The moonlighting peroxiredoxin-glutaredoxin in Neisseria meningitidis binds plasminogen via a C-terminal lysine residue and contributes to survival in a whole blood model.

Neisseria meningitidis is a human-restricted bacterium that can invade the bloodstream and cross the blood-brain barrier resulting in life-threatening sepsis and meningitis. Meningococci express a cytoplasmic peroxiredoxin-glutaredoxin (Prx5-Grx) hybrid protein that has also been identified on the bacterial surface. Here, recombinant Prx5-Grx was confirmed as a plasminogen (Plg)-binding protein, in an interaction which could be inhibited by the lysine analogue ε-aminocapronic acid. rPrx5-Grx derivatives bearing a substituted C-terminal lysine residue (rPrx5-GrxK244A), but not the active site cysteine residue (rPrx5-GrxC185A) or the sub-terminal rPrx5-GrxK230A lysine residue, exhibited significantly reduced Plg-binding. The absence of Prx5-Grx did not significantly reduce the ability of whole meningococcal cells to bind Plg, but under hydrogen peroxide-mediated oxidative stress, the N. meningitidis Δpxn5-grx mutant survived significantly better than the wild-type or complemented strains. Significantly, using human whole blood as a model of meningococcal bacteremia, it was found that the N. meningitidis Δpxn5-grx mutant had a survival defect compared with the parental or complemented strain, confirming an important role for Prx5-Grx in meningococcal pathogenesis.

The meningococcal vaccine antigen GNA2091 is an analogue of YraP and plays key roles in outer membrane stability and virulence.

GNA2091 is one of the components of the 4-component meningococcal serogroup B vaccine (4CMenB) vaccine and is highly conserved in all meningococcal strains. However, its functional role has not been fully characterized. Here we show that nmb2091 is part of an operon and is cotranscribed with the nmb2089, nmb2090, and nmb2092 adjacent genes, and a similar but reduced operon arrangement is conserved in many other gram-negative bacteria. Deletion of the nmb2091 gene causes an aggregative phenotype with a mild defect in cell separation; differences in the outer membrane composition and phospholipid profile, in particular in the phosphoethanolamine levels; an increased level of outer membrane vesicles; and deregulation of the zinc-responsive genes such as znuD. Finally, the ∆2091 strain is attenuated with respect to the wild-type strain in competitive index experiments in the infant rat model of meningococcal infection. Altogether these data suggest that GNA2091 plays important roles in outer membrane architecture, biogenesis, homeostasis, and in meningococcal survival in vivo, and a model for its role is discussed. These findings highlight the importance of GNA2091 as a vaccine component.-Seib, K. L., Haag, A. F., Oriente, F., Fantappiè, L., Borghi, S., Semchenko, E. A., Schulz, B. L., Ferlicca, F., Taddei, A. R., Giuliani, M. M., Pizza, M., Delany, I. The meningococcal vaccine antigen GNA2091 is an analogue of YraP and plays key roles in outer membrane stability and virulence.

Declining Incidence of Invasive Meningococcal Disease in South Africa: 2003-2016.

BACKGROUND: Invasive meningococcal disease (IMD) is endemic to South Africa, where vaccine use is negligible. We describe the epidemiology of IMD in South Africa. METHODS: IMD cases were identified through a national, laboratory-based surveillance program, GERMS-SA, from 2003-2016. Clinical data on outcomes and human immunodeficiency virus (HIV) statuses were available from 26 sentinel hospital sites. We conducted space-time analyses to detect clusters of serogroup-specific IMD cases. RESULTS: Over 14 years, 5249 IMD cases were identified. The incidence was 0.97 cases per 100 000 persons in 2003, peaked at 1.4 cases per 100 000 persons in 2006, and declined to 0.23 cases per 100 000 persons in 2016. Serogroups were confirmed in 3917 (75%) cases: serogroup A was present in 4.7% of cases, B in 23.3%, C in 9.4%; W in 49.5%; Y in 12.3%, X in 0.3%; Z in 0.1% and 0.4% of cases were non-groupable. We identified 8 serogroup-specific, geo-temporal clusters of disease. Isolate susceptibility was 100% to ceftriaxone, 95% to penicillin, and 99.9% to ciprofloxacin. The in-hospital case-fatality rate was 17% (247/1479). Of those tested, 36% (337/947) of IMD cases were HIV-coinfected. The IMD incidence in HIV-infected persons was higher for all age categories, with an age-adjusted relative risk ratio (aRRR) of 2.5 (95% confidence interval [CI] 2.2-2.8; P < .001) from 2012-2016. No patients reported previous meningococcal vaccine exposure. Patients with serogroup W were 3 times more likely to present with severe disease than those with serogroup B (aRRR 2.7, 95% CI 1.1-6.3); HIV coinfection was twice as common with W and Y diseases (aRRR W = 1.8, 95% CI 1.1-2.9; aRRR Y = 1.9, 95% CI 1.0-3.4). CONCLUSIONS: In the absence of significant vaccine use, IMD in South Africa decreased by 76% from 2003-2016. HIV was associated with an increased risk of IMD, especially for serogroup W and Y diseases.

