Meningococcus

Clin Exp Immunol, 2000 May, 120(2), 338 - 45
The role of Fcgamma receptor polymorphisms and C3 in the immune defence against Neisseria meningitidis in complement-deficient individuals; Fijen CA et al.; Individuals with either a late (C5-9) complement component deficiency (LCCD) or properdin deficiency are at increased risk to develop meningococcal disease, often due to serogroups W135 and Y . Anti-meningococcal defence in both LCCD persons and properdin-deficient individuals without bactericidal antibodies depends mainly on phagocytosis . Three types of opsonin receptors are involved in phagocytosis by polymorphonuclear cells (PMN) . These represent the polymorphic FcgammaRIIa (CD32) and FcgammaRIIIb (CD16b) receptors, and the C3 receptor CR3 (CD11b/CD18) . When the distribution of FcgammaRIIa and FcgammaRIIIb allotypes was assessed in 15 LCCD and in 15 properdin-deficient patients with/without previous meningococcal disease, we found the combination of FcgammaRIIa-R/R131 with FcgammaRIIIb-NA2/NA2 allotypes to be associated with previous meningococcal disease (odds ratio 13.9, Fisher's test P = 0.036) . No such relation was observed in the properdin-deficient patients . The importance of FcgammaRIIa allotypes was also demonstrated using in vitro phagocytosis assays . PMN from FcgammaRIIa-R/R131 homozygous donors internalized IgG2 opsonized meningococci W135 significantly (P < 0.05) less than PMN from FcgammaRIIa-H/H131 donors . When properdin-deficient serum was tested, it was observed that reconstitution with properdin resulted in enhanced PMN phagocytosis of the W135 meningococci (P = 0.001) . This enhanced phagocytosis was parallelled by an increase in C3 deposition onto the opsonized meningococci W135 (r = 0.6568, P = 0 . 01) . We conclude that the occurrence of meningococcal disease in LCCD patients is associated with certain FcgammaR allotypes . Properdin-deficient individuals are susceptible to meningococcal disease because of an insufficient C3 deposition on the surface of meningococci, resulting in insufficient phagocytosis.

Eur J Pediatr, 2000 Apr, 159(4), 277 - 82
Life-threatening heart failure in meningococcal septic shock in children: non-invasive measurement of cardiac parameters is of important prognostic value; Hagmolen of ten Have W et al.; Heart failure is a life-threatening complication of fulminant meningococcal septic shock (MSS) . Depression of left ventricular function, in particular, is thought to be due to circulating meningococcal endotoxin . Myocardial failure leads to ventricular dilation expressed by an increased left-ventricle end-diastolic diameter (LVED) . With ultrasonography, LVED can be accurately measured as well as the shortening fraction (SF) . In an evaluative study we investigated the accuracy of the SF and compared it to the accuracy of the Glasgow meningococcal septicemia prognostic score (GMSPS) in the prediction of mortality in children with fulminant MSS . In 27 children admitted in a 4-year period with a presumptive clinical diagnosis of fulminant MSS, hypotension persisted for more than 1 h despite volume loading and inotropic therapy . Seven of these children died (26%); all had an SF <0.30 and a GMSPS > or =10 (the sensitivity of both scores was 100%) . Positive predictive values of the SF and GMSPS were 41% and 58% respectively . CONCLUSIONS: SF can be used in addition to other severity scores in clinical decision-making and contribute to the selection of children with the worst prospects for inclusion in experimental treatment studies.

Eur J Pediatr, 2000 Apr, 159(4), 232 - 6
Pediatric risk of mortality (PRISM) score in meningococcal disease; van Brakel MJ et al.; To assess the pediatric risk of mortality (PRISM) score as a prognostic scoring system in severe meningococcal disease, the files of 53 consecutive patients admitted to a tertiary pediatric intensive care with a clinical diagnosis of meningococcal disease and positive cultures from blood and/or cerebrospinal fluid were analysed . PRISM-score-based expected mortality was compared with observed mortality . Expected mortality in the whole study population was 29% while observed mortality was 19% (P<0.05) . The highest expected and observed mortality was found in septicaemic patients without (documented) meningitis, while meningitis patients without septicaemia had the lowest mortality . All patients with a mortality risk below 18.3% (n = 29) survived whereas all those with a mortality risk of 65% or higher (n = 7) died . Of the 17 patients with a mortality risk between 18.3% and 63.9%, 14 survived and 3 died . The area under the receiver-operating characteristic (ROC) curve was 0.94, which is at least comparable with the best-performing meningococcal-disease-specific scoring systems . CONCLUSION: The PRISM score is a useful generic measure of severity of illness in meningococcal disease and can be used to determine the effectiveness of different treatment strategies.

