Liu , Jie Zhang , Lisha Ding , Xiaoqin Huang , Zhaoqing Yang , Shaohui Ma

Abstract Coxsackievirus A16 (CV‐A16) commonly causes mild symptoms, but severe diseases such as aseptic meningitis, encephalitis, and even fatal cases, have been reported. Thirteen CV‐A16 strains were isolated from patients with severe hand, foot, and mouth disease in Yunnan, Southwest China from 2009–2015. Subgenotype B1a and B1b of CV‐A16 were predominantly circulating the region with B1b the predominant strain in recent years. The mean rate of nucleotide substitution based on the VP1 gene sequence was 4.545 × 10‐3 sub/site/year from 2009 to 2015. These results may help to understand the genetic diversity of CV‐A16 and develop a CV‐A16 vaccine. This article is protected by copyright. All rights reserved.

Reuter, G., Pankovics, P., Boros, A.

Astroviruses are thought to be enteric pathogens. Since 2010, a certain group of astroviruses has increasingly been recognized, using up-to-date random amplification and high-throughput next-generation sequencing (NGS) methods, as potential neurovirulent (Ni) pathogens of severe central nervous system (CNS) infections, causing encephalitis, meningoencephalitis, and meningoencephalomyelitis. To date, neurovirulent astrovirus cases or epidemics have been reported for humans and domesticated mammals, including mink, bovines, ovines, and swine. This comprehensive review summarizes the virology, epidemiology, pathology, diagnosis, therapy, and future perspective related to neurovirulent astroviruses in humans and mammals, based on a total of 30 relevant articles available in PubMed (searched by use of the terms "astrovirus/encephalitis" and "astrovirus/meningitis" on 2 March 2018). A paradigm shift should be considered based on the increasing knowledge of the causality-effect association between neurotropic astroviruses and CNS infection, and attention should be drawn to the role of astroviruses in unknown CNS diseases.

M. E. Coldiron et al.

Esayas Kebede Gudina, Markos Tesfaye, Andreas Wieser, Hans-Walter Pfister, Matthias Klein

by Esayas Kebede Gudina, Markos Tesfaye, Andreas Wieser, Hans-Walter Pfister, Matthias Klein Background The mortality and neurologic sequelae associated with acute bacterial meningitis (ABM) remain high despite advances in medical care. The main aim of this study was to evaluate short-term outcome in patients treated as bacterial meningitis at a teaching hospital in Ethiopia to identify factors that could be focused on to improve outcome in this setting. Methods A hospital based longitudinal study was conducted at Jimma University Hospital in southwest Ethiopia from March 1, 2013 to December 31, 2015. Participants of this study were patients of age 18 years and older who were treated as confirmed or possible cases of ABM. Patients were followed throughout their hospital stay for change in their clinical course and predefined end points. A multivariable analysis was done to identify factors associated with unfavorable outcomes. Result 90 patients admitted with diagnosis of acute bacterial meningitis were included in the study; cerebrospinal fluid was analysed for 85 (94.4%) of them. Causative bacteria were isolated in 26 (28.9%) patients only; most of these isolates (84.6%) were either Streptococcus pneumoniae or Neisseria meningitidis. Patients managed as cases of ABM at the hospital suffered from a high rate of unfavorable outcome (36.7%) and an overall mortality rate of 22.2%. Impaired level of consciousness (AOR = 0.766, 95% CI = 0.589–0.995), dexamethasone therapy (AOR = 4.676, 95% CI = 1.12–19.50) and fever persisting after two days of admission (AOR = 24.226, 95% CI = 5.24–111.96) were found to be independently associated with unfavorable outcome. Conclusion Outcome in patients treated for ABM at the hospital was found to be poor. Impaired mentation, treatment with adjunctive dexamethasone and persistent fever were found to be associated with poor outcome. Thus, development of clinical guidelines for treatment of ABM that suit the local context is essential to improve patient management and outcome.

Abstract Background Asking people how they would seek healthcare in a hypothetical situation can be an efficient way to estimate healthcare utilization, but it is unclear how intended healthcare use corresponds to actual healthcare use. Methods We performed a cross-sectional survey between August and September 2012 among households in Soweto and Klerksdorp, South Africa, to compare healthcare seeking behaviors intended for hypothetical common infectious syndromes (pneumonia, influenza-like illness [ILI], chronic respiratory illness, meningitis in persons of any age, and diarrhea in a child

Jean-Philippe Auger, Dominic Dolbec, David Roy, Mariela Segura, Marcelo Gottschalk