Impact of pre-hospital antibiotic therapy on mortality in invasive meningococcal disease: a propensity score study.

The role of pre-hospital antibiotic therapy in invasive meningococcal diseases remains unclear with contradictory data. The aim was to determine this role in the outcome of invasive meningococcal disease. Observational cohort study of patients with/without pre-hospital antibiotic therapy in invasive meningococcal disease attended at the Hospital Universitari de Bellvitge (Barcelona) during the period 1977-2013. Univariate and multivariate analyses of mortality, corrected by propensity score used as a covariate to adjust for potential confounding, were performed. Patients with pre-hospital antibiotic therapy were also analyzed according to whether they had received oral (group A) or parenteral antibiotics (early therapy) (group B). Five hundred twenty-seven cases of invasive meningococcal disease were recorded and 125 (24%) of them received pre-hospital antibiotic therapy. Shock and age were the risk factors independently related to mortality. Mortality differed between patients with/without pre-hospital antibiotic therapy (0.8% vs. 8%, p = 0.003). Pre-hospital antibiotic therapy seemed to be a protective factor in the multivariate analysis of mortality (p = 0.038; OR, 0.188; 95% CI, 0.013-0.882). However, it was no longer protective when the propensity score was included in the analysis (p = 0.103; OR, 0.173; 95% CI, 0.021-1.423). Analysis of the oral and parenteral pre-hospital antibiotic groups revealed that there were no deaths in early therapy group. Patients able to receive oral antibiotics had less severe symptoms than those who did not receive pre-hospital antibiotics. Age and shock were the factors independently related to mortality. Early parenteral therapy was not associated with death. Oral antibiotic therapy in patients able to take it was associated with a beneficial effect in the prognosis of invasive meningococcal disease.

Epidemiology of invasive meningococcal disease in Greece, 2006-2016.

The present study describes the epidemiology of invasive meningococcal disease (IMD) in Greece for the period 2006-2016. Combined data from notified and laboratory-confirmed IMD cases were obtained from the two involved National Centres (Epidemiology and Reference Laboratory). Laboratory identification and typing was carried out by both conventional (culture) and molecular methods (PCR, MLST, PorA, and FetA typing). A total of 796 IMD cases were notified; of those, 720 (91%) were laboratory confirmed. Overall, a decline on the annual incidence of confirmed cases was observed, ranging from 0.91 (2006) to 0.47 (2016) /100,000. A similar trend was observed in most age groups especially in children 0-4 years (7.7 to 2.9/100,000), with the exception of an increase in the incidence rate in adults > 20 years (0.21 to 0.32/100,000). The overall case fatality rate was 6.5% (52/796), annual range 2-13%. Among 658 strains which were typed by sero/genogroup, 80% were identified as MenB (annual range 65-92%); however, a decline was observed in MenB incidence from 5.3 (2006) to 2.7 (2016), among infants and toddlers, while MenW (1%), MenY (2%), and MenA (1%) remained low. During the 11 years, the annual incidence of IMD declined by 50%, especially in the 0-4-year age group, due mainly to MenB. Continuous surveillance of IMD is important for the development of future vaccination and public health policies.

Sex Difference in Meningococcal Disease Mortality, New York City, 2008-2016.

Background: The case fatality rate (CFR) from invasive meningococcal disease (IMD) in New York City (NYC) is greater than national figures, with higher rates among females than males across all age groups. Methods: We conducted a retrospective cohort study among 151 persons aged ≥15 years diagnosed with IMD in NYC during 2008-2016 identified through communicable disease surveillance. We examined demographic, clinical, and community-level associations with death to confirm the elevated risk of mortality among female IMD patients after adjusting for confounders and to determine factors associated with female IMD mortality. Relative risks of death were estimated using multivariable log-linear Poisson regression with a robust error variance. Results: Females had a higher CFR (n = 23/62; 37%) following IMD than males (n = 17/89; 19%) (adjusted relative risk [aRR], 2.1; 95% confidence interval [CI], 1.2-3.8). Controlling for demographic and clinical factors, there was a significant interaction between sex and fatal outcomes related to meningitis: the relative risk of death for females with meningitis was 13.7 (95% CI, 3.2-58.1) compared with males. In the model restricted to females, altered mental status (aRR, 7.5; 95% CI, 2.9-19.6) was significantly associated with an increased risk of death. Conclusions: Female mortality from IMD was significantly increased compared with males, controlling for other predictors of mortality. Sex-based differences in recognition and treatment need to be evaluated in cases of meningococcal disease. Our study highlights the importance of analyzing routine surveillance data to identify and address disparities in disease incidence and outcomes.