Arkh Patol, 2000 Mar-Apr, 62(2), 52 - 7
{Inflammation mediators in pathogenesis of infection-toxic shock of meningococcal etiology}; Val'kov AIu et al.; Up-to-date advances made in understanding of the events underlying meningococcal infection-toxic shock (ITS) are reviewed . Endotoxin properties, its interaction with transport protein and specific membrane receptors entailing activation of macrophages and secretion of cytokines TNF and IL-1 are described . Both of them are considered as major mediators of ITS . Recent information about activation of complement and coagulation cascades, changes of kinetic and functional properties of polymorphonuclear leukocytes are summarized . As to secondary mediators, the emphasis is placed on bioregulatory system L-arginine-NO . A scheme of pathogenesis of meningococcal ITS is provided . The latter is corresponding both clinically and morphologically to other endotoxin shocks and its peculiarities in excessive activation of coagulation system.

Intensive Care Med, 2000, 26 Suppl 1, S89 - 97
Genetic dissection of the molecular pathogenesis of severe infection; Kwiatkowski D; A fundamental question for the intensivist is why some individuals but not others succumb to life-threatening infection . A growing body of evidence indicates that both the risk of acquiring infection and the risk of developing severe complications are determined by host genetic factors . These include a number of single gene defects with devastating consequences, e . g . interferon-gamma receptor mutations that lead to fatal infections with ubiquitous mycobacteria, but such examples are relatively rare . Of greater importance for routine clinical practice is the potentially vast number of genetic variants with subtle effects on the regulation or function of specific immunological, physiological and metabolic mediators . Such polygenic traits do not obey simple patterns of familial segregation seen for monogenic disorders, and their clinical investigation is further complicated by the environmental variability of infectious exposure . Recent advances in this field have therefore largely stemmed from hospital-based case-controlled studies that have uncovered disease associations with specific DNA polymorphisms in candidate gene regions . For example, tumour necrosis factor polymorphisms have been associated with susceptibility to malaria and other infections; chemokine receptor polymorphisms with susceptibility to HIV; natural resistance-associated macrophage protein 1 with tuberculosis; and mannose binding lectin polymorphisms with meningococcal disease . A much greater number of genetic associations will emerge as the full extent of human genomic diversity becomes known . The challenge for clinical investigators is to generate an epidemiological framework for population- and family-based association studies, which is sufficiently robust to exclude population artifacts and sufficiently powerful to be able to dissect true disease-causing polymorphisms from linked genetic markers . In the long term this approach promises to identify host mediators that are critical for pathogenesis and immunity and to yield molecular insights into the complex processes of human gene regulation . This information is likely to be of considerable value in designing more effective approaches to the treatment and prevention of life-threatening infectious disease.

