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.

Fiona McGill, Michael J Griffiths, Laura J Bonnett, Anna Maria Geretti, Benedict D Michael, Nicholas J Beeching, David McKee, Paula Scarlett, Ian J Hart, Kenneth J Mutton, Agam Jung, Guleed Adan, Alison Gummery, Wan Aliaa Wan Sulaiman, Katherine Ennis, Antony P Martin, Alan Haycox, Alastair Miller, Tom Solomon, UK Meningitis Study Investigators

Viruses are the most commonly identified cause of meningitis in UK adults, and lead to substantial long-term morbidity. Delays in getting a lumbar puncture and unnecessary treatment with antivirals were associated with longer hospital stays. Rapid diagnostics and rationalising treatments might reduce the burden of meningitis on health services.

Catherine H Bozio, Jeni Vuong, E Kainne Dokubo, Mosoka P Fallah, Lucy A McNamara, Caelin C Potts, John Doedeh, Miatta Gbanya, Adam C Retchless, Jaymin C Patel, Thomas A Clark, Henry Kohar, Thomas Nagbe, Peter Clement, Victoria Katawera, Nuha Mahmoud, Harouna M Djingarey, Anne Perrocheau, Dhamari Naidoo, Mardia Stone, Roseline N George, Desmond Williams, Alex Gasasira, Tolbert Nyenswah, Xin Wang, LeAnne M Fox, Liberian Meningococcal Disease Outbreak Response Team

This outbreak featured high attack and case fatality rates. Clinical presentation was broadly consistent with previous meningococcal disease outbreaks, but predominance of gastrointestinal symptoms was unusual compared with previous African meningitis epidemics. The outbreak strain was genetically similar to NmC CC10217, which caused meningococcal disease outbreaks in Niger and Nigeria. CC10217 had previously been identified only in the African meningitis belt.

Seilesh Kadambari, Heli Harvala, Peter Simmonds, Andrew J Pollard, Manish Sadarangani

Human parechovirus infections are the second most common cause of viral meningitis in children. These infections are most frequently seen in infants younger than 90 days. Clinical manifestations include encephalitis, meningitis, myocarditis, and sepsis, which can lead to serious neurodevelopmental sequelae in young infants. Molecular techniques, including PCR assays, are the preferred diagnostic methods and have contributed to an increase in reported cases, along with an increasing awareness of the causal role of human parechovirus in infant diseases.

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

M. Klein, C. Höhne, B. Angele, T. Högen, H.W. Pfister, H. Tüfekci, U. Koedel

Therapy with antibiotics, dexamethasone, and supportive intensive care has improved the prognosis of pneumococcal meningitis, but mortality remains high. Here, we investigated an adjunctive combination therapy of the non-bacteriolytic antibiotic daptomycin plus several anti-inflammatory agents to identify the currently most promising adjunctive combination therapy for pneumococcal meningitis.

Stott, K. E., Beardsley, J., Whalley, S., Kibengo, F. M., Mai, N. T. H., Kolamunnage-Dona, R., Hope, W., Day, J.

There is a limited understanding of the population pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAmB) for cryptococcal meningitis (CM). A PK study was conducted in n=42 patients receiving DAmB 1 mg/kg q24h. A 2-compartment PK model was developed. Patient weight influenced clearance and volume in the final structural model. Monte Carlo simulations estimated drug exposure associated with various DAmB dosages. A search was conducted for trials reporting outcomes of CM patients treated with DAmB monotherapy and a meta-analysis was performed.The PK parameter means (standard deviation) were: clearance, 0.03 (0.01) x weight + 0.95 (0.02) litres/hour; volume, 0.89 (0.90) x weight + 1.54 (1.13) litres; first-order rate constant from central to peripheral compartment, 7.12 (6.50) hours-1; from peripheral to central compartment, 12.13 (12.50) hours-1. The meta-analysis suggested that DAmB dosage explained most of the heterogeneity in cerebrospinal fluid (CSF) sterility, but not in mortality outcomes. Simulations of area under concentration-time curve (AUC144-168) resulted in median (interquartile range) values 5.83 mg.h/litre (4.66-8.55), 10.16 (8.07-14.55) and 14.51 (11.48-20.42), with dosages of 0.4, 0.7 and 1.0 mg/kg q24h respectively.DAmB PK is described adequately by a linear model that incorporates weight on clearance and volume. Inter-patient PK variability is modest and unlikely to be responsible for variability in clinical outcome. There is a discord between the impact that drug exposure has on CSF sterility and on mortality outcomes, which may be due to cerebral pathology not reflected in CSF fungal burden, in addition to clinical variables.

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.

Barash, J. R., Castles, J. B., Arnon, S. S.