Unusual Initial Abdominal Presentations of Invasive Meningococcal Disease.

Background: Invasive meningococcal disease (IMD) is recognized as septicemia and/or meningitis. However, early symptoms may vary and are frequently nonspecific. Early abdominal presentations have been increasingly described. We aimed to explore a large cohort of patients with initial abdominal presentations for association with particular meningococcal strains. Methods: Confirmed IMD cases in France between 1991 and 2016 were screened for the presence within the 24 hours before diagnosis of at least 1 of the following criteria (1) abdominal pain, (2) gastroenteritis with diarrhea and vomiting, or (3) diarrhea only. Whole-genome sequencing was performed on all cultured isolates. Results: We identified 105 cases (median age, 19 years) of early abdominal presentations with a sharp increase since 2014. Early abdominal pain alone was the most frequent symptom (n = 67 [64%]), followed by gastroenteritis (n = 26 [25%]) and diarrhea alone (n = 12 [11%]). Twenty patients (20%) had abdominal surgery. A higher case fatality rate (24%) was observed in these cases compared to 10.4% in all IMD in France (P = .007) with high levels of inflammation markers in the blood. Isolates of group W were significantly more predominant in these cases compared to all IMD. Most of these isolates belonged to clonal complex 11 of the sublineages of the South American-UK strain. Conclusions: Abdominal presentations are frequently provoked by hyperinvasive isolates of meningococci. Delay in the management of these cases and the virulence of the isolates may explain the high fatality rate. Rapid recognition is a key element to improve their management.

CD46 accelerates macrophage-mediated host susceptibility to meningococcal sepsis in a murine model.

CD46, a membrane cofactor expressed on all nucleated human cells, plays an essential role in suppressing autoimmune reactions and protecting host cells from complement-mediated attack. Human transgenic CD46 homozygous mice (CD46+/+ ) are prone to lethal sepsis upon infection with Neisseria meningitidis (N. meningitidis). However, the underlying mechanisms are poorly understood. Here, we determined thatCD46+/+ mice produce large numbers of M1 type macrophages with enhanced surface expression of MHC II and production of pro-inflammatory mediators such as IL-6, TNF, IL-12, and IL-1ß In the presence of M-CSF or GM-CSF, CD46 signaling enhances monocyte-macrophage differentiation. Additionally, CD46+/+ macrophages rapidly undergo apoptosis upon LPS challenge or meningococcal infection, which could contribute to uncontrolled bacterial dissemination in vivo. Adoptive transfer of CD46+/+ peritoneal macrophages aggravated septic responses in wild-type mice, but the depletion of macrophages partially alleviated septic reactions in CD46+/+ mice after N. meningitidis infection. Our findings reveal a novel role of CD46 in accelerating inflammatory responses upon meningococcal infection or LPS stimulation by regulating the functional polarization and survival of macrophages.

Vaccine-preventable child deaths in New South Wales from 2005 to 2014: How much is preventable?

AIM: To identify and describe potentially vaccine-preventable child deaths in New South Wales (NSW). METHODS: Child deaths in NSW from 2005 to 2014 potentially preventable by vaccination were identified from the NSW Child Death Register (maintained by the NSW Ombudsman) and the Notifiable Conditions Information Management System (NSW Health). Medical and post-mortem records were reviewed. Cases were classified as vaccine-preventable based on the strength of evidence for the relevant infection causing death and likelihood that death was preventable through vaccination. A two-source capture-recapture method was used to estimate the true number of deaths. Age-specific mortality rate and number of deaths by disease, area of residence and comorbidity were analysed. Deaths were classified as preventable based on vaccine availability, eligibility under the National Immunisation Program, age and presence of any contraindications. RESULTS: Fifty-four deaths were identified as definitely or probably due to diseases for which a vaccine was available, with a total average annual mortality rate of 0.33 per 100 000 children and 2.1 per 100 000 infants. Two thirds of deaths occurred in children with no identified comorbidities. Twenty-three deaths were classified as preventable or potentially preventable by vaccination, with influenza (12 deaths) and meningococcal disease (five deaths) most common. An additional 15 deaths would be potentially preventable as of August 2016 due to immunisation recommendation changes including maternal vaccination. CONCLUSION: Maternal vaccination along with increased uptake of childhood influenza vaccination could reduce child deaths, particularly from influenza.