Pediatr Infect Dis J, 2000 Apr, 19(4), 324 - 8
Meningococcal disease in Dallas County, Texas: results of a six-year population-based study; Pastor P et al.; OBJECTIVE: Neisseria meningitidis is an important cause of serious bacterial infection in children and adults in the US . From 1992 to 1997 invasive disease caused by N . meningitidis was studied among 1.9 million residents of Dallas County, TX METHODS: The demographic characteristics and diagnoses of 151 patients were identified through active, population-based surveillance and review of medical records . Serogroups were determined for strains infecting 129 (85%) patients . RESULTS: The average annualized incidence rate was 1.3 cases per 100,000 person years and was highest for children <1 year (13 cases/100,000 person years) . Older patients (50+ years old) were more likely to present with pneumonia and less likely to present with meningitis than younger patients . Neither the fatality rate nor the duration of hospitalization for surviving patients was associated with age . Among patients with a known serogroup, serogroup C disease was found in 35% of cases <1 year old, 64% of those 1 to 49 years old and 44% of those 50+ years old . Serogroup B strains were isolated from 26% of patients <1 year, 17% of patients 1 to 49 years old and none of the patients 50+ years old . Serogroup Y disease increased from 22% to 35% of cases between 1992 and 1997 (P = 0.03) . This serogroup was identified in 26% of patients <1 year old, 17% of patients 1 to 49 years old and in 50% of patients 50+ years old . Serogroup C and Y accounted for 61% of cases in children <1 year old and for 79% of cases in all age groups . CONCLUSION: The results underscore the importance of conjugate vaccines for serogroups C and Y.

Vaccine, 2000 Jun 1, 18(24), 2686 - 92
Immunogenicity and reactogenicity of a group C meningococcal conjugate vaccine compared with a group A+C meningococcal polysaccharide vaccine in adolescents in a randomised observer-blind controlled trial; Choo S et al.; This study evaluated the immunogenicity and reactogenicity of a group C meningococcal conjugate vaccine (MenC) compared with a group A+C meningococcal polysaccharide vaccine (MenPS) in healthy adolescents . Subjects were randomised to receive one dose of either MenC (n=92) or MenPS (n=90) . Group C meningococcal IgG antibody concentrations and bactericidal titres were higher in the MenC group than the MenPS group at 1 month (22.8 U/ml vs 4.0 U/ml, p<0.001, and 87 vs 20, p<0.001, respectively) and 12 months (6.1 U/ml vs 3.0 U/ml, p<0.001, and 81.3 vs 20.2, p<0.001, respectively) . No differences in post immunisation reaction rates were noted between the two vaccinated groups . This study demonstrated the safety and enhanced immunogenicity of the candidate meningococcal conjugate vaccine as compared with the licensed polysaccharide vaccine in adolescents.

Vaccine, 2000 Jun 1, 18(24), 2656 - 60
Seroconversion and duration of immunity after vaccination against group C meningococcal infection in young children; Espin Rios I et al.; An increase in the incidence of group C meningococcal disease was observed in the Murcia Region (Spain) during 1996-1997 . In September 1997, a massive vaccination campaign was implemented among the population aged 18 months to 19 years . The aim of this study was to assess the seroconversion rate of children aged 18-59 months and the persistence of immune response 1 year after vaccination . A total of 296 children were included . Blood samples were obtained before vaccination and 1 month and 1 year after vaccination . Three point seven percent of the children had bactericidal antibody titres of >/=1:8 before vaccination . One month after vaccination seroconversion was 63.7%, with a growing trend related to age at vaccination (p<0.0001) . The increase in antibody titres was shown to be quantitatively greater above the age of 36 months (p<0.0001) . One year after vaccination only 4.3% of the children who initially seroconverted still had bactericidal activity . Seroconversion in children under 5 increases with age but antibodies decline rapidly in the year following vaccination.

Vaccine, 2000 May 22, 18(23), 2476 - 81
Effect of sequence variation in meningococcal PorA outer membrane protein on the effectiveness of a hexavalent PorA outer membrane vesicle vaccine; Martin SL et al.; Though meningococcal serogroup C conjugate vaccines have been introduced into the UK infant immunisation schedule, there is currently no vaccine solution for serogroup B disease . PorA outer membrane protein (OMP) is a potential serogroup B vaccine candidate . A hexavalent PorA outer membrane vesicle (OMV) vaccine has been evaluated in phase I and II trials with promising results . This vaccine contains six different PorA OMPs each representing a different serosubtype . However, considerable sequence variation occurs in the variable regions (VRs) encoding these serosubtypes . By using recombinant P1.5,10 PorA variants we have demonstrated that the killing of this particular serosubtype combination was due mainly to the induction of antibody to the VR2 (P1.10) epitope region, and that after three or four doses of vaccine there was a significant reduction in the killing of variants P1.10a (three doses, p<0.0001; four doses, p = 0.003) and P1.10f (three doses, p<0.0001; four doses, p = 0.002), as compared to responses to the P1.10 strain, when the P1.10 serosubtype was used as the immunogen . Since large numbers of serosubtype variants are known to exist, this finding may have implications for the use of PorA as a meningococcal serogroup B vaccine.