Infant botulism is an infectious intestinal toxemia that results from colonization of the infant large bowel by Clostridium botulinum (or rarely, by neurotoxigenic C. baratii or C. butyricum), with subsequent intraintestinal production and absorption of botulinum neurotoxin that then produces flaccid paralysis. The disease is often initially misdiagnosed as suspected sepsis or meningitis, diagnoses that require prompt empiric antimicrobial therapy. Antibiotics may also be needed to treat infectious complications of infant botulism, such as pneumonia or urinary tract infection. Clinical evidence suggests (see included case report) that broad-spectrum antibiotics that are eliminated by biliary excretion may cause progression of the patient’s paralysis by lysing C. botulinum vegetative cells in the large bowel lumen and thereby increasing the amount of botulinum neurotoxin available for absorption. The purpose of this antimicrobial susceptibility study was to identify an antimicrobial agent with little or no activity against C. botulinum that could be used to treat infant botulism patients initially diagnosed with suspected sepsis or meningitis, or who acquired secondary infections, without lysing C. botulinum. Testing of 12 antimicrobial agents indicated that almost all California infant botulism patient isolates are susceptible to most clinically utilized antibiotics and are also susceptible to newer antibiotics not previously tested against large numbers of C. botulinum patient isolates. No antibiotic with little or no activity against C. botulinum was identified. These findings reinforce the importance of promptly treating infant botulism patients with Human Botulism Immune Globulin (BIG-IV; BabyBIG®).

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.

Yuvaraj Jayaraman, Balaji Veeraraghavan, Girish Kumar Chethrapilly Purushothaman, Bharathy Sukumar, Boopathi Kangusamy, Ambujam Nair Kapoor, Nivedita Gupta, Sanjay Madhav Mehendale, Hospital Based Sentinel Surveillance of Bacterial Meningitis (HBSSBM) Network Team

by Yuvaraj Jayaraman, Balaji Veeraraghavan, Girish Kumar Chethrapilly Purushothaman, Bharathy Sukumar, Boopathi Kangusamy, Ambujam Nair Kapoor, Nivedita Gupta, Sanjay Madhav Mehendale, Hospital Based Sentinel Surveillance of Bacterial Meningitis (HBSSBM) Network Team Background Worldwide, acute bacterial meningitis is a major cause of high morbidity and mortality among under five children, particularly in settings where vaccination for H. influenzae type b, S. pneumoniae and N. meningitidis is yet to be introduced in the national immunization programs. Estimation of disease burden of bacterial meningitis associated with these pathogens can guide the policy makers to consider inclusion of these newer vaccines in the immunization programs. A network of hospital based sentinel surveillance was established to generate baseline data on the burden of bacterial meningitis among children aged less than 5 years in India and to provide a platform for impact assessment following introduction of the Pentavalent and Pneumococcal Conjugate Vaccines (PCV). Methods During surveillance carried out in select hospitals across India in 2012–2013, information regarding demographics, immunization history, clinical history, treatment details and laboratory investigations viz. CSF biochemistry, culture, latex agglutination and PCR was collected from children aged 1 to 59 months admitted with suspected bacterial meningitis. Results A total of 3104 suspected meningitis cases were enrolled from 19,670 children admitted with fever at the surveillance hospitals. Of these, 257 cases were confirmed as cases of meningitis. They were due to S. pneumoniae (82.9%), H. influenzae type b (14.4%) and N. meningitidis (2.7%). Highest prevalence (55.3%) was observed among children 1 to 11 months. Antimicrobial susceptibility testing revealed considerable resistance among S. pneumoniae isolates against commonly used antibiotics such as cotrimoxazole, erythromycin, penicillin, and cefotaxime. More commonly prevalent serotypes of S. pneumoniae in circulation included 6B, 14, 6A and 19F. More than 90% of serotypes identified were covered by Pneumococcal Conjugate Vaccine 13. Conclusions We observed that S. pneumoniae was the commonest cause of bacterial meningitis in hospitalized children under five years of age in India. Continued surveillance is expected to provide valuable information and trends in future, to take an informed decision on introduction of pneumococcal vaccination in Universal Immunization Programme in India and will also eventually help in post-vaccination impact evaluation.

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.

Deng, L., Mu, R., Weston, T. A., Spencer, B. L., Liles, R., Doran, K. S.

