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Objective: To give an overview of the recently reported literature on the aetiologies of meningitis and encephalitis in western sub-Saharan Africa., Methods: We conducted a scoping review following PRISMA guidance on published meningitis and encephalitis cases in the 16 countries of the United Nations-defined western sub-Saharan African region as identified in cohort studies, case series, and case reports, published 01/01/2000-08/01/2020, and available in four databases in August 2020 with an abstract in English, French or Italian., Results: There were 38 distinct pathogens identified from 91 cohort studies' data and 48 case reports or case series' data. In cohort-level data, the majority of cases were caused by Neisseria meningitidis (71.5%), Streptococcus pneumoniae (17.6%) and Haemophilus influenzae (7.3%). In case report- and case series-level data, 40.5% of patients were <18 years old, 28.6% were female, and 28.6% were known to be immunocompromised. The case fatality rate was 39.3%. The most commonly reported pathogens among immunocompetent patients were Salmonella species (13 cases) and Ebola virus (9 cases), and the most commonly reported pathogen among immunocompromised patients was Cryptococcus neoformans (18 cases). Most cohort cases (52.3%) derived from Niger followed by Burkina Faso (28.6%). Most cases from single reports or series were reported from Nigeria (21.4%), Mali (20.2%) and Burkina Faso (19.0%)., Conclusions: Given the small number of pathogens reported, our findings underscore the need to better screen, diagnose and monitor populations in western sub-Saharan Africa for additional CNS pathogens, including those posing significant outbreak risks., (© 2021 John Wiley & Sons Ltd.)

Background: Meningococcal meningitis (MM) is a life-threatening disease associated with approximately 10% case fatality rates and neurological sequelae in 10-20% of the cases. Recently, we have shown that the matrix metalloproteinase (MMP) inhibitor BB-94 reduced brain injury in a mouse model of MM. The present study aimed to assess whether doxycycline (DOX), a tetracycline that showed a neuroprotective effect as adjuvant therapy in experimental pneumococcal meningitis (PM), would also exert a beneficial effect when given as adjunctive therapy to ceftriaxone (CRO) in experimental MM., Methods: BALB/c mice were infected by the intracisternal route with a group C Neisseria meningitidis strain. Eighteen h post infection (hpi), animals were randomised for treatment with CRO [100 mg/kg subcutaneously (s.c.)], CRO plus DOX (30 mg/kg s.c.) or saline (control s.c.). Antibiotic treatment was repeated 24 and 40 hpi. Mouse survival and clinical signs, bacterial counts in cerebella, brain damage, MMP-9 and cyto/chemokine levels were assessed 48 hpi., Results: Analysis of bacterial load in cerebella indicated that CRO and CRO + DOX were equally effective at controlling meningococcal replication. No differences in survival were observed between mice treated with CRO (94.4%) or CRO + DOX (95.5%), (p > 0.05). Treatment with CRO + DOX significantly diminished both the number of cerebral hemorrhages (p = 0.029) and the amount of MMP-9 in the brain (p = 0.046) compared to untreated controls, but not to CRO-treated animals (p > 0.05). Levels of inflammatory markers in the brain of mice that received CRO or CRO + DOX were not significantly different (p > 0.05). Overall, there were no significant differences in the parameters assessed between the groups treated with CRO alone or CRO + DOX., Conclusions: Treatment with CRO + DOX showed similar bactericidal activity to CRO in vivo, suggesting no antagonist effect of DOX on CRO. Combined therapy significantly improved mouse survival and disease severity compared to untreated animals, but addition of DOX to CRO did not offer significant benefits over CRO monotherapy. In contrast to experimental PM, DOX has no adjunctive activity in experimental MM.

Neisseria meningitidis, a gram-negative diplococcus, is typically an asymptomatic coloniser of the oropharynx and nasopharynx. Passage of N. meningitidis into the bloodstream can cause invasive meningococcal disease (IMD), a potentially life-threatening illness with rapid onset that generally presents as meningitis, septicemia or both. Serogroup W IMD has been increasing in prevalence in recent years, and observations suggest that it may present with atypical signs and symptoms. Herein, a literature search was performed to identify trends in atypical serogroup W IMD presentation in order to review those that are most prevalent. Findings indicate that the most prevalent atypical presentations of serogroup W IMD include acute gastrointestinal (GI) symptoms, septic arthritis and bacteremic pneumonia or severe upper respiratory tract infection, notably epiglottitis. Atypical clinical presentation is associated with higher case fatality rates and can lead to misdiagnoses. Such risks highlight the need for clinicians to consider IMD in their differential diagnoses of patients with acute GI symptoms, septic arthritis or bacteremic pneumonia, primarily in regions where serogroup W is prevalent.

Introduction: Invasive meningococcal disease (IMD) is uncommon but still causes considerable public health burden due to its high mortality and morbidity. This review aims to quantitatively synthesise all published evidence pertinent to mortality caused by IMD and assess the effect of age and serogroup on case fatality rates (CFRs)., Methods: The PubMed and Embase databases, and the Cochrane Library were searched. Articles reporting national CFRs and published in English between January 2000 and May 2018 were eligible. The studies reporting mortality resulting from a specific symptom of IMD (e.g. meningococcal meningitis) were excluded. Mixed-effects logistic regression with a restricted cubic spline was used to analyse CFRs as a function of age. Random-effects meta-analyses were performed to estimate an overall CFR and CFRs by serogroup., Results: Among 48 eligible studies reporting national CFRs, 40 studies were included in meta-analyses representing 163,758 IMD patients. CFRs ranged from 4.1% to 20.0% with the pooled overall CFR of 8.3% (95% confidence interval (CI): 7.5-9.1%). Serogroup B was associated with a lower pooled CFR (6.9% (95%CI: 6.0-7.8%)) than other serogroups (W: 12.8% (95%CI: 10.7-15.0%); C: 12.0% (95%CI: 10.5-13.5%); Y: 10.8% (95%CI: 8.2-13.4%)). The meta-analysis was not performed for serogroup A (MenA) cases due to a small number of MenA patients who were enrolled in eligible studies. For laboratory confirmed IMD cases, the predicted CFR was 9.0% in infants, gradually decreased to 7.0% in 7-year olds, subsequently increased to 15.0% in young adults aged 28 years, stabilised between 15 and 20% in mid-aged adults and reached a high in elderly people., Conclusions: Our findings can provide useful information for better understanding the mortality risks, and quantifying the burden associated with IMD mortality., (Copyright © 2019. Published by Elsevier Ltd.)

Neisseria meningitidis infections in sub-Saharan Africa usually present with distinct symptoms of meningitis but very rarely as fulminant septicemia when reaching hospitals. In Europe, development of persistent meningococcal shock and multiple organ failure occurs in up to 30% of patients and is associated with a bacterial load of >10 6 /ml plasma or serum. We have prospectively studied 27 Ethiopian patients with meningococcal infection as diagnosed and quantified with real-time PCR in the cerebrospinal fluid (CSF) and serum. All presented with symptoms of meningitis and none with fulminant septicemia. The median N. meningitidis copy number (NmDNA) in serum was < 3.5 × 10 3 /ml, never exceeded 1.8 × 10 5 /ml, and was always 10-1000 times higher in CSF than in serum. The levels of LPS in CSF as determined by the limulus amebocyte lysate assay were positively correlated to NmDNA copy number ( r = 0.45, P = 0.030), levels of IL-1 receptor antagonist, ( r = 0.46, P = 0.017), and matrix metallopeptidase-9 (MMP-9; r = 0.009). We also compared the inflammatory profiles of 19 mediators in CSF of the 26 meningococcal patients (2 died and 2 had immediate severe sequelae) with 16 patients with Streptococcus pneumoniae meningitis (3 died and 3 with immediate severe sequelae). Of 19 inflammatory mediators tested, 9 were significantly higher in patients with pneumococcal meningitis and possibly linked to worse outcome.

In serogroup C Neisseria meningitidis , the cssA ( siaA ) gene codes for an UDP- N -acetylglucosamine 2-epimerase that catalyzes the conversion of UDP- N -acetyl-α-d-glucosamine into N -acetyl-d-mannosamine and UDP in the first step in sialic acid biosynthesis. This enzyme is required for the biosynthesis of the (α2→9)-linked polysialic acid capsule and for lipooligosaccharide (LOS) sialylation. In this study, we have used a reference serogroup C meningococcal strain and an isogenic cssA knockout mutant to investigate the pathogenetic role of surface-exposed sialic acids in a model of meningitis based on intracisternal inoculation of BALB/c mice. Results confirmed the key role of surface-exposed sialic acids in meningococcal pathogenesis. The 50% lethal dose (LD 50 ) of the wild-type strain 93/4286 was about four orders of magnitude lower than that of the cssA mutant. Compared to the wild-type strain, the ability of this mutant to replicate in brain and spread systemically was severely impaired. Evaluation of brain damage evidenced a significant reduction in cerebral hemorrhages in mice infected with the mutant in comparison with the levels in those challenged with the wild-type strain. Histological analysis showed the typical features of bacterial meningitis, including inflammatory cells in the subarachnoid, perivascular, and ventricular spaces especially in animals infected with the wild type. Noticeably, 80% of mice infected with the wild-type strain presented with massive bacterial localization and accompanying inflammatory infiltrate in the corpus callosum , indicating high tropism of meningococci exposing sialic acids toward this brain structure and a specific involvement of the corpus callosum in the mouse model of meningococcal meningitis., (Copyright © 2019 American Society for Microbiology.)

Background: Invasive meningococcal disease (IMD) is a highly lethal disease. Diagnosis is commonly performed by culture or Realtime-PCR (qPCR)., Aims: Our aim was to evaluate, retrospectively, whether culture positivity correlates with higher bacterial load and fatal outcome. Our secondary aim was to compare culture and qPCR sensitivity., Methods: The National Register for Molecular Surveillance was used as data source. Cycle threshold (CT), known to be inversely correlated with bacterial load, was used to compare bacterial load in different samples., Results: Three-hundred-thirteen patients were found positive for Neisseria meningitidis by qPCR, or culture, or both; 41 died (case fatality rate 13.1%); 128/143 (89.5%) blood samples and 138/144 (95.8%) CSF were positive by qPCR, 37/143 (25.9%) blood samples and 45/144 (31.2%) CSF were also positive in culture. qPCR was 3.5 times (blood) or 3.1 times (CSF) more sensitive than culture in achieving a laboratory diagnosis of IMD (OR 24.4; 95% CI 12.2-49.8; p < .10-4; Cohen's κ 0.08 for blood and OR 49.0; 95% CI 19.1-133.4; p<10-4; Cohen's κ 0.02; for CSF). Positivity of culture did not correlate with higher bacterial loads in blood (mean CT 27.7±5.71, and CT 28.1±6.03, p = 0.739 respectively in culture positive or negative samples) or in CSF (mean CT 23.1±4.9 and 24.7±5.4 respectively in positive or negative CSF samples, p = 0.11).CT values in blood from patients who died were significantly lower than in patients who survived (respectively mean 18.0, range 14-23 and mean 29.6, range 16-39; p<10-17). No deaths occurred in patients with CT in blood over 23. Positive blood cultures were found in 10/25 (40%) patients who died and in 32/163 (19.6%) patients who survived, p = 0.036, OR 2.73; 95% CL 1.025-7.215), however 60% of deaths would have remained undiagnosed with the use of culture only., Conclusions: In conclusion our study demonstrated that qPCR is significantly (at least 3 times) more sensitive than culture in the laboratory confirmation of IMD. The study also demonstrated that culture negativity is not associated with lower bacterial loads and with less severe cases. On the other side, in patients with sepsis, qPCR can predict fatal outcome since higher bacterial load, evaluated by qPCR, appears strictly associated with most severe cases and fatal outcome. The study also showed that molecular techniques such as qPCR can provide a valuable addition to the proportion of diagnosed and serotyped cases of IMD., Competing Interests: SG received a scholarship from GSK for meningococcal epidemiology; GSK did not participate in study design, data analysis, manuscript writing and in any other aspects related to the present work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors have no other conflict of interest.

Background: On April 25, 2017, a cluster of unexplained illnesses and deaths associated with a funeral was reported in Sinoe County, Liberia. Molecular testing identified Neisseria meningitidis serogroup C (NmC) in specimens from patients. We describe the epidemiological investigation of this cluster and metagenomic characterisation of the outbreak strain., Methods: We collected epidemiological data from the field investigation and medical records review. Confirmed, probable, and suspected cases were defined on the basis of molecular testing and signs or symptoms of meningococcal disease. Metagenomic sequences from patient specimens were compared with 141 meningococcal isolate genomes to determine strain lineage., Findings: 28 meningococcal disease cases were identified, with dates of symptom onset from April 21 to April 30, 2017: 13 confirmed, three probable, and 12 suspected. 13 patients died. Six (21%) patients reported fever and 23 (82%) reported gastrointestinal symptoms. The attack rate for confirmed and probable cases among funeral attendees was 10%. Metagenomic sequences from six patient specimens were similar to a sequence type (ST) 10217 (clonal complex [CC] 10217) isolate genome from Niger, 2015. Multilocus sequencing identified five of seven alleles from one specimen that matched ST-9367, which is represented in the PubMLST database by one carriage isolate from Burkina Faso, in 2011, and belongs to CC10217., Interpretation: 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., Funding: US Global Health Security., (Copyright © 2018 World Health Organization. Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd.. All rights reserved.)

We estimated the long-term socioeconomic consequences and health care costs of Neisseria meningitidis meningitis (NM). The prospective cohort study included Danish individuals with onset of NM in childhood and adolescence, diagnosed between 1980 and 2009. Health care costs and socioeconomic data were obtained from nationwide administrative and health registers. Two thousand nine hundred two patients were compared with 11,610 controls matched for age, gender, and other sociodemographic characteristics. In the follow-up analysis at the age of 30 years, 1028 patients were compared with 4452 controls. We found that (1) NM caused increased mortality at disease onset, but after adequate treatment, the mortality rate was similar to that of the general population; (2) neurological and eye diseases were more frequently observed in patients; (3) patients had significantly lower grade-point averages; (4) patients had lower income even when transfer payments were taken into account; and (5) patients' initial health care costs were elevated.Conclusion: NM has significant influence on mortality, morbidity, education, and income. We suggest that the management of patients with previous meningococcal meningitis should focus on early educational and social interventions to improve social and health outcomes. What is known: • Meningococcal meningitis is a severe infectious disease affecting children and adolescents with high rates of mortality and complications. What is new: • Meningococcal meningitis causes increased mortality at disease onset, but after adequate treatment the mortality rate is similar to that of the general population. • Meningococcal meningitis in childhood and adolescence has a major long-term effect on morbidity, health care costs, education, employment, and income.

Background: Nigeria reports high rates of mortality linked with recurring meningococcal meningitis outbreaks within the African meningitis belt. Few studies have thoroughly described the response to these outbreaks to provide strong and actionable public health messages. We describe how time delays affected the response to the 2016/2017 meningococcal meningitis outbreak in Nigeria., Methods: Using data from Nigeria Centre for Disease Control (NCDC), National Primary Health Care Development Agency (NPHCDA), World Health Organisation (WHO), and situation reports of rapid response teams, we calculated attack and death rates of reported suspected meningococcal meningitis cases per week in Zamfara, Sokoto and Yobe states respectively, between epidemiological week 49 in 2016 and epidemiological week 25 in 2017. We identified when alert and epidemic thresholds were crossed and determined when the outbreak was detected and notified in each state. We examined response activities to the outbreak., Results: There were 12,535 suspected meningococcal meningitis cases and 877 deaths (CFR: 7.0%) in the three states. It took an average time of three weeks before the outbreaks were detected and notified to NCDC. Four weeks after receiving notification, an integrated response coordinating centre was set up by NCDC and requests for vaccines were sent to International Coordinating Group (ICG) on vaccine provision. While it took ICG one week to approve the requests, it took an average of two weeks for approximately 41% of requested vaccines to arrive. On the average, it took nine weeks from the date the epidemic threshold was crossed to commencement of reactive vaccination in the three states., Conclusion: There were delays in detection and notification of the outbreak, in coordinating response activities, in requesting for vaccines and their arrival from ICG, and in initiating reactive vaccination. Reducing these delays in future outbreaks could help decrease the morbidity and mortality linked with meningococcal meningitis outbreaks., Competing Interests: The authors have declared that no competing interests exist.

The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced in the Brazilian National Immunization Program in March 2010, scheduled at 2, 4, and 6 months, with a booster at 12-15 months of age. The meningococcal C conjugate vaccine (MCC) was introduced in November 2010, scheduled at 3 and 5 months, with a booster dose at 12-15 months of age and no catch-up for older age groups. In this interrupted time-series analysis study, we used Brazilian mortality data from 2005 to 2015 for children under five years of age (excluding data from the state of Bahia) to assess the combined impact of these vaccines on the overall burden of meningitis mortality among children aged 0-23 months and 2-4 years, as defined using meningitis and meningococcemia specific International Classification of Diseases - tenth revision codes. Secular trends and seasonality were taken into account. We found significant reductions for both age groups relative to those observed for the comparison group of diseases, with immediate effects after the transition period (2010-2011) of 29.2% and 27.5% for children aged 0-23 months and 2-4 years, respectively. These immediate effects were sustained throughout the post-vaccination period (2012-2015). In total, 337 deaths were averted by the combined effect of both vaccines, 238 (95%CI 169-319) for children aged 0-23 months and 99 (95%CI 56-144) for those aged 2-4 years. These results add strong evidence in support of investments in these vaccines by low and middle-income countries.

Introduction: Following the significant reduction of Neisseria meningitidis A (NmA) in most parts of northern Nigeria, a new strain of Neisseria meningitidis C (NmC) emerged in 2013 causing outbreaks in the north and recently spreading to southern parts of the Nigeria. This study provides detailed epidemiological investigation in the last four years., Methods: Analysis of confirmed and suspected cases of meningitis in Kebbi, Nigeria from 2014 to June 2017 detected through Integrated Disease Surveillance and Response., Results: Of the 2776 cases, 1568 were males, and 1208 females. The median age of males and females was 10 and 11 years (Interquartile range of ages is 9 years) respectively. The attack rate (AR) per 100,000 in the state between 2014 and 2017 was 13.2, 46.7, 2.2 and 3.2 respectively. Case fatality rate (CFR) in 2014 was highest in the 4 years analysed at 13.8%. Binary logistic regression analysis suggests that the odds of confirmation of meningitis was 3.6 (Odds ratio, OR 3.60, 95% CI 1.58-8.2; p = 0.002) times as high in the age group 6-10 years and 2.4 times in the age group 11-19 years compared to the age group 0-5 years (OR 2.44, 95% CI 1.09-5.48; p = 0.03). An epidemic of NmC in 2015, led to a reactive vaccination campaign in selected wards in Aliero and Jega targeting age groups 1-29 years old, with a coverage of 72% and 51% respectively. In 2016-2017 Aliero and Jega local government areas (LGA) had no recorded deaths due to meningitis, a significant improvement over 2015 mortality rates (MR) per 100,000 of 33.4 and 12.2 respectively., Conclusion: The CFR in the state is still very high, suggesting the need for a more coordinated approach aimed at improving disease notification and early treatment. Vaccination in Aliero and Jega LGAs have demonstrated the usefulness of meningococcal C vaccine in reduction of morbidity and mortality., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Invasive meningococcal disease (IMD) is a major public health problem worldwide. An epidemic of serogroup C (NmC) IMD occurred in 2010 in the city of Salvador. In this study, we describe the antigenic and genetic characterization of meningococcal isolates collected from meningitis cases in Salvador from 2001 to 2012. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were performed for the analysis of IMD isolates. A total of 733 cases were identified, and the serogroup was determined for 391 (53.0%) of these. Most cases were caused by NmC (53%) or B (47%). The most prevalent strains were B:4,7:P1.19,15 (32.9%; 129/391) and C:23:P1.14-6 (28.6%; 112/391). Based on PFGE/MLST analysis, 71.3% (77/108 PFGE-tested isolates) clustered as two clones of sequence type ST-3779 and ST-3780, both belonging to the ST-103 clonal complex. ST-3779 has been detected in Salvador since 1996 and together with ST-3780 became predominant after 2005. There was a predominance of C:23:P1.14-6, ST-3779/3780 in Salvador during the period of 2007-2012, establishing a major clonal lineage, which remained in the community for a long time; this has serious implications for public health, particularly in terms of prevention and control strategies of IMD., (Copyright © 2017 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

On April 25, 2017, a cluster of unexplained illness and deaths among persons who had attended a funeral during April 21-22 was reported in Sinoe County, Liberia (1). Using a broad initial case definition, 31 cases were identified, including 13 (42%) deaths. Twenty-seven cases were from Sinoe County (1), and two cases each were from Grand Bassa and Monsterrado counties, respectively. On May 5, 2017, initial multipathogen testing of specimens from four fatal cases using the Taqman Array Card (TAC) assay identified Neisseria meningitidis in all specimens. Subsequent testing using direct real-time polymerase chain reaction (PCR) confirmed N. meningitidis in 14 (58%) of 24 patients with available specimens and identified N. meningitidis serogroup C (NmC) in 13 (54%) patients. N. meningitidis was detected in specimens from 11 of the 13 patients who died; no specimens were available from the other two fatal cases. On May 16, 2017, the National Public Health Institute of Liberia and the Ministry of Health of Liberia issued a press release confirming serogroup C meningococcal disease as the cause of this outbreak in Liberia.

Background: Meningococcal disease can lead to death or disability within hours after onset. Pre-admission antibiotics aim to reduce the risk of serious disease and death by preventing delays in starting therapy before confirmation of the diagnosis., Objectives: To study the effectiveness and safety of pre-admission antibiotics versus no pre-admission antibiotics or placebo, and different pre-admission antibiotic regimens in decreasing mortality, clinical failure, and morbidity in people suspected of meningococcal disease., Search Methods: We searched CENTRAL (6 January 2017), MEDLINE (1966 to 6 January 2017), Embase (1980 to 6 January 2017), Web of Science (1985 to 6 January 2017), LILACS (1982 to 6 January 2017), and prospective trial registries to January 2017. We previously searched CAB Abstracts from 1985 to June 2015, but did not update this search in January 2017., Selection Criteria: Randomised controlled trials (RCTs) or quasi-RCTs comparing antibiotics versus placebo or no intervention, in people with suspected meningococcal infection, or different antibiotics administered before admission to hospital or confirmation of the diagnosis., Data Collection and Analysis: Two review authors independently assessed trial quality and extracted data from the search results. We calculated the risk ratio (RR) and 95% confidence interval (CI) for dichotomous data. We included only one trial and so did not perform data synthesis. We assessed the overall quality of the evidence using the GRADE approach., Main Results: We found no RCTs comparing pre-admission antibiotics versus no pre-admission antibiotics or placebo. We included one open-label, non-inferiority RCT with 510 participants, conducted during an epidemic in Niger, evaluating a single dose of intramuscular ceftriaxone versus a single dose of intramuscular long-acting (oily) chloramphenicol. Ceftriaxone was not inferior to chloramphenicol in reducing mortality (RR 1.21, 95% CI 0.57 to 2.56; N = 503; 308 confirmed meningococcal meningitis; 26 deaths; moderate-quality evidence), clinical failures (RR 0.83, 95% CI 0.32 to 2.15; N = 477; 18 clinical failures; moderate-quality evidence), or neurological sequelae (RR 1.29, 95% CI 0.63 to 2.62; N = 477; 29 with sequelae; low-quality evidence). No adverse effects of treatment were reported. Estimated treatment costs were similar. No data were available on disease burden due to sequelae., Authors' Conclusions: We found no reliable evidence to support the use pre-admission antibiotics for suspected cases of non-severe meningococcal disease. Moderate-quality evidence from one RCT indicated that single intramuscular injections of ceftriaxone and long-acting chloramphenicol were equally effective, safe, and economical in reducing serious outcomes. The choice between these antibiotics should be based on affordability, availability, and patterns of antibiotic resistance.Further RCTs comparing different pre-admission antibiotics, accompanied by intensive supportive measures, are ethically justified in people with less severe illness, and are needed to provide reliable evidence in different clinical settings.

Background: Limited data are available describing the post-licensure safety of meningococcal vaccines, including Menveo®. We reviewed reports of adverse events (AEs) to the Vaccine Adverse Event Reporting System (VAERS) to assess safety in all age groups., Methods: VAERS is a national spontaneous vaccine safety surveillance system co-administered by the Centers for Disease Control and Prevention and the US Food and Drug Administration. We searched the VAERS database for US reports of adverse events in persons who received Menveo from 1 January 2010 through 31 December 2015. We clinically reviewed reports and available medical records for serious AEs, selected pre-specified outcomes, and vaccination during pregnancy. We used empirical Bayesian data mining to identify AEs that were disproportionately reported after receipt of Menveo., Results: During the study period, VAERS received 2614 US reports after receipt of Menveo. Of these, 67 were classified as serious, including 1 report of death. Adolescents (aged 11-18years) accounted for 74% of reports. Most of the reported AEs were non-serious and described AEs consistent with data from pre-licensure studies. Anaphylaxis and syncope were the two most common events in the serious reports. We did not identify any new safety concerns after review of AEs that exceeded the data mining threshold, although we did observe disproportionate reporting for terms that were not associated with an adverse event (e.g., "incorrect drug dosage form administered", "wrong technique in drug usage process"). Although reports were limited, we did not find any evidence for concern regarding the use of Menveo during pregnancy., Conclusions: In our review of VAERS reports, findings of AEs were consistent with the data from pre-licensure studies. Vaccine providers should continue to emphasize and adhere to proper administration of the vaccine., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Meningococcal meningitis is a public health problem. The aim of this study was to describe the clinical characteristics of patients with meningococcal meningitis, and to identify associated factors with mortality. This was a retrospective study, between 2006 and 2011, at a referral center in São Paulo, Brazil. Logistic regression analysis was used to identify factors associated with mortality. We included 316 patients. The median age was 16 years (IQR: 7-27) and 60% were male. The clinical triad: fever, headache and neck stiffness was observed in 89% of the patients. The cerebrospinal triad: pleocytosis, elevated protein levels and low glucose levels was present in 79% of patients. Factors associated with mortality in the multivariate model were age above 50 years, seizures, tachycardia, hypotension and neck stiffness. The classic clinical and laboratory triads of meningococcal meningitis were variable. The fatality rate was low. Age, seizures and shock signs were independently associated with mortality.

We describe clinical symptoms, case-fatality rates, and prevalence of sequelae during an outbreak of Neisseria meningitidis serogroup C infection in a rural district of Niger. During home visits, we established that household contacts of reported case-patients were at higher risk for developing meningitis than the general population.

Background: Bacterial meningitis is a life-threatening emergency that is still associated with high mortality and poor outcome., Objective: The purpose of this article is to provide a review of clinical presentation, diagnostic procedure, therapy, and prognosis in bacterial meningitis. Prognostic factors which could be influenced positively are identified and a focused procedure in the emergency setting and for the treatment of complications are provided., Material and Methods: This work is based on a literature search (PubMed, guidelines) and personal experience (standard operating procedures, SOP)., Results: Despite improved health care, bacterial meningitis is still associated with high mortality and poor neurological outcome, which has remained largely unaltered during recent decades. Diagnosis and, more importantly, effective therapy of bacterial meningitis are often delayed, having an immediate negative influence on clinical outcome. Neurological and nonneurological complications often necessitate intensive care and may occur rapidly or in the further course of the disease., Conclusion: Immediate initiation of effective therapy is crucial to positively influence mortality and neurological outcome. Antibiotics should be administered within 30 min after admission. To achieve this, a focused and well-organized procedure in the emergency setting is necessary. Because of intra- and extracranial complications, patients need to be treated on intensive care units including neurological expertise and interdisciplinary support.

Objectives: Despite the availability of vaccines, children are the people most often affected by epidemic meningococcal meningitis. The pattern of the epidemic meningococcal meningitis outbreak in Northern Nigeria in 2009 and the Neisseria meningitidis strains responsible for this epidemic are described here., Methods: A retrospective cross-sectional study was conducted in 16 states, involving 48 local government areas (LGAs), 91 health facilities, and 96 communities. Data collection involved in-depth interviews with key informants from the federal to the community level, a review of records, and a solution-oriented national workshop with participants from all states of the Federation. Cerebrospinal fluid (CSF) samples were collected from some of the suspected cases at the start of the outbreak and were tested using the rapid Pastorex latex agglutination kit., Results: Kastina (11153, 20.4%), Jigawa (8643, 15.8%), Bauchi (8463, 15.5%), Kano (6811, 12.4%), and Gombe (6110, 11.2%) were the states with the highest prevalence of meningitis. The states of Nasarawa (11.0%), Adamawa (8.0%), and Borno (7.6%) recorded the highest percentage of deaths, while the Shongom (Gombe State 12.5%), Illela (Sokoto State 9.8%), and Ikara (Kaduna State 9.1%) LGAs recorded the most deaths amongst cases seen., Conclusions: The testing of CSF samples during meningitis outbreaks is recommended in order to monitor the occurrence of the multiple meningitis serotypes during these outbreaks and to direct serotype-specific vaccination response activities., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Use of recently licensed vaccines against Neisseria meningitidis serogroup B (NmB) will depend partly on disease burden estimates. We systematically reviewed NmB incidence and mortality worldwide between January, 2000, and March, 2015, incorporating data from 37 articles and 12 websites. Most countries had a yearly invasive NmB incidence of less than 2 per 100,000 people. Within these relatively low incidence rates (compared with common causes of invasive bacterial diseases), substantial variation was detected between countries, with a notably higher incidence in Australia, Europe, North America, and South America. China and India had reports only of sporadic cases, and except for South Africa, sub-Saharan Africa showed a near absence of disease. In countries with consistently collected data, NmB incidence has tended to decrease, even as the proportion of invasive meningococcal disease cases caused by serogroup B has increased. With few exceptions, case-fatality ratios were fairly consistent, ranging between 3% and 10%. In high-income countries, incidence rates of NmB were relatively low compared with other vaccine-preventable diseases and might be decreasing. High case-fatality ratios, substantial disease-related morbidity, and the threat of outbreaks could nevertheless make NmB an attractive target for preventive and reactive immunisation programmes. The low availability of data from low-income and middle-income countries suggests the need for improved surveillance before vaccination strategies are designed., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Several countries consider the implementation of a meningococcal serogroup B vaccine for young children and/or serogroup C or ACWY conjugate vaccine for adolescents. Representative information on clinical course of invasive meningococcal disease (IMD) is useful to evaluate cost-effectiveness of vaccination. Information on the relation between infecting meningococcal clonal complex (CC), disease course and outcome of IMD is scarce., Methods: A retrospective study using Dutch surveillance data on IMD from June 1999 to June 2011. Clinical information was retrieved from hospital records. The effect of age, comorbidity, clinical manifestation, serogroup, and CC on disease course and outcome was assessed in multivariable analyses. Meningococcal CCs were assessed by multilocus sequence typing., Results: Clinical information was retrieved for 879 IMD cases: 48% of patients presented with meningitis, 17% with septic shock, and 22% with septic shock plus meningitis. Development of septic shock was not related to CC or serogroup. Median (interquartile range) duration of hospital admission was 10 (8-13) days. Intensive care unit admittance (38%) was higher for patients aged ≥10 years and patients with septic shock (P-values ≤.001). Case-fatality rate (8%) and development of sequelae (29%) was dependent on age and clinical manifestation (P-values ≤.001) and not affected by comorbidity, CC, or serogroup., Conclusions: IMD still coincides with a considerable disease burden and mortality. Disease course and outcome depend mainly on age and clinical manifestation and less on meningococcal CC or serogroup., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Bacterial meningitis among critically ill adult patients remains associated with both high mortality and frequent, persistent disability. Vancomycin was added to treatment with a third-generation cephalosporin as recommended by French national guidelines. Because animal model studies had suggested interest in the use of rifampin for treatment of bacterial meningitis, and after the introduction of early corticosteroid therapy (in 2002), there was a trend toward increasing rifampin use for intensive care unit (ICU) patients. The aim of this article is to report on this practice., Methods: Five ICUs participated in the study. Baseline characteristics and treatment data were retrospectively collected from charts of patients admitted with a diagnosis of acute bacterial meningitis during a 5-year period (2004-2008). The ICU mortality was the main outcome measure; Glasgow Outcome Scale and 3-month mortality were also assessed., Results: One hundred fifty-seven patients were included. Streptococcus pneumoniae and Neisseria meningitidis were the most prevalent causative microorganisms. The ICU mortality rate was 15%. High doses of a cephalosporin were the most prevalent initial antimicrobial treatment. The delay between admission and administration of the first antibiotic dose was correlated with ICU mortality. Rifampin was used with a cephalosporin for 32 patients (ranging from 8% of the cohort for 2004 to 30% in 2008). Administration of rifampin within the first 24 h of hospitalization could be associated with a lower ICU survival. Statistical association between such an early rifampin treatment and ICU mortality reached significance only for patients with pneumococcal meningitis (p=0.031) in univariate analysis, but not in the logistic model., Conclusions: We report on the role of rifampin use for patients with community-acquired meningitis, and the results of this study suggest that this practice may be associated with lower mortality in the ICU. Nevertheless, the only independent predictors of ICU mortality were organ failure and pneumococcal infection. Further studies are required to confirm these results and to explain how rifampin use would reduce mortality.

Background: Neisseria meningitidis causes 500 000 cases of septicemia and meningitis worldwide annually, with approximately 200 cases in Canada each year. Previous studies describe a case-fatality rate of 5%-15% and up to 20% of survivors suffering from long-term disability., Methods: This study was performed in Canada between 2002 and 2011; the study area included >50% of the country's population. We identified risk factors associated with death and the development of complications in children and adults admitted to hospital with confirmed invasive meningococcal disease (IMD). Clinical information was obtained from hospital records. Risk factors for death and complications were analyzed by univariate and multivariable analyses., Results: Of 868 individuals hospitalized with IMD, there were 73 deaths (8.4%) and 157 (18%) developed complications. The most common complications were hearing loss (5.4%), skin scarring (5.4%), amputation (3.4%), renal dysfunction (2.6%), and seizures (2.5%). Mortality was independently associated with shock (adjusted odds ratio [aOR], 23.30; P<.0001), age (aOR, 1.02 per 1-year increased age; P<.0001), symptom onset within 24 hours of admission (aOR, 1.80; P=.0471), and admission to the intensive care unit (aOR, 0.41; P=.0196). Development of complications was independently associated with seizures (aOR, 4.55; P<.0001), shock (aOR, 3.10; P<.0001), abnormal platelet count (aOR, 2.14; P=.0002), bruising (aOR, 3.17; P=.0059), abnormal white blood cell count (aOR, 0.52; P=.0100), and prior antibiotic exposure (aOR, 0.27; P=.0273)., Conclusions: Outcomes following IMD remain poor in this resource-rich setting in the 21st century. These data identify priorities for clinical management of adults and children with IMD, and provide prognostic information for affected patients and their families and cost-effectiveness analyses for meningococcal vaccine programs., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

We evaluated the outcome of invasive meningococcal disease in children <15 years of age (n = 181). Neisseria meningitidis serogroup B comprised 78% of bacterial isolates. Case fatality rate was 11.6%. In follow-up interviews (115/160 survivors, 72%), at least 1 long-term sequela was reported in 38/115 children (33%), including learning-academic difficulties (22.6%), hearing impairment (7%), neurologic (12.2%), behavioral (14.8%) and motor (10.4%) deficits.

Background: Recent research into the treatment of bacterial meningitis has examined the innate immune system, specifically the complement system, as a potential target for adjuvant therapy. However, the effects of blocking the complement system may be pathogen dependent., Methods: We measured cerebrospinal fluid (CSF) levels of complement components C1q, C3a, iC3b, C5a, sC5b-9, CFH and MBL in 310 patients with pneumococcal and meningococcal meningitis from a prospective nationwide cohort study. The CSF complement component levels were successfully determined for between 289 (93%) and 307 (99%) patients, depending on available volumes of stored CSF., Results: Complement factors C1q and MBL as well as common complement pathway factors C3a, iC3b, C5a, sC5b-9 and complement regulator CFH were all elevated in patients with bacterial meningitis as compared to the controls. CSF levels of complement components C5a and sC5b-9 were higher in patients with pneumococcal meningitis compared to those with meningococcal meningitis. After correction for age, immunocompromised state and level of consciousness, the CSF concentrations of C5a and sC5b-9 remained different between causative microorganisms (P = 0.006 and P = 0.016 respectively). In pneumococcal meningitis high C5a and C5b-9 levels are associated with the occurrence of systemic complications, unfavorable outcome and death, whereas an inverse relationship between C5b-9 levels and mortality is observed in meningococcal meningitis., Conclusions: Our study shows striking variations in complement activation depending on the pathogen responsible for the bacterial meningitis. In pneumococcal meningitis, high CSF complement levels were a strong indicator of disease severity and mortality, however in meningococcal meningitis, an inverse relationship between sC5b-9 and mortality was observed., (Copyright © 2014. Published by Elsevier Ltd.)

Background: Neisseria meningitidis is a leading etiologic agent of severe invasive disease. The objective of the study was to characterise invasive meningococcal disease (IMD) epidemiology in Poland during the last decade, based on laboratory confirmed cases., Methods: The study encompassed all invasive meningococci collected between 2002 and 2011 in the National Reference Centre for Bacterial Meningitis. The isolates were re-identified and characterised by susceptibility testing, MLST analysis, porA and fetA sequencing. A PCR technique was used for meningococcal identification directly from clinical materials., Results: In the period studied, 1936 cases of IMD were confirmed, including 75.6% identified by culture. Seven IMD outbreaks, affecting mostly adolescents, were reported; all were caused by serogroup C meningococci of ST-11. The highest incidence was observed among children under one year of age (15.71/100,000 in 2011). The general case fatality rate in the years 2010-2011 was 10.0%. Meningococci of serogroup B, C, Y and W-135 were responsible for 48.8%, 36.6%, 1.2% and 1.2% of cases, respectively. All isolates were susceptible to third generation cephalosporins, chloramphenicol, ciprofloxacin, and 84.2% were susceptible to penicillin. MLST analysis (2009-2011) revealed that among serogroup B isolates the most represented were clonal complexes (CC) ST-32CC, ST-18CC, ST-41/44CC, ST-213CC and ST-269CC, and among serogroup C: ST-103CC, ST-41/44CC and ST-11CC., Conclusions: The detection of IMD in Poland has changed over time, but observed increase in the incidence of the disease was mostly attributed to changes in the surveillance system including an expanded case definition and inclusion of data from non-culture diagnostics.

Bacterial meningitis remains important cause of morbidity and mortality worldwide, particularly in developing countries. This study analyzed the data from sentinel surveillance for bacterial meningitis among children <5 years of age hospitalized in largest children's hospital in Tbilisi, capital of Georgia and adult patients hospitalized in infectious diseases hospital during 2006-2010 with suspected bacterial meningitis. The surveillance is conducted by National Center for Disease Control and Public Health (NCDCPH). The number of patients with identified organism was 127 (19 %). In the subsample of patients with laboratory confirmed bacterial meningitis Streptococcus pneumoniae was the most frequently isolated organism (67 cases, 52.8 %), followed by. influenza (17 cases, 13.4 %) and Neisseria meningitidis (16 cases, 12.6 %). The number of patients with suspected TB meningitis was 27 (21.3 %). The overall case fatality rate in the subgroup of patients with identified organism was 12.3 %. The highest mortality was observed among TB patients (22.2 %) with 14.3 % mortality for N. meningitidis and 10.3 % for S. pneumoniae. No lethal outcome was observed among patients with Haemophilus influenzae.

Gram-negative bacteria infection is sometimes followed by septic shock. This serious health condition is caused by the segregation of the lipopolysaccharide (LPS) from bacterial membrane into the bloodstream. Due to bacterial resistance, new antibiotics are needed. Most of the active antibiotics possess bactericidal effect, but lack LPS neutralization properties to prevent or neutralize septic shock. Antimicrobial peptides are a new class of antibiotics not prone to bacterial resistance, because their main target is the membrane. It is difficult for bacteria to critically change their membrane composition without affecting its molecular processes. rBPI21 is a recombinant antimicrobial peptide developed from an antimicrobial protein produced in neutrophils, the bactericidal/permeability-increasing protein (BPI) that ended phase III clinical trials against meningitis with success, reducing serious complications, such as amputations. It interacts preferentially with LPS with high affinity and at the same time has bactericidal effect. Here, we gather evidence that the interaction of the rBPI21 with LPS is mainly electrostatic, first, followed by massive LPS aggregation, which is correlated with its clearance from the bloodstream. The molecular mechanism at membrane level includes the peptide interactions with negatively charged phospholipids that promote outer and inner membrane hemi(fusion). This perturbation is followed by membrane permeabilization.

Background: An affordable, highly immunogenic Neisseria meningitidis serogroup A meningococcal conjugate vaccine (PsA-TT) was licensed for use in sub-Saharan Africa in 2009. In 2010, Burkina Faso became the first country to implement a national prevention campaign, vaccinating 11·4 million people aged 1-29 years. We analysed national surveillance data around PsA-TT introduction to investigate the early effect of the vaccine on meningitis incidence and epidemics., Methods: We examined national population-based meningitis surveillance data from Burkina Faso using two sources, one with cases and deaths aggregated at the district level from 1997 to 2011, and the other enhanced with results of cerebrospinal fluid examination and laboratory testing from 2007 to 2011. We compared mortality rates and incidence of suspected meningitis, probable meningococcal meningitis by age, and serogroup-specific meningococcal disease before and during the first year after PsA-TT implementation. We assessed the risk of meningitis disease and death between years., Findings: During the 14 year period before PsA-TT introduction, Burkina Faso had 148 603 cases of suspected meningitis with 17 965 deaths, and 174 district-level epidemics. After vaccine introduction, there was a 71% decline in risk of meningitis (hazard ratio 0·29, 95% CI 0·28-0·30, p<0·0001) and a 64% decline in risk of fatal meningitis (0·36, 0·33-0·40, p<0·0001). We identified a statistically significant decline in risk of probable meningococcal meningitis across the age group targeted for vaccination (62%, cumulative incidence ratio [CIR] 0·38, 95% CI 0·31-0·45, p<0·0001), and among children aged less than 1 year (54%, 0·46, 0·24-0·86, p=0·02) and people aged 30 years and older (55%, 0·45, 0·22-0·91, p=0·003) who were ineligible for vaccination. No cases of serogroup A meningococcal meningitis occurred among vaccinated individuals, and epidemics were eliminated. The incidence of laboratory-confirmed serogroup A N meningitidis dropped significantly to 0·01 per 100 000 individuals per year, representing a 99·8% reduction in the risk of meningococcal A meningitis (CIR 0·002, 95% CI 0·0004-0·02, p<0·0001)., Interpretation: Early evidence suggests the conjugate vaccine has substantially reduced the rate of meningitis in people in the target age group, and in the general population because of high coverage and herd immunity. These data suggest that fully implementing the PsA-TT vaccine could end epidemic meningitis of serogroup A in sub-Saharan Africa., Funding: None., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Neisseria meningitidis serogroup C has emerged as a cause of epidemic disease in Hefei. The establishment of serogroup C as the predominant cause of endemic disease has not been described., Methods: We conducted national laboratory-based surveillance for invasive meningococcal disease during 2000-2010. Isolates were characterized by pulsed-field gel electrophoresis and multilocus sequence typing., Results: A total of 845 cases of invasive meningococcal disease were reported. The incidence increased from 1.25 cases per 100,000 population in 2000 to 3.14 cases per 100,000 in 2003 (p < 0.001), and peaked at 8.43 cases per 100,000 in 2005. The increase was mainly the result of an increase in the incidence of serogroup C disease. Serogroup C disease increased from 2/23 (9%) meningococcal cases and 0.11 cases per 100,000 in 2000 to 33/58 (57%) cases and 1.76 cases per 100,000 in 2003 (p < 0.01). Patients infected with serogroup C had serious complications more frequently than those infected with other serogroups. Specifically, 161/493 (32.7%) cases infected with serogroup C had at least one complication. The case-fatality rate of serogroup C meningitis was 11.4%, significantly higher than for serogroup A meningitis (5.3%, p = 0.021). Among patients with meningococcal disease, factors associated with death in univariate analysis were age of 15-24 years, infection with serogroup C, and meningococcemia., Conclusions: The incidence of meningococcal disease has substantially increased and serogroup C has become endemic in Hefei. The serogroup C strain has caused more severe disease than the previously predominant serogroup A strain.

Background: The GPIP/ACTIV (Groupe de Pathologie Infectieuse Pédiatrique and Association Clinique et Thérapeutique Infantile du Val de Marne) set up an active surveillance network to analyze the epidemiological, clinical and biological features of meningococcal meningitis., Methods: French pediatric wards working with 166 microbiology laboratories enrolled all children (0-18 years old) with bacterial meningitis. Risk factors, signs and symptoms, vaccination status, cerebrospinal fluid analysis, treatments and case fatality rate were recorded., Results: Since 2001, 1661 meningococcal meningitis were reported among 3769 (44.1%) bacterial meningitis. Mean age was 4.4- year- old (± 4.8, median 2.5) and 2/3 cases occurred in children under 5- year- old (68.8%). Serogroup B (61.3%) is preponderant following by serogroup C (27.0%). 27.5% of children had received an antibiotic treatment 24 hours before lumbar puncture. A shock is reported in 31.0% of cases. No cases of meningococcal meningitis C has been reported in children vaccinated with a conjugate vaccine. Two children vaccinated with MenBvac(®) vaccine had a meningitis B14:P1.7,16. Global case fatality rate was 6.5% but was higher (9.2%) for serogroup C than for serogroup B (5.9%) (p=0.02)., Conclusion: This is among the largest series of microbiologically documented meningococcal meningitis to date (1661 cases). In France, meningococcal is responsible for approximately 50 % of meningitis. Effective meningococcal serogroup B vaccine and serogroup C vaccination recommendation could control the burden of meningococcal meningitis., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

The aim of the present study was to evaluate the potential role of cerebrospinal fluid soluble urokinase receptor (suPAR) level, infection and age as risk factors for fatal outcome in patients suspected of having meningitis and/or bacteraemia on admission to hospital. A total of 545 cerebrospinal fluid samples from patients with clinically suspected meningitis were sent to the Hellenic National Meningitis Reference Laboratory. Ten of 545 (1.83%) patients died. Analysis by receiver operating characteristics (ROC) curve revealed that both suPAR and age were significant for prediction of fatal outcome. Patients with levels of suPAR above the cut-off values and age ≥ 51 years, or patients in which either Neisseria meningitis or Streptococcus pneumoniae were detected were categorized as high risk patients. The combination of the above three predictors (suPAR, age and infectious agent) in a logistic regression model with outcome of infection as the dependent variable yielded an overall odds ratio (OR = 85.7, 95% CI 10.6-690.2) with both sensitivity and specificity being equal to the value of 0.9. In conclusion, suPAR, age and type of infection have an additive effect in predicting mortality among patients suspected of meningitis.

Macrophage migration inhibitory factor (MIF) is an abundantly expressed proinflammatory cytokine playing a critical role in innate immunity and sepsis and other inflammatory diseases. We examined whether functional MIF gene polymorphisms (-794 CATT(5-8) microsatellite and -173 G/C SNP) were associated with the occurrence and outcome of meningococcal disease in children. The CATT(5) allele was associated with the probability of death predicted by the Pediatric Index of Mortality 2 (P=0.001), which increased in correlation with the CATT(5) copy number (P=0.04). The CATT(5) allele, but not the -173 G/C alleles, was also associated with the actual mortality from meningoccal sepsis [OR 2.72 (1.2-6.4), P=0.02]. A family-based association test (i.e., transmission disequilibrium test) performed in 240 trios with 1 afflicted offspring indicated that CATT(5) was a protective allele (P=0.02) for the occurrence of meningococcal disease. At baseline and after stimulation with Neisseria meningitidis in THP-1 monocytic cells or in a whole-blood assay, CATT(5) was found to be a low-expression MIF allele (P=0.005 and P=0.04 for transcriptional activity; P=0.09 and P=0.09 for MIF production). Taken together, these data suggest that polymorphisms of the MIF gene affecting MIF expression are associated with the occurrence, severity, and outcome of meningococcal disease in children.

All hospital discharges and deaths related to invasive meningococcal disease, meningococcal meningitis and meningococcemia in the general population from 1997 to 2008 in Spain were obtained. Among the 11,611 meningococcal infection related discharges 53% were meningococcal meningitis and 55% were meningococcemia. The annual hospitalization rate was 2.33, 1.23 and 1.29 cases per 100,000 for invasive meningococcal disease, meningococcal meningitis and meningococcemia, respectively. 846 deaths for invasive meningococcal disease, 235 for meningococcal meningitis and 605 for meningococcemia were reported. Although an important decrease in meningococcal infections related morbidity and mortality has occurred in the last twelve years in Spain, they still continue being major causes of hospitalization and death, especially in the children up to 2 years of age. Future preventive measures, such as vaccination with vaccines covering new conjugated serogroups (B and ACYW135), could further improve population health., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Neisseria meningitidis serogroups B and C have been responsible for the majority of invasive meningococcal disease in Europe. Recently, an increase of N. meningitidis disease due to serogroup Y has been noted in Sweden (in 2010, the proportion was 39%, with an incidence of 0.23 per 100,000 population), as well as in other northern European countries. We aimed to investigate the clonal pattern of the emerging serogroup Y in Sweden during 2000 to 2010. The serogroup Y isolates identified during this time (n=85) were characterised by multilocus sequence typing and sequencing of the fetA, fHbp, penA, porA and porB genes. The most frequent clone (comprising 28 isolates) with identical allele combinations of the investigated genes, was partly responsible for the observed increased number of N. meningitidis serogroup Y isolates. It was sulfadiazine resistant, with genosubtype P1.5-2,10-1,36-2, sequence type 23, clonal complex 23, porB allele 3-36, fetA allele F4-1, fHbp allele 25 and penA allele 22. The first case with disease due to this clone was identified in 2002: there was a further case in 2004, six during 2006 to 2007, eight during 2008 to 2009, with a peak of 12 cases in 2010. An unusual increase of invasive disease in young adults (aged 20–29 years) caused by this clone was shown, but no increase in mortality rate was observed.

Background: Meningococcal meningitis is a major cause of disease worldwide, with frequent epidemics particularly affecting an area of sub-Saharan Africa known as the "meningitis belt". Neisseria meningitidis group A (MenA) is responsible for major epidemics in Africa. Recently W-135 has emerged as an important pathogen. Currently, the strategy for control of such outbreaks is emergency use of meningococcal (MC) polysaccharide vaccines, but these have a limited ability to induce herd immunity and elicit an adequate immune response in infant and young children. In recent times initiatives have been taken to introduce meningococcal conjugate vaccine in these African countries. Currently there are two different types of MC conjugate vaccines at late stages of development covering serogroup A and W-135: a multivalent MC conjugate vaccine against serogroup A,C,Y and W-135; and a monovalent conjugate vaccine against serogroup A. We aimed to perform a structured assessment of these emerging meningococcal vaccines as a means of reducing global meningococcal disease burden among children under 5 years of age., Methods: We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In the first stage we systematically reviewed the literature related to emerging MC vaccines relevant to 12 criteria of interest. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). They answered questions from CHNRI framework and their "collective optimism" towards each criterion was documented on a scale from 0 to 100%., Results: For MenA conjugate vaccine the experts showed very high level of optimism (~ 90% or more) for 7 out of the 12 criteria. The experts felt that the likelihood of efficacy on meningitis was very high (~ 90%). Deliverability, acceptability to health workers, end users and the effect on equity were all seen as highly likely (~ 90%). In terms of the maximum potential impact on meningitis disease burden, the median potential effectiveness of the vaccines in reduction of overall meningitis mortality was estimated to be 20%; (interquartile range 20-40% and min. 8%, max 50 %). For the multivalent meningococcal vaccines the experts had similar optimism for most of the 12 CHNRI criteria with slightly lower optimism in answerability and low development cost criteria. The main concern was expressed over the cost of product, its affordability and cost of implementation., Conclusions: With increasing recognition of the burden of meningococcal meningitis, especially during epidemics in Africa, it is vitally important that strategies are taken to reduce the morbidity and mortality attributable to this disease. Improved MC vaccines are a promising investment that could substantially contribute to reduction of child meningitis mortality world-wide.

Meningococcal disease has historically been associated with military populations, particularly during periods of mobilization. Although the U.S. military has now been engaged in conflicts for nearly a decade, the incidence of meningococcal disease in the U.S. population as a whole has reached historic lows. Despite vaccination of all service members in basic military training, the risk of meningococcal disease appears to be equal to or greater than that of the civilian population. These 3 case reports of recent fatalities in the U.S. military and their historic contexts illustrate the circumstances under which meningococcus can strike and highlight the need for continued vigilance in military populations.

Background: Neisseria meningitidis meningitis represents approximately one-half of the meningococcal cases in French children. To explore the contribution of bacterial typing in improving the management of cases, we aimed to describe clinical characteristics and mortality of meningococcal meningitis in children reported to the multicenter survey system, GPIP/ACTIV, in association with phenotypes/genotypes of bacterial isolates., Methods: From 2001 to 2005, 259 pediatric wards and 168 microbiology laboratories enrolled all children with bacterial meningitis. Risk factors, vaccination status, signs and symptoms, cerebrospinal fluid analysis, treatments and case fatality rate were recorded., Results: A total of 962 cases of Neisseria meningitidis meningitis among a total of 2131 bacterial meningitis (45%) were recorded (mean age, 4.5 +/- 4.7 years). Serogroup distribution of the isolates was 62.3%, 33.7%, 2.9%, 0.6%, and 0.6% for serogroups B, C, W135, A and Y, respectively. The major clonal complexes were ST-41/44 (32.2%), ST-11 (21.9%), ST-32 (20.8%), ST-8 (8.2%), and ST-269 (4.9%). Despite global heterogeneity of the isolates, 2 phenotypes/genotypes were of interest. Isolates of the phenotype/genotype B:14:P1.7,16/ST-32 (56% clustered in the region of Haute Normandie) were observed in older children (8.6 years) and were associated with a higher case fatality rate (12%) than were other phenotypes of serogroup B. The phenotype/genotype C:2a:P1.5/ST-11 was found in 26.3% of serogroup C cases and was possibly associated with a higher mortality among serogroup C (9.9% for C and 5.9% for B, P = 0.04)., Conclusions: This large survey provides data that could be important for implementation of future vaccines. Typing of meningococcal isolates could contribute to an understanding of prognosis in meningococcal meningitis.

Objectives: We aimed to compare the incidence of meningococcal disease amongst HIV-infected and uninfected individuals and to evaluate whether HIV is a risk factor for mortality and bacteremia amongst patients with meningococcal disease., Design: Cohort surveillance study., Methods: We conducted laboratory-based surveillance for meningococcal disease in Gauteng Province, South Africa. HIV status and outcome data were obtained at sentinel sites. Incidence in HIV-infected and uninfected persons was calculated assuming a similar age-specific HIV prevalence in tested and untested individuals. Risk factors for death and bacteremia (as compared with meningitis) were evaluated using multivariable logistic regression., Results: From 2003 to 2007, 1336 meningococcal cases were reported. Of 504 patients at sentinel sites with known outcome, 308 (61%) had HIV serostatus data. HIV prevalence amongst cases of meningococcal disease was higher than the population HIV prevalence in all age groups. The incidence of meningococcal disease in HIV-infected individuals was elevated in all age groups with an age-adjusted relative risk of 11.3 [95% confidence interval (CI) 8.9-14.3, P < 0.001]. The case-fatality ratio (CFR) was 20% (27/138) amongst HIV-infected and 11% (18/170) amongst HIV-uninfected individuals [odds ratio (OR) 2.1, 95% CI 1.1-3.9]. On multivariable analysis, CFR was greater amongst patients with bacteremia (35%, 29/82) compared with meningitis (7%, 16/226) (OR 7.8, 95% CI 3.4-17.7). HIV infection was associated with increased odds of bacteremia (OR 2.7, 95% CI 1.5-5.0)., Conclusion: HIV-infected individuals may be at increased risk of meningococcal disease. The increased CFR in HIV-infected patients may be explained by their increased odds of bacteremia compared to meningitis.

Background: Meningococcal disease remains a significant illness with an overall mortality of around 8%. The majority of deaths occur in the first 24 hours, before the commencement of specialist care. Missing a diagnosis of meningococcal disease is a fear among health care practitioners., Objective: This article presents a guide to identifying the salient features of meningococcal sepsis and initial management strategies in the primary care setting., Discussion: Initial presentation is often nonspecific and therefore it is important to have a high index of suspicion in children presenting with fever, lethargy, myalgia, vomiting and headache. These children should be monitored and reviewed carefully. If a nonblanching rash develops, immediate treatment, liaison with a paediatric intensive care unit and urgent hospital transfer is required. Initial management involves assessment and regular review of airway, breathing and circulation. Antibiotics (preferably intravenous cephalosporin) should be administered before hospital transfer.

Background and Objectives: Neisseria meningitidis infection causes an important morbidity and mortality in Spain. Our study aims to estimate the burden of hospital admissions for meningococcal infection in Spain during a nine-year period (1997-2005) by analyzing the Spanish hospital surveillance system., Methods: An epidemiological retrospective study was conducted. Data were obtained from the national surveillance system for hospital data (Conjunto Mínimo Básico de Datos) maintained by the Ministry of Health. Information about hospitalizations, age, length of stay in hospital, mortality and cost per patient was obtained., Results: There were 1137 hospital discharges for meningococcal disease (International Classification of Diseases 9th Clinical Modification: ICD 9 CM code 036 in any listed diagnosis) during the study period. Annual incidence was 2.41 cases per 100,000 individuals. Mortality rate and case-fatality rate were 0.19 cases per 100,000 population and 7.7%, respectively. The average length of hospitalization was 12 days. The youngest age group showed the highest hospitalizations incidence (24.42 hospitalizations per 100,000 population in those under 4 years of age) but the case-fatality rate was higher in the oldest group (11% in patients over 30 years). These hospitalizations imply an annual cost of 592,980 euro to the Madrid Health System., Conclusions: Our study shows that meningococcal infection is still an important cause of hospital admissions and mortality in Madrid, resulting in a high cost to the Health Care System., (2009 Elsevier España, S.L. All rights reserved.)

To identify determinants for mortality and sequelae and to analyse the spatial distribution of meningococcal disease, we linked four national Danish registries. In the period 1974-2007, 5924 cases of meningococcal disease were registered. Our analysis confirms known risk factors for a fatal meningococcal disease outcome, i.e. septicaemia and high age (>50 years). The overall case-fatality rate was 7.6%; two phenotypes were found to be associated with increased risk of death; C:2a:P1.2,5 and B:15:P1.7,16. B:15:P1.7,16 was also associated with excess risk of perceptive hearing loss. The incidence rates of meningococcal disease were comparable between densely and less densely populated areas, but patients living further from a hospital were at significantly higher risk of dying from the infection. To improve control of meningococcal disease, it is important to understand the epidemiology and pathogenicity of virulent 'successful clones', such as C:2a:P1.2,5 and B:15:P1.7,16, and, eventually, to develop vaccines against serogroup B.