Clin Infect Dis, 2000 Apr, 30(4), 648 - 51 Epub 2000 Apr 20.
Preventing meningococcal infection in college students; Harrison LH; The incidence of invasive meningococcal disease in adolescents and young adults of high school and college age has recently increased in the United States . Recent studies indicate that certain groups of college students are at increased risk . This has led to the recent Advisory Committee Immunization Practices recommendation that college freshman dormitory residents be provided information about meningococcal infection and the benefits of vaccination . Future studies will need to focus on the potential vaccine prevention of the increased risk of meningococcal infection in persons of high school age, particularly as new conjugate meningococcal vaccines become available.

Clin Infect Dis, 2000 Apr, 30(4), 643 - 7 Epub 2000 Mar 30.
Fulminant meningococcal septicemia: dissociation between plasma thrombopoietin levels and platelet counts; Bjerre A et al.; Thrombopoietin (TPO), interleukin (IL)-6, and platelets were measured serially in 9 patients with fulminant meningococcal septicemia and consumption coagulopathy . The results were compared with those of patients with meningococcal meningitis and mild meningococcemia (n=10) and with those of healthy control subjects (n=19) . TPO levels in control subjects were below the detection limit (<63 pg/mL) . In patients with fulminant meningococcal septicemia, the median TPO level on admission was 193 pg/mL (range, 133-401 pg/mL), and the level peaked within 3-7 days (median, 488 pg/mL; range, 239-1334 pg/mL) . Platelet counts remained low, despite the elevated TPO levels . In patients with meningitis or meningococcemia, the median TPO level on admission was 112 pg/mL (range, <63-695 pg/mL), and the TPO level was not detectable within 48 h . Platelet counts for these patients remained within normal limits . Maximum IL-6 levels in patients with septicemia were observed on admission (median, 5317 pg/mL; range, 188-651,000 pg/mL) and increased earlier than TPO levels . In patients with fulminant septicemia, TPO level increases significantly whereas the level of circulating platelets does not.

FEMS Immunol Med Microbiol, 2000 May, 28(1), 79 - 85
Meningococcal serogroup C-specific IgG antibody responses and serum bactericidal titres in children following vaccination with a meningococcal A/C polysaccharide vaccine; Borrow R et al.; In the UK, a co-ordinated series of phase II studies is being undertaken with meningococcal serogroup C conjugate (MCC) vaccines . The use of meningococcal A/C polysaccharide (MACP) vaccines in control arms in young children has been avoided because of the well recognised short comings of these vaccines . Following a cluster of serogroup C disease centred on a day nursery, intervention by MACP vaccination was performed as an outbreak control measure . Using this cohort, serogroup C-specific IgG ELISA and serum bactericidal assays (SBA) were performed using both de-O-acetylated (Oac(-)) and acetylated (Oac(+)) serogroup C antigen, the measurement of primarily high avidity antibody and using baby rabbit or human complement in the SBA . The effect of subject age (either less than or greater than 2 years of age) was assessed for the different assays and significant differences (P<0.05) were found using both antigen sources in the high avidity ELISA and in the rabbit complement SBA but not in the standard ELISA . When assessing results from different studies it is important that methodologies utilised allow such comparisons since the choice of reagents can have a profound influence . The importance of standardised assays is paramount at a time where immunogenicity trials are replacing efficacy trials for the introduction of MCC vaccines.