Pre-admission antibiotics for suspected cases of meningococcal disease.

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.

Clinical characteristics and public health management of invasive meningococcal group W disease in the East Midlands region of England, United Kingdom, 2011 to 2013.

In England and Wales, meningococcal disease caused by group W has historically been associated with outbreaks of disease among travellers to high-risk countries. Following a large outbreak associated with travel to the Hajj in 2000, the number of cases declined and, in 2008, only 19 laboratory-confirmed cases were identified nationally. In 2013, in the East Midlands region of England, eight cases of meningococcal disease caused by this serogroup were recorded, compared with six from 2011 to 2012. To explore this further, data for all cases with a date of onset between 1 January 2011 and 31 December 2013 were collected. Data collected included geographical location, clinical presentation and outcome. Fourteen cases were identified; two died as a result of their illness and two developed long-term health problems. No commonality in terms of geographical location, shared space or activities was identified, suggesting that group W is circulating endemically with local transmission. Clinical presentation was variable. Half presented with symptoms not typical of a classical meningococcal disease, including two cases of cellulitis, which may have implications for clinicians, in terms of timely identification and treatment, and public health specialists, for offering timely antibiotic chemoprophylaxis to close contacts.

[Meningococcal C conjugate vaccine: Impact of a vaccination program and long-term effectiveness in Navarra, Spain, 2000-2014]. / Vacuna conjugada frente al meningococo C: impacto del programa de vacunación y efectividad a largo plazo en Navarra, 2000-2014.

BACKGROUND: Since 2000, when the meningococcal serogroupC conjugate vaccine (MenCC) was introduced in the childhood immunization schedule in Spain, several changes in the schedule and catch-up campaigns have been performed. We aim to estimate the impact and effectiveness of this vaccine in Navarra up to 2014. METHODS: The impact of the vaccination program was analysed by comparing incidence, mortality and lethality rates of disease before (1995-1999) and after (2004-2014) the introduction of the MenCC. Vaccine effectiveness was estimated using the screening method (Farrington) and the indirect cohort method (Broome). Data on cases were obtained from the active surveillance of meningococcal disease. RESULTS: During 1995-1999 the mean annual incidence of meningococcalC disease was 1.32 per 100,000, and 7.18 per 100,000 in children younger than 15years. The fall of meningococcalC disease incidence was significant in cohorts targeted for vaccination from the beginning and progressive in the general population. No cases were reported between 2011 and 2014. The estimated vaccine effectiveness was 96% by the screening method, and 99% by the indirect cohort method. CONCLUSION: The MenCC vaccination program has been successful in decreasing the incidence rate of serogroupC meningococcal disease in Navarra, and schedule changes have maintained high vaccine effectiveness throughout the study period.

Disease Burden of Invasive Meningococcal Disease in the Netherlands Between June 1999 and June 2011: A Subjective Role for Serogroup and Clonal Complex.

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.

Increase in endemic Neisseria meningitidis capsular group W sequence type 11 complex associated with severe invasive disease in England and Wales.

BACKGROUND: In England and Wales, the incidence of invasive meningococcal disease has been declining for more than a decade, but meningococcal group W (MenW) cases have been increasing since 2009. METHODS: Public Health England conducts enhanced national surveillance of invasive meningococcal disease in England and Wales. Detailed clinical information was obtained for all laboratory-confirmed MenW cases diagnosed during 3 epidemiologic years (2010-2011 to 2012-2013), alongside whole-genome sequencing analysis of the clinical isolates. RESULTS: The year-on-year increase in invasive MenW disease across all age groups since 2009-2010 was due to rapid endemic expansion of a single clone belonging to the sequence type 11 complex (cc11). In 2013-2014, MenW was responsible for 15% of all invasive meningococcal disease. All but 1 of the recent MenW:cc11 isolates were very closely related, consistent with recent clonal expansion. Clinical follow-up of all 129 MenW cases diagnosed during 2010-2011 to 2012-2013 revealed that most patients were previously healthy (n = 105 [81%]), had not travelled abroad prior to illness and the majority presented with septicemia (n = 63 [49%]), meningitis (n = 16 [12%]) or both (n = 21 [16%]); however, one-quarter had atypical presentations including pneumonia (n = 15 [12%]), septic arthritis (n = 9 [7%]), and epiglottitis/supraglottitis (n = 5 [4%]). Forty-eight (37%) required intensive care and 15 (12%) died. There was no association between infecting strain, clinical disease, or outcome. CONCLUSIONS: The recent increase in invasive MenW disease in England and Wales is due to rapid endemic expansion of a single clone belonging to cc11 and is associated with severe disease with unusual clinical presentations. This increase will require careful monitoring in the coming years.