Streptococcus agalactiae (Group B Streptococcus, GBS) is often a commensal bacterium that colonizes healthy adults asymptomatically and is a frequent inhabitant of the vaginal tract in women. However, in immune-compromised individuals, particularly the newborn, GBS may transition to an invasive pathogen and cause serious disease. Despite currently recommended intrapartum antibiotic prophylaxis for GBS-positive mothers, GBS remains a leading cause of neonatal septicemia and meningitis. To adapt to the various host environments encountered during its disease cycle, GBS possesses multiple two-component regulatory systems (TCS). Here we investigate the contribution of a transcriptional regulator containing a LytTR domain, LtdR, to GBS pathogenesis. Disruption of the ltdR gene in the GBS chromosome resulted in a significant increase in bacterial invasion into human cerebral microvascular endothelial cells (hCMEC) in vitro as well as greater penetration of the Blood-Brain Barrier (BBB) and the development of meningitis in vivo. Correspondingly, infection of hCMEC with the ltdR mutant resulted in increased secretion of pro-inflammatory cytokines IL-8, CXCL-1, and IL-6. Further, using a mouse model of GBS vaginal colonization, we observed that the ltdR mutant was cleared more readily from the vaginal tract and also resulted in increased cytokine production from human vaginal epithelial cells. RNA-sequencing revealed global transcriptional differences between the ltdR mutant and the parental WT GBS strain. These results suggest that LtdR regulates many bacterial processes that can influence GBS-host interactions to promote both bacterial persistence and disease progression.

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.

Chi Li, Wen-ya Feng, Ai-wei Lin, Guo Zheng, Yan-chun Wang, Yan-jun Han, Jian-min Zhong, Jing Bi, Qiong Luo, Fang-chao Zhao, Ping Jin, Ling-yun Guo, Na Li, Jie Yu, Xiao-tao Yang, Jun Liang, Ji-kui Deng, Yong-jun Li, Yu-jiao Wang, Xiong-ying Yu, Dong-meng Wang, Liang Ru, Juan Chen, Yong-hong Yang, Qiao-zhi Yang, Gang Liu

To explore the clinical characteristics and etiology of bacterial meningitis (BM) in Chinese children.

Yu, J., Li, B., Chen, X., Lu, J., Wang, D., Gu, T., Kong, W., Wu, Y.

Streptococcus pneumoniae is a major cause of invasive pneumococcal disease, septicemia and meningitis that can result in high morbidity rates in children under five years old. The current polysaccharide-based vaccines can provide type-specific immunity, but a broad spectrum vaccine would provide greater coverage. Therefore, developing pneumococcal protein-based vaccines that can extend to more sera types is highly important.In this study, we vaccinated mice with a systemic vaccine via the subcutaneous (s.c.) route, which is a mixture of fusion protein PsaA-PspA23 and a single protein PspA4, with aluminum hydroxide as an adjuvant. As a comparison, mice were immunized intranasally with a mucosal vaccine, which is a mixture of PspA2-PA-BLP and PspA4-PA-BLP, via the intranasal (i.n.) route. Both immunization processes were followed by challenging with Streptococcus pneumonia bacterial from two different PspA families. Specific IgG titers in the serum and specific IgA titers in the mucosa were determined following immunizations. Bacteria loads and survival rates after challenge were compared.Both the systemic vaccine and the mucosal vaccine induced a significant increase of IgG against PspAs. Only the mucosal vaccine also induced specific IgA in the mucosa. The two vaccines provided protection, but each vaccine showed an advantage. The systemic vaccine induced higher serum antibodies, whereas the mucosal vaccine limited the bacterial load in the lung and blood. Therefore, co-immunizations with both types of vaccines may be implemented in the future.

J.M. Balada-Llasat, Ning Rosenthal, Rodrigo Hasbun, Louise Zimmer, Christine C. Ginocchio, Steven Duff, Jessica Chung, Samuel Bozzette

To determine the associated cost related to diagnosis and treatment of meningoencephalitis (ME) in adult patients in the United States.

L. Allan-Blitz et al.

Lindi-Marie Coetzee, Naseem Cassim, Charlotte Sriruttan, Mabatho Mhlanga, Nelesh P. Govender, Deborah Kim Glencross

by Lindi-Marie Coetzee, Naseem Cassim, Charlotte Sriruttan, Mabatho Mhlanga, Nelesh P. Govender, Deborah Kim Glencross Introduction Cryptococcal meningitis (CM) is an opportunistic fungal disease with a high mortality among HIV-positive patients with severe immunosuppression (CD4 count…

K.L. Chew, C.K. Lee, G.B. Cross, L.H.W. Lum, B. Yan, R. Jureen

Cryptococcosis is a fungal infection caused by Cryptococcus neoformans and Cryptococcus gattii. Although it typically affects immunocompromised patients, it can cause disease in immunocompetent patients. The range of clinical infections includes chronic skin infections, lung infections and meningitis. Diagnostic modalities include cryptococcal antigen (CrAg) detection tests and culture from infected sites. More recently, the Biofire meningitis/encephalitis (ME) panel (bioMérieux, Marcy l’Etoile, France) was added to the range of available tests for cryptococcal meningitis.