Am J Med Sci, 2000 Apr, 319(4), 255 - 7
Primary meningococcal pneumonia in elderly patients; Reddy TS et al.; Neisseria meningitidis infection in humans usually manifests as meningitis and septicemia with skin manifestations . Infections of the respiratory tract with N meningitidis have been documented in the past, but often this organism is not routinely considered in the differential diagnosis of pneumonia . The pathogenic role of N meningitidis in lower respiratory tract infections may be underestimated because its isolation is difficult, particularly when oropharyngeal flora are present . We profile 2 elderly patients with primary meningococcal pneumonia to show the importance of Gram stain and culture in early diagnosis . These modalities helped guide treatment and prophylactic measures.

Can Commun Dis Rep, 1999 Sep 15, 25, 1 - 12
An Advisory Committee Statement (ACS) . Committee to Advise on Tropical Medicine and Travel (CATMAT) . Statement on meningococcal vaccination for travellers; Clinical features et al.; Meningococcal Reference Unit, Withington Hospital, Manchester, UKOBJECTIVES: To describe the epidemiological, clinical and laboratory features of meningococcal meningitis and the effects of antibiotics on laboratory investigations under current clinical practices in England and Wales . METHODS: Using a telephone questionnaire, information was gathered on 103 cases with a clinical diagnosis of meningococcal meningitis . Included were cases with samples submitted to the Public Health Laboratory Service (PHLS), Meningococcal Reference Unit (MRU) over a 5-month period in 1997 . Tests included microscopic examination, latex agglutination and culture for Neisseria meningitidis, and at MRU confirmation of identification and characterization of isolates and meningococcal polymerase chain reaction (PCR) analysis on blood and cerebrospinal fluids (CSF) . RESULTS: Clinically 45% of the cases had predominantly meningitis and 55% had septicaemia and meningitis . Only 29% of the cases received pre-admission benzylpenicillin, and 66% were given antibiotics within an hour of hospital attendance . Microbiological confirmation was achieved in 97 cases, 46 (44%) by traditional tests and 92 (89%) by PCR assay, including some with both . The blood culture positive rate was 23 (22%), but in predominant meningitis the rate was only 10% (5/46) . PCR was the sole method of confirmation in 48 cases . Seventy percent of the plasma samples referred were reactive by PCR assay, but all samples taken more than 24 h after hospital antibiotics were non-reactive . PCR-based techniques increased the overall number of cases with a serogroup identified by 44% . Lumbar punctures were performed in 73 of the cases and microbiological confirmation was achieved in 67 (92%) of these cases, compared to 26/30 without lumbar puncture (LP) . Eighty-nine percent of the CSF samples referred were reactive by PCR; 50% of the CSF samples taken more than 24 h after hospital antibiotics were reactive, whilst none were positive by culture or microscopy . CONCLUSION: Due to variable clinical manifestations, early diagnosis and treatment was difficult . Laboratory confirmation has been improved by the introduction of PCR-based techniques . Meningococcal DNA was detected by molecular methods in CSF samples taken up to 72 h after commencement of antibiotics . During this period patients could be stabilized and the chances of complications attendant upon early LP reduced . In addition to providing accurate epidemiological information, confirming the diagnosis may alter the extent and length of follow-up.

Nature, 2000 Mar 30, 404(6777), 502 - 6
Complete DNA sequence of a serogroup A strain of Neisseria meningitidis Z2491; Parkhill J et al.; Neisseria meningitidis causes bacterial meningitis and is therefore responsible for considerable morbidity and mortality in both the developed and the developing world . Meningococci are opportunistic pathogens that colonize the nasopharynges and oropharynges of asymptomatic carriers . For reasons that are still mostly unknown, they occasionally gain access to the blood, and subsequently to the cerebrospinal fluid, to cause septicaemia and meningitis . N . meningitidis strains are divided into a number of serogroups on the basis of the immunochemistry of their capsular polysaccharides; serogroup A strains are responsible for major epidemics and pandemics of meningococcal disease, and therefore most of the morbidity and mortality associated with this disease . Here we have determined the complete genome sequence of a serogroup A strain of Neisseria meningitidis, Z2491 . The sequence is 2,184,406 base pairs in length, with an overall G+C content of 51.8%, and contains 2,121 predicted coding sequences . The most notable feature of the genome is the presence of many hundreds of repetitive elements, ranging from short repeats, positioned either singly or in large multiple arrays, to insertion sequences and gene duplications of one kilobase or more . Many of these repeats appear to be involved in genome fluidity and antigenic variation in this important human pathogen.