by Jean-Philippe Auger, Dominic Dolbec, David Roy, Mariela Segura, Marcelo Gottschalk Streptococcus suis serotype 2 is an important porcine bacterial pathogen and zoonotic agent responsible for sudden death, septic shock, and meningitis. However, serotype 2 strains are heterogeneous, composed of a multitude of sequence types (STs) whose distribution greatly varies worldwide. Of the virulence factors presently described for S. suis, the capsular polysaccharide (CPS) is a critical factor implicated in a multitude of functions, including in impairment of phagocytosis and innate immune cell activation by masking underlying bacterial components. However, these roles have been described using Eurasian ST1 and ST7 strains, which greatly differ from North American ST25 strains. Consequently, the capacity of the CPS to mask surface antigens and putative virulence factors in non-Eurasian strains remains unknown. Herein, the role of the S. suis serotype 2 CPS of a prototype intermediate virulent North American ST25 strain, in comparison with that of a virulent European ST1 strain, with regards to interactions with dendritic cells, as well as virulence during the systemic phase of infection, was evaluated. Results demonstrated that the CPS remains critical for virulence and development of clinical disease regardless of strain background, due to its requirement for survival in blood. However, its role in the interactions with dendritic cells is strain-dependent. Consequently, certain key characteristics associated with the CPS are not necessarily applicable to all S. suis serotype 2 strains. This indicates that though certain factors may be important for S. suis serotype 2 virulence, strain background could be as determining, reiterating the need in using strains from varying backgrounds in order to better characterize the S. suis pathogenesis.

Wiederhold, N. P., Najvar, L. K., Garvey, E. P., Brand, S. R., Xu, X., Ottinger, E. A., Alimardanov, A., Cradock, J., Behnke, M., Hoekstra, W. J., Schotzinger, R. J., Jaramillo, R., Olivo, M., Kirkpatrick, W. R., Patterson, T. F.

Cryptococcal meningitis is a significant cause of morbidity and mortality in immunocompromised patients. VT-1129 is a novel fungal-specific Cyp51 inhibitor with potent in vitro activity against Cryptococcus species. Our objective was to evaluate the in vivo efficacy VT-1129 against cryptococcal meningitis. Mice were inoculated intracranially with C. neoformans. Oral treatment with VT-1129, fluconazole, or placebo began 1 day later and continued for either 7 or 14 days, and brains and plasma were collected on day 8 or 15, 1 day after therapy ended, and fungal burden was assessed. In the survival study, treatment continued until day 10 or day 28 after which mice were monitored off-therapy until day 30 or day 60, respectively, to assess survival. Fungal burden was also assessed in the survival arm. VT-1129 plasma and brain concentrations were also measured. VT-1129 reached a significant maximal survival benefit (100%) at a dose of 20 mg/kg once daily. VT-1129 at doses of ≥ 0.3 mg/kg/day and each dose of fluconazole significantly reduced brain tissue fungal burden compared to control after both 7 and 14 days of dosing. Fungal burden was also undetectable in most mice treated with dose of ≥ 3 mg/kg/day, even ≥ 20 days after dosing had stopped in the survival arm. In contrast, rebounds in fungal burden were observed with fluconazole. These results are consistent with the VT-1129 concentrations, which remained elevated long after dosing had stopped. These data demonstrate the potential utility of VT-1129 to have a marked impact in the treatment of cryptococcal meningitis.

Abstract Background Trichosporon species may colonize the skin, respiratory tract and gastrointestinal tract of human beings. The yeast is recognized as etiological agent of white piedra, a superficial mycosis. Nevertheless, immunocompromised hosts may develop invasive Trichosporonosis. Central nervous system trichosporonosis is a very rare clinical manifestation. In fact, only a few cases have been published in the literature and none of them was caused by Trichosporon inkin. Case presentation Here we report the first clinical case of meningoencephalitis due to this species in a female previously healthy patient under corticosteroids and antibiotics therapy for several months. She was submitted to an invasive procedure to remove a left sided acoustic neuroma and further developed a cerebrospinal fistula. After some days of the procedure, she presented a predominantly and intensive occipital holocranial headache, followed by vomiting, hyporexia, weight loss, asthenia, irritability, difficulty to concentrate and rotator vertigo. The patient further developed a cerebrospinal fistula in the occipital region and was submitted to a surgical correction. After several months of clinical interventions, she was diagnosed with CNS Trichosporonosis, after Magnetic Resonance Imaging and positive microbiological cultures obtained within two different occasions (2 weeks apart). Despite the antifungal therapy with Amphotericin B and Voriconazole, the patient did not survive. Conclusions Despite CNS Fungal infections are mostly due to Cryptococcus spp., other emergent yeasts, such as T. inkin may be considered as a likely etiological agent. This is the first case report of CNS Trichosporonosis, where species identification was performed with rDNA sequencing.

Jarvis J, Harrison T.

Mukap, M., Sprod, C., Tefuarani, N., Laman, M., Page-Sharp, M., Salman, S., Moore, B. R., Batty, K. T., Davis, T. M. E., Manning, L.

Background: Dried blood spot (DBS) antibiotic assays can facilitate pharmacokinetic (PK) studies in situations where venous blood sampling is logistically and/or ethically challenging. In this study we aimed to demonstrate the validity of a DBS ceftriaxone assay in a PK study of children from Papua New Guinea (PNG) with severe illness, a setting in which healthcare resources are limited and anemia is common.Methods: Using a previously validated liquid chromatography-mass spectroscopy (LC-MS/MS) assay, serial plasma and DBS ceftriaxone concentrations were measured in PNG children aged 5-10 years with acute bacterial meningitis or severe pneumonia. The concentration-time data were incorporated into population PK models.Results: Ten children were recruited with an admission hematocrit of 0.22-0.52. Raw data demonstrated good correlation between plasma and DBS concentrations (Spearman rs =0.94 [95% confidence interval 0.91-0.97], P