Gallegos, Cinthia; Tobowlosky, Farrell; Nigo, Masayuki; Hasbun, Rodrigo

Objectives: To report the prevalence of delayed cerebral injury in adults with bacterial meningitis and explore its association with adjunctive steroids. Design: Retrospective analysis of adults with bacterial meningitis between 2005 and 2016. Setting: Ten hospitals in the Greater Houston area. Patients: Consecutive subjects with culture proven community-acquired bacterial meningitis. Intervention: Subjects were categorized as receiving or not adjunctive steroids within 4 hours. Measurements and Main Results: A total of 120 patients were identified who were admitted with community-acquired bacterial meningitis. Delayed cerebral injury was seen in five of 120 patients (4.1%); all five patients had fever and abnormal neurologic examinations. Adjunctive steroids within 4 hours were more likely given to those with delayed cerebral injury (5/5,100% vs 43/115, 37.5%; p = 0.01). Of the patients who developed delayed cerebral injury, three had Streptococcus pneumoniae, one had methicillin-resistant Staphylococcus aureus, and one had Listeria monocytogenes isolated. We observed an adverse clinical outcome as defined by the Glasgow Outcome Scale in four of the five patients (80%). Conclusions: Delayed cerebral injury occurred in 4.1% of adults with bacterial meningitis, and it was associated with the use of adjunctive steroids. Future studies should explore the etiology and prevention of this devastating complication. Drs. Gallegos, Nigo, and Tobowlosky screened the patients and did the data collection. Dr. Gallegos created the first draft of the article. Dr. Hasbun designed the study. Dr. Hasbun participated in the data interpretation and edited the article. Dr. Hasbun wrote the final draft of the article and made all the changes suggested by the coauthors. Supported, in part, by Grant A Starr Foundation. Dr. Hasbun is a consultant for bioMérieux and a speaker for Pfizer, Merck, Medicines Company, and BioFire. Dr. Hasbun received funding from BioFire Diagnostics, Biomeriaux, and Merck. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Rodrigo.Hasbun@uth.tmc.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Tropical Medicine & International Health, EarlyView.

T. Gupalova, G. Leontieva, T. Kramskaya, K. Grabovskaya, E. Bormotova, D. Korjevski, A. Suvorov

by T. Gupalova, G. Leontieva, T. Kramskaya, K. Grabovskaya, E. Bormotova, D. Korjevski, A. Suvorov Streptococcus agalactiae, or group B streptococcus (GBS), is an important pathogen as it is the leading cause of neonatal deaths due to sepsis, meningitis or bacterial pneumonia. Although the development of an effective and safe GBS vaccine is on the agenda of many research labs, there is no GBS vaccine on the market yet. In the present study we attempted to engineer a live vaccine strain based on Bac, a surface protein of GBS, incorporated into a surface fimbrial protein of probiotic Enterococcus. The resulting strain induced specific systemic and local immune responses in mice and provided protection against GBS when administered via the intranasal, oral or intravaginal immunization routes.

Jimenez de Oya, N., Blazquez, A.-B., Casas, J., Saiz, J.-C., Martin Acebes, M. A.

Mosquito-borne flaviviruses are a group of RNA viruses that constitute global threats for human and animal health. Replication of these pathogens is strictly dependent on cellular lipid metabolism. We have evaluated the effect of the pharmacological activation of Adenosine Monophosphate-activated Protein Kinase (AMPK), a master regulator of lipid metabolism, on the infection of three medically relevant flaviviruses: West Nile virus (WNV), Zika virus (ZIKV) and dengue virus (DENV). WNV is responsible for recurrent outbreaks of meningitis and encephalitis affecting humans and horses worldwide. ZIKV has caused a recent pandemic associated with birth defects (microcephaly), reproductive disorders, and severe neurological complications (Guillain-Barré syndrome). DENV is the etiological agent of the most prevalent mosquito-borne viral disease that can induce a potentially lethal complication called severe dengue. Our results showed, for the first time, that activation of AMPK using the specific small molecule activator PF-06409577 reduced both WNV, ZIKV, and DENV infection. This antiviral effect was associated to an impairment of viral replication due to the modulation of host cell lipid metabolism exerted by the compound. These results support that the pharmacological activation of AMPK, which currently constitutes an important pharmacological target for human diseases, could also provide a feasible approach for broad-spectrum host-directed antiviral discovery.

Hickerson B, Westover J, Jung K, et al.

AbstractLymphocytic choriomeningitis virus (LCMV) poses a substantial risk to immunocompromised individuals. The case fatality rate in recent clusters of LCMV infection in immunosuppressed organ transplantation recipients has exceeded 70%. In the present study, we demonstrate potent antiviral activity of favipiravir against acute, disseminated LCMV infection in NZB mice. Treatment resulted in complete protection against mortality and dramatic reductions in viral loads. In contrast, ribavirin, the current antiviral of choice, was mostly ineffective. Our findings, and the high lethality associated with LCMV infection in transplant recipients, support the consideration of favipiravir as a first-line therapeutic option.

Abstract Background Limited data are available on the effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) in resource-poor settings and PCV naïve populations. The Dominican Republic introduced PCV13 in September 2013 using a 2 + 1 schedule (2, 4, and 12 months) without a catch-up campaign. We evaluated PCV13 effectiveness against vaccine-type (VT) invasive pneumococcal disease (IPD) among children in the Dominican Republic. Methods We conducted a matched case-control study. A case-patient was defined as VT-IPD identified by culture or polymerase chain reaction (PCR) from a normally sterile-site in a hospitalized child who was age-eligible to have received ≥1 PCV13 dose. Four age- and neighborhood-matched controls were enrolled for each case-patient. We collected demographic, vaccination history, and risk factor data. Conditional logistic regression was performed. Vaccine effectiveness was calculated as (1- adjusted matched odds ratio for vaccination) X 100%. Results We enrolled 39 case-patients and 149 matched-controls. Most case-patients had pneumonia with pleural effusion (64%), followed by meningitis (28%) and septicemia (13%). The most common pneumococcal serotypes identified included 14 (18%), 3 (13%), 19A (10%), and 1 (8%). Fewer case-patients had ≥1 PCV13 dose as compared to controls (61.5% vs. 80.0%; p = 0.006). Adjusting for malnutrition and socioeconomic status, VE of ≥1 PCV13 dose compared to no doses was 67.2% (95% CI: 2.3% to 90.0%). Only 44% of controls were up-to-date for PCV13, suggesting low vaccine coverage in the population. Conclusions We found that PCV13 provided individual protection against VT-IPD in this resource-poor setting with a PCV-naïve population, despite low PCV13 coverage. Expanding vaccination coverage might increase PCV13 impact.

Abstract Background As an opportunistic pathogen, E. gallinarum mainly leads to nosocomial infections, and it’s multi-drug resistance has gained more and more attention. Central nervous system infections caused by E. gallinarum are rare, but have been reported more often in recent years. The previous cases were generally secondary to neurosurgery, especially ventriculoperitoneal shunts. In recent years, the cases largely occurred in patients with impaired immune function. The patient in our report may have had dual risk factors (immune impairment and an invasive surgical procedure). Case presentation The patient, a 35-year-old female, was admitted to our hospital for headaches of 3 days duration accompanied by nausea and vomiting for 2 days. The patient had fevers and chills for 3 days before admission; the peak body temperature was 38.5 °C. The patient had a splenectomy in our hospital 2 years earlier for thrombocytopenia and was thought to be immunocompromised. The abnormal findings on physical examination and laboratory testing were as follows: neck stiffness, present; lumbar puncture: pressure, 300 mmH2O; Pandy’s test, positive; white blood cell (WBC) count, 1536 × 106/L; monocyte count, 602 × 106/L; monocyte percentage, 39.2%; multinucleate cell count, 934 × 106/L; multinucleate cell percentage, 60.8%; protein, 1.08 g/L; WBC count, 21.1 × 109/ L; neutrophil percentage, 85.3%; neutrophil count, 20.55 × 109/L; C reactive protein (CRP): 136.4 mg/L; procalcitonin, 6.70 ng/mL. The patient was given meropenem (2.0 g, intravenous infusion, every 8 h) for anti-infection supplemented with other symptomatic support treatments. The patient’s fever and headache had no significant relief. Conclusions Central nervous system infections caused by E. gallinarum are rare, but should be suspected, particularly inpatients with impaired immune function or ineffective treatment. Avoiding long-term invasive treatment and improving immunity are helpful to reduce the occurrence of E. gallinarum infections. Early detection and diagnosis, as well as rational antibiotic use, are the keys to achieve satisfactory efficacy.

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.

Tatiana Metcalf, Jaime Soria, Silvia M. Montano, Eduardo Ticona, Carlton A. Evans, Luz Huaroto, Matthew Kasper, Eric S. Ramos, Nicanor Mori, Podjanee Jittamala, Kesinee Chotivanich, Irwin F. Chavez, Pratap Singhasivanon, Sasithon Pukrittayakamee, Joseph R. Zunt

by Tatiana Metcalf, Jaime Soria, Silvia M. Montano, Eduardo Ticona, Carlton A. Evans, Luz Huaroto, Matthew Kasper, Eric S. Ramos, Nicanor Mori, Podjanee Jittamala, Kesinee Chotivanich, Irwin F. Chavez, Pratap Singhasivanon, Sasithon Pukrittayakamee, Joseph R. Zunt Background Meningitis caused by Mycobacterium tuberculosis is a major cause of morbidity and mortality worldwide. We evaluated the performance of cerebrospinal fluid (CSF) testing with the GeneXpert MTB/RIF assay versus traditional approaches for diagnosing tuberculosis meningitis (TBM). Methods Patients were adults (n = 37) presenting with suspected TBM to the Hospital Nacional Dos de Mayo, Lima, Peru, during 12 months until 1st January 2015. Each participant had a single CSF specimen that was divided into aliquots that were concurrently tested for M. tuberculosis using GeneXpert, Ziehl-Neelsen smear and culture on solid and liquid media. Drug susceptibility testing used Mycobacteria Growth Indicator Tube (MGIT 960) and the proportions method. Results 81% (30/37) of patients received a final clinical diagnosis of TBM, of whom 63% (19/30, 95% confidence intervals, CI: 44–80%) were HIV-positive. 22% (8/37, 95%CI: 9.8–38%), of patients had definite TBM. Because definite TBM was defined by positivity in any laboratory test, all laboratory tests had 100% specificity. Considering the 30 patients who had a clinical diagnosis of TBM: diagnostic sensitivity was 23% (7/30, 95%CI: 9.9–42%) for GeneXpert and was the same for all culture results combined; considerably greater than 7% (2/30, 95%CI: 0.82–22%) for microscopy; whereas all laboratory tests had poor negative predictive values (20–23%). Considering only the 8 patients with definite TBM: diagnostic sensitivity was 88% (7/8, 95%CI: 47–100%) for GeneXpert; 75% (6/8, 95%CI: 35–97%) for MGIT culture or LJ culture; 50% (4/8, 95%CI 16–84) for Ogawa culture and 25% (2/8, 95%CI: 3.2–65%) for microscopy. GeneXpert and microscopy provided same-day results, whereas culture took 20–56 days. GeneXpert provided same-day rifampicin-susceptibility results, whereas culture-based testing took 32–71 days. 38% (3/8, 95%CI: 8.5–76%) of patients with definite TBM with data had evidence of drug-resistant TB, but 73% (22/30) of all clinically diagnosed TBM (definite, probable, and possible TBM) had no drug-susceptibility results available. Conclusions Compared with traditional culture-based methods of CSF testing, GeneXpert had similar yield and faster results for both the detection of M. tuberculosis and drug-susceptibility testing. Including use of the GeneXpert has the capacity to improve the diagnosis of TBM cases.

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.

Anouk M. Oordt-Speets, Renee Bolijn, Rosa C. van Hoorn, Amit Bhavsar, Moe H. Kyaw

by Anouk M. Oordt-Speets, Renee Bolijn, Rosa C. van Hoorn, Amit Bhavsar, Moe H. Kyaw Bacterial meningitis is a global public health concern, with several responsible etiologic agents that vary by age group and geographical area. The aim of this systematic review and meta-analysis was to assess the etiology of bacterial meningitis in different age groups across global regions. PubMed and EMBASE were systematically searched for English language studies on bacterial meningitis, limited to articles published in the last five years. The methodological quality of the studies was assessed using a customized scoring system. Meta-analyses were conducted to determine the frequency (percentages) of seven bacterial types known to cause meningitis: Escherichia coli, Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae, group B Streptococcus agalactiae, Staphylococcus aureus, and Listeria monocytogenes, with results being stratified by six geographical regions as determined by the World Health Organization, and seven age groups. Of the 3227 studies retrieved, 56 were eligible for the final analysis. In all age groups, S. pneumoniae and N. meningitidis were the predominant pathogens in all regions, accounting for 25.1–41.2% and 9.1–36.2% of bacterial meningitis cases, respectively. S. pneumoniae infection was the most common cause of bacterial meningitis in the ‘all children’ group, ranging from 22.5% (Europe) to 41.1% (Africa), and in all adults ranging from 9.6% (Western Pacific) to 75.2% (Africa). E. coli and S. pneumoniae were the most common pathogens that caused bacterial meningitis in neonates in Africa (17.7% and 20.4%, respectively). N. meningitidis was the most common in children aged ±1–5 years in Europe (47.0%). Due to paucity of data, meta-analyses could not be performed in all age groups for all regions. A clear difference in the weighted frequency of bacterial meningitis cases caused by the different etiological agents was observed between age groups and between geographic regions. These findings may facilitate bacterial meningitis prevention and treatment strategies.

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.

Tugume L, Rhein J, Hullsiek K, et al.

AbstractBackgroundCryptococcal meningitis can occur in persons with less apparent immunosuppression. We evaluated clinical characteristics and outcomes of persons with HIV-related Cryptococcus presenting with higher CD4 counts.MethodsWe enrolled 736 participants from two prospective cohorts in Uganda and South Africa from November 2010 to May 2017. We compared participants with CD4 =100 cells/mcL. Participants with CD4 >=100 cells/mcL presented more often with altered mental status (52% vs 39%; P=.03) despite a 10-fold lower initial median CSF fungal burden of 7,850 (IQR 860–65,500) vs 79,000 (IQR 7,400–380,000) CFU/mL; P=100 cells/mcL had higher median CSF levels of interferon-gamma,interleukin (IL)-6, IL-8, and IL-13; and lower monocyte chemokine, CCL2 (P=100 cells/mcL presented more frequently with altered mental status despite having 10-fold lower fungal burden and with greater Th2 (IL-13) immune response. Higher CD4 count was protective despite an increased propensity for immune-mediated damage, consistent with damage-response framework.

Ali Pormohammad , Mohammad Javad Nasiri , Seyed Mohammad Riahi , Fatemeh Fallah

Abstract Introduction Human immunodeficiency virus (HIV)‐infected individuals are at increased risk for all forms of extrapulmonary tuberculosis (TB), including tuberculous meningitis (TBM). This study aimed to investigate the frequency of HIV in patients with TBM. Methods PubMed, Embase, Web of Science and Cochrane Library were searched for articles including relevant data. Stata version 14.0 (StataCorp, College Station, Texas, USA) was used to analyse the data. Results Twenty studies were identified. The pooled frequency of HIV among adult patients with TBM was 38.0% (95% CI: 21.0–57.0; I2 = 97%). In children (under the age of 15 years), 6.0% (95% CI: 1.0–13.0; I2 = 0.0%) had HIV infection. In patients with bacterial meningitis other than TBM, 36.0% (95% CI: 19.0–53.0; I2 = 100%) were HIV‐infected. Conclusions A relatively high frequency of HIV in patients with TBM was indicated by our study. Establishment of diagnostic criteria and effective treatment strategies for TBM/HIV co‐infection are recommended for better management of patients with TBM+HIV.

Shaw, K. J., Schell, W. A., Covel, J., Duboc, G., Giamberardino, C., Kapoor, M., Moloney, M., Soltow, Q. A., Tenor, J. L., Toffaletti, D. L., Trzoss, M., Webb, P., Perfect, J. R.

Cryptococcal meningitis (CM), caused primarily by Cryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. Here we evaluated the in vitro and in vivo activity of several compounds including APX001A and its prodrug APX001, currently in clinical development for invasive fungal infections. These compounds target the conserved Gwt1 enzyme that is required for the localization of glycosylphosphatidyl inositol (GPI)-anchored cell wall mannoproteins in fungi.The Gwt1 inhibitors had low MIC values, ranging from 0.004 μg/mL to 0.5 μg/mL against both C. neoformans and C. gattii. APX001A and APX2020 demonstrated in vitro synergy with fluconazole (FICI 0.37). In a CM model, APX001 and fluconazole each, alone, reduced log10 colony forming units (CFU)/g brain (0.78 and 1.04, respectively), whereas the combination resulted in a reduction of 3.52 log10 CFU/g brain.Efficacy as measured by a reduction in brain and lung fungal burden was also observed for another Gwt1 inhibitor prodrug, APX2096, where dose dependent reductions in fungal burden ranged between 5.91 and 1.79 log10 CFU/g lung and between 7.00 and 0.92 log10 CFU/g brain, representing near or complete sterilization of lung and brain tissue at the higher doses. These data support further clinical evaluation of this new class of antifungal agents for CM.

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.

J. Bodilsen, Merete Storgaard, L. Larsen, L. Wiese, J. Helweg-Larsen, A.-M. Lebech, C. Brandt, C. Østergaard, H. Nielsen, the DASGIB study group

To monitor epidemiological trends of infectious meningitis (bacterial and viral) and encephalitis in Denmark.

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.

Abstract Background Invasive Meningococcal Disease (IMD) is a rare and critical disease in Japan. Most of these cases are caused by capsulated Neisseria meningitidis strains. Non-capsulated (non-typable) strains are considered relatively low-pathogenic and can colonize in the nasopharynx of healthy children and young adults. As far as could be ascertained, only twelve IMD cases due to non-capsulated strains have been reported in the literature. No clear risk factors could be identified in a literature review (unknown or immunocompetent, seven cases; C6 deficiency, three cases). Case presentation We report a Japanese male taxi driver with bacteremia and meningitis due to non-capsulated N. meningitidis. He had a fever and shaking chills. Ceftriaxone was administered, and the patient finally recovered. During the clinical course, relative adrenal insufficiency occurred and was treated with hydrocortisone. A hidden co-morbidity, immunoglobulin G4 (IgG4)-related disease, was revealed in the past surgical history (a resection of bilateral orbital tumors), which included symptoms (swelling lachrymal glands and lymph nodes), elevated IgG4, immunoglobulin E, and hypocomplementemia. He recovered finally and no recurrence was observed. Conclusions Our IMD case is the first reported in Japan, where IMD is not considered pandemic. The patient had a history of IgG4-related disease, although we could not establish a clear relationship between the patient’s IMD and co-morbidity. A collection of further clinical cases might establish the risk factors and characteristics of IMD that could be caused by this neglected pathogen, non-capsulated N. meningitidis.

Abstract Background Although paradoxical reactions (PRs) to anti-tuberculosis (anti-TB) therapy during treatment are well-established occurrences, PRs presenting as a new lesion after the completion of treatment are extremely rare, and little is known about the management of such cases, particularly of central nervous system (CNS) tuberculosis. Case presentation A 27-year-old female, with a past medical history of tuberculous meningitis 10 years ago and who completed the anti-TB treatment with asymptomatic remnant tuberculomas in the basal cistern, was admitted to our hospital because of a headache and the worsening of pre-existing visual disturbance. Contrast-enhanced T1-weighted brain magnetic resonance imaging (MRI) revealed new tuberculomas in the left sylvian fissure with a diffuse low signal around it. Because repeated polymerase chain reaction and Mycobacterium tuberculosis culture presented negative results and the patient had no laboratory data suggestive of a relapse of tuberculous meningitis, she was diagnosed with late-onset post-treatment PRs and treated with oral corticosteroids, tapered off over 1 year. Eventually, the symptoms were relieved, and the tuberculomas disappeared. Conclusions Clinicians should consider the possibility of PRs long after the completion of tuberculous meningitis treatment. Hence, a precise MRI-based examination is imperative for the follow-up of CNS tuberculosis, and the unnecessary administration of anti-TB drugs should be avoided. The use of corticosteroids as a treatment option for post-treatment PRs is seemingly safe when the isolated M. tuberculosis is sensitive to the first-line anti-TB therapy.

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.

Dr. Chandrakant S Moghe , Dr. Pramod Goel , Dr. Jalam Singh , Dr. Naina Ram Nayak , Dr. Meera Dhuria , Dr. Ruchi Jain , Dr. Rajesh Yadav , Dr. Ekta Saroha , Dr. Samir V Sodha , Dr. C S Aggarwal , Dr. Srinivas Venkatesh

Abstract Mumps, a vaccine‐preventable disease, causes inflammation of salivary glands and may cause severe complications such as encephalitis, meningitis, deafness, and orchitis/oophoritis. In India, mumps vaccine is not included in the universal immunization program and during 2009‐2014, 72 outbreaks with >1500 cases were reported. In August 2016, a suspected mumps outbreak was reported in Jaisalmer block, Rajasthan. We investigated to confirm the etiology, describe epidemiology, and recommend prevention and control measures. We defined a case as swelling in the parotid region in a Jaisalmer block resident between June 23 and September 10, 2016. We searched for cases in health facilities and house‐to‐house in affected villages and hamlets. We tested blood samples of cases for mumps IgM ELISA. We found 162 cases (60% males) with median age of 9.4 years (range: 7 month‐38 years) and 65 (40%) were females. Symptoms included fever (70%) and bilateral swelling in neck (65%). None were vaccinated against mumps. Most (84%) cases were school‐going children (3‐16 years old). The overall attack rate was 2%. Village A, with two hamlets, had the highest attack rate (hamlet 1=13% and hamlet 2=12%). School A of village A, hamlet 1 which accommodated 200 children in two classrooms had an attack rate of 55%. Of 18 blood samples from cases, 11 tested positive for mumps IgM ELISA. This was a confirmed mumps outbreak in Jaisalmer bl0ock that disproportionately affected school‐going children. We recommended continued surveillance, five‐day absence from school, and vaccination. This article is protected by copyright. All rights reserved.

Nahoko Katayama Ueda, Kiwamu Nakamura, Hayato Go, Hiroki Takehara, Nozomi Kashiwabara, Kazuaki Arai, Hiromu Takemura, Yoshiyuki Namai, Keiji Kanemitsu