Pediatr Clin North Am, 2000 Apr, 47(2), 449 - 63
A step ahead . Infant protection through maternal immunization; Munoz FM et al.; The concept of maternal immunization to prevent infectious diseases during a period of increased vulnerability in infants is not new and is supported by historical experience and carefully conducted studies of various viral and bacterial vaccines . Candidate vaccines should be minimally reactogenic, immunogenic, and safe for maternal immunization to be considered as a disease prevention strategy . The possibilities increase as more potential candidate vaccines for use during pregnancy become available, including conjugate meningococcal vaccines, parainfluenza virus type 3 purified subunit vaccines, herpes simplex virus, cytomegalovirus, and HIV vaccines . Additional research on the safety and efficacy of maternal immunization must continue to effect the development of infectious diseases in neonates and infants.

Int J Epidemiol, 2000 Feb, 29(1), 180 - 8
Mathematical modelling of infection and disease due to Neisseria meningitidis and Neisseria lactamica; Coen PG et al.; BACKGROUND: Invasive meningococcal disease, due to Neisseria meningitidis, is an important cause of morbidity and mortality in young children and adolescents . Nasopharyngeal carriage of meningococci (MC), is most prevalent in young adults whereas carriage of Neisseria lactamica (LC), a related non-pathogenic organism, is most prevalent in young children . The objective of this study was to use modelling techniques to test hypotheses on the processes that govern the incidence of meningococcal disease (MD) . METHODS: Deterministic compartmental models were fitted to age structured data sets of MC, LC and MD . RESULTS: The model most consistent with the available data sets is one where LC inhibits MC, an inhibition that lasts for a mean of 4.7 years . The hypothesis that LC also acts as a natural immunogen against MD was consistent with this model . The second peak of MD observed among adolescents could be due to the peak in the acquisition of MC in this age group . CONCLUSIONS: The role of LC as a natural immunogen against asymptomatic and symptomatic meningococcal infection was consistent with available field data . If the introduction of novel meningococcal vaccines into a population changes the prevalence of MC or LC, this could have a substantial impact on the effectiveness of immunization programmes . This paper demonstrates the potential utility of modelling to estimate these effects.

Pediatr Infect Dis J, 2000 Mar, 19(3), 187 - 95
Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children . Northern California Kaiser Permanente Vaccine Study Center Group; Black S et al.; OBJECTIVE: To determine the efficacy, safety and immunogenicity of the heptavalent CRM197 pneumococcal conjugate vaccine against invasive disease caused by vaccine serotypes and to determine the effectiveness of this vaccine against clinical episodes of otitis media . METHODS: The Wyeth Lederle Heptavalent CRM197 (PCV) was given to infants at 2, 4, 6 and 12 to 15 months of age in a double blind trial; 37,868 children were randomly assigned 1:1 to receive either the pneumococcal conjugate vaccine or meningococcus type C CRM197 conjugate . The primary study outcome was invasive disease caused by vaccine serotype . Other outcomes included overall impact on invasive disease regardless of serotype, effectiveness against clinical otitis media visits and episodes, impact against frequent and severe otitis media and ventilatory tube placement . In addition the serotype-specific efficacy against otitis media was estimated in an analysis of spontaneously draining ears . RESULTS: In the interim analysis in August, 1998, 17 of the 17 cases of invasive disease caused by vaccine serotype in fully vaccinated children and 5 of 5 of partially vaccinated cases occurred in the control group for a vaccine efficacy of 100% . Blinded case ascertainment was continued until April, 1999 . As of that time 40 fully vaccinated cases of invasive disease caused by vaccine serotype had been identified, all but 1 in controls for an efficacy of 97.4% (95% confidence interval, 82.7 to 99.9%), and 52 cases, all but 3 in controls in the intent-to-treat analysis for an efficacy of 93.9% (95% confidence interval, 79.6 to 98.5%) . There was no evidence of any increase of disease caused by nonvaccine serotypes . Efficacy for otitis media against visits, episodes, frequent otitis and ventilatory tube placement was 8.9, 7.0, 9.3 and 20.1% with P < 0.04 for all . In the analysis of spontaneously draining ears, serotype-specific effectiveness was 66.7% . CONCLUSION: This heptavalent pneumococcal conjugate appears to be highly effective in preventing invasive disease in young children and to have a significant impact on otitis media.

Pathology, 2000 Feb, 32(1), 42 - 5
Detection and serogroup determination of Neisseria meningitidis in CSF by polymerase chain reaction (PCR); Porritt RJ et al.; A PCR protocol for the detection and serogroup determination of Neisseria meningitidis in CSF from 85 cases of suspected meningitis was evaluated . Screening assays for both IS1106 and the ctrA gene were used to detect meningococcal DNA, and a further two assays using the siaD gene were performed to determine the serogroup . PCR results were compared with results of bacteriological culture and discrepant results resolved by analysis of clinical data and further laboratory test results . The resolved sensitivity and specificity of the PCR screening assay were 89 and 100%, and those of bacteriological culture were 37 and 100%, respectively . The siaD B/C PCR assay was able to determine a serogroup in 85% of cases positive by the PCR screening assay compared with 50% of cases where a serogroup was determined by traditional methods . PCR is a useful tool for diagnosis of meningococcal meningitis when Gram stain and culture tests are negative, a situation that may arise when antibiotic treatment has commenced prior to lumbar puncture.

Vaccine, 2000 May 8, 18(22), 2359 - 67
A comparison of multiple regimens of pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine and pneumococcal polysaccharide vaccine in toddlers; Blum MD et al.; Children who had been randomized to receive one dose of either heptavalent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine (PCV) or 23-valent pneumococcal polysaccharide vaccine (PN23) at 12, 15, or 18 months of age were subsequently randomized to receive a booster injection of either PCV or PN23 12 months later . For those children who received a priming dose of PCV (N=75) compared to PN23 (N=48) at 12, 15, or 18 months of age, higher serum antibody concentrations were achieved 1 month following a booster injection of either PCV or PN23 for all serotypes tested (p<0.001) . Within the group of children receiving a priming dose of PCV, those children who received a booster dose of PN23 developed higher serum antibody concentrations for four of the seven serotypes tested and similar opsonic antibody titers to serotype 6B, yet more frequent erythema (p=0.030) and pain or soreness (p=0.024) at the injection site compared to those boosted with PCV . In conclusion, a single dose of PCV at 12-18 months of age primed for responses to booster doses of either PCV or PN23 12 months later . For those children who received a priming dose of PCV, boosting with PN23 resulted in more frequent injection site pain and erythema than boosting with PCV, yet higher antibody concentrations for most of the serotypes tested.

Commun Dis Intell, 1999 Apr 15, 23(4), 97 - 101
Meningococcal disease and the law: does non-notification really happen?
Robinson P.
In Victoria, legislation clearly makes the notification of clinical or confirmed cases of meningococcal disease mandatory . Statistical modelling suggests that meningococcal disease is significantly under-notified, and that incorrect codes might be being ascribed to some in-patient episodes . The aims of this study were (i) to test the assumption that cases identified as non-notified cases were true cases, and (ii) to identify the reasons for non-detection on the hospital separation database and non-notification to the infectious diseases unit . Of 26 cases not identified on the in-patient dataset, the main causes were either being given completely incorrect ICD-9-CM codes (11 cases) or being given codes for a different type of meningitis (8 cases) . Of 29 non-notified admissions, most were clinically (17) or microbiologically (6) confirmed cases, although 5 were coded in error and were not cases of meningococcal disease . Therefore, although the allocation of incorrect ICD-9-CM codes at separation was a major reason for discrepancy, non-notification was a real and recent problem . It is also possible that some clinical staff did not understand the relationship between Neisseria meningitidis and meningococcal disease, the public health implications of this infection, or the law relating to it.

J Biol Chem, 2000 Mar 31, 275(13), 9716 - 24
Structural relationships and sialylation among meningococcal L1, L8, and L3,7 lipooligosaccharide serotypes; McLeod Griffiss J et al.; Eighteen of 34 endemic meningococcal case strains were of the L8 lipooligosaccharide (LOS) type; four of these were both L3 and L7 (L3,7), and seven were L1 . L1 structures arose by alternative terminal Gal substitutions of lactosyl diheptoside L8 structures, as determined by electrospray ionization and other mass spectrometric techniques, and enzymatic and chemical degradations (Structures L1 and L1a) . {see text for structure} The more abundant molecule, designated L1, had a trihexose globosyl alpha chain; the less abundant one, designated L1a, had a beta-lactosyl alpha chain and a parallel alpha-lactosaminyl gamma chain . A P(k) globoside (Galalpha1-->4Galbeta1-->4 Glc-R) monoclonal antibody bound 9/10 L1 strains, but a P(1) globoside (Galalpha1-->4Galbeta1-->4GlcNAc-R) mAb bound none of them . alpha-Galactosidase caused loss of both L1 structures and creation of L8 structures; beta-galactosidase caused loss of the L8 determinant . The L1/P(k) glycose was partially sialylated . Some LOS also had unsubstituted basal beta-GlcNAc additions . These structural relationships explain co-expression of L8, L1, and L3,7 serotypes.

BMJ, 2000 Mar 25, 320(7238), 846 - 9
Changing carriage rate of Neisseria meningitidis among university students during the first week of term: cross sectional study; Neal KR et al.; OBJECTIVE: To determine the rates of, and risk factors for, meningococcal carriage and acquisition among university students . DESIGN: Repeated cross sectional study . PARTICIPANTS: 2,507 students in their first year at university . MAIN OUTCOME MEASURES: Prevalence of carriage of meningococci and risk factors for carriage and acquisition of meningococci . RESULTS: Carriage rates for meningoccoci increased rapidly in the first week of term from 6.9% on day 1, to 11.2% on day 2, to 19.0% on day 3, and to 23.1% on day 4 . The average carriage rate during the first week of term in October among students living in catered halls was 13.9% . By November this had risen to 31.0% and in December it had reached 34 . 2% . Independent associations for acquisition of meningococci in the autumn term were frequency of visits to a hall bar (5-7 visits: odds ratio 2.7, 95% confidence interval 1.5 to 4.8), active smoking (1.6, 1.0 to 2.6), being male (1.6, 1.2 to 2.2), visits to night clubs (1 . 3, 1.0 to 1.6), and intimate kissing (1.4, 1.0 to 1.8) . Lower rates of acquisition were found in female only halls (0.5, 0.3 to 0.9) . The most commonly acquired meningococcal strain was C2a P1.5 (P1.2), which has been implicated in clusters of invasive meningococcal disease at other UK universities . CONCLUSIONS: Carriage rates of meningococci among university students increase rapidly in the first week of term, with further increases during the term . The rapid rate of acquisition may explain the increased risk of invasive meningococcal disease and the timing of cases and outbreaks in university students.

Infect Immun, 2000 Apr, 68(4), 2082 - 95
Molecular and biological analysis of eight genetic islands that distinguish Neisseria meningitidis from the closely related pathogen Neisseria gonorrhoeae; Klee SR et al.; The pathogenic species Neisseria meningitidis and Neisseria gonorrhoeae cause dramatically different diseases despite strong relatedness at the genetic and biochemical levels . N . meningitidis can cross the blood-brain barrier to cause meningitis and has a propensity for toxic septicemia unlike N . gonorrhoeae . We previously used subtractive hybridization to identify DNA sequences which might encode functions specific to bacteremia and invasion of the meninges because they are specific to N . meningitidis and absent from N . gonorrhoeae . In this report we show that these sequences mark eight genetic islands that range in size from 1.8 to 40 kb and whose chromosomal location is constant . Five of these genetic islands were conserved within a representative set of strains and/or carried genes with homologies to known virulence factors in other species . These were deleted, and the mutants were tested for correlates of virulence in vitro and in vivo . This strategy identified one island, region 8, which is needed to induce bacteremia in