Using linked birth, notification, hospital and mortality data to examine false-positive meningococcal disease reporting and adjust disease incidence estimates for children in New South Wales, Australia.

Meningococcal disease is a rare, rapidly progressing condition which may be difficult to diagnose, disproportionally affects children, and has high morbidity and mortality. Accurate incidence estimates are needed to monitor the effectiveness of vaccination and treatment. We used linked notification, hospital, mortality and birth data for all children of an Australian state (2000-2007) to estimate the incidence of meningococcal disease. A total of 595 cases were notified, 684 cases had a hospital diagnosis, and 26 cases died from meningococcal disease. All deaths were notified, but only 68% (466/684) of hospitalized cases. Of non-notified hospitalized cases with more than one clinical admission, most (90%, 103/114) did not have meningococcal disease recorded as their final diagnosis, consistent with initial 'false-positive' hospital meningococcal disease diagnosis. After adjusting for false-positive rates in hospital data, capture-recapture estimation suggested that up to four cases of meningococcal disease may not have been captured in either notification or hospital records. The estimated incidence of meningococcal disease in NSW-born and -resident children aged 0-14 years was 5·1-5·4 cases/100 000 child-years at risk, comparable to international estimates using similar methods, but lower than estimates based on hospital data.

The impact of the meningococcal serogroup C conjugate vaccine in Canada between 2002 and 2012.

BACKGROUND: Before 2001, the incidence of invasive meningococcal disease (IMD) in Canada was 1.0 per 100 000 per year, with 40% of cases caused by serogroup C organisms. During 2001-2005 all provinces introduced the meningococcal serogroup C conjugate vaccine (MCCV) into their routine infant immunization schedule. METHODS: Active, prospective, population-based surveillance of IMD in children and adults was conducted by the Canadian Immunization Monitoring Program, ACTive (IMPACT) during 2002-2012. Inclusion criteria were admission to hospital and identification of Neisseria meningitidis from a sterile site. Incidence was estimated using population census data from Statistics Canada. RESULTS: Prior to MCCV introduction, serogroup C disease incidence was 0.07-0.25 per 100 000 per year depending on the province. Following vaccine introduction, serogroup C disease decreased to <0.05 per 100 000 per year, with a reduction of 14% per year (P = .0014). A decrease occurred in all provinces, despite differing schedules being implemented. The largest decrease of 83% (from 0.27 to 0.05 per 100 000 per year) occurred in the 15-24 year age group (P = .0100) who were not vaccinated in all provinces. There was no impact on the incidence of nonserogroup C disease over the same period (P = .9811). CONCLUSIONS: MCCV dramatically reduced the incidence of serogroup C IMD in Canada through both direct and indirect effects. The observation that disease incidence decreased with different schedules suggests that the doses at 12 months (common to all provinces) and adolescence (7 of 8 provinces studied) were critical in achieving disease control.

A functional microsatellite of the macrophage migration inhibitory factor gene associated with meningococcal disease.

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.

The epidemiology of meningococcal disease in Latin America 1945-2010: an unpredictable and changing landscape.

Meningococcal disease is mostly endemic in Latin America, with periodic occurrences of outbreaks and epidemics over the last few decades. This literature review summarizes the available epidemiological data for this region between 1945 and 2010. Incidence rates and serogroup distribution differ from country to country and over time. Serogroups A, B, and C have all been major causes of meningococcal disease since the 1970s. In the last decade serogroups W135 and Y may now be emerging in certain countries, with serogroup A virtually disappearing. Although progress has been made in improving and coordinating the surveillance of invasive disease, the uniformity and quality of reported data reflect the fact that the current surveillance systems focus on passive rather than active reporting, hence the reliability of data may vary between countries. Consideration of vaccination policies to control meningococcal disease can only be made with a sufficient understanding of the changing epidemiology in the region.

A simple meningococcal sepsis prognostic score: focusing on the human animal.

A simple cheap meningococcal sepsis prognostic score based on readily available, rapid, objective laboratory base excess and platelet count was developed and validated retrospectively. This BEP score should facilitate sepsis clinical trials, allowing study of the relevant human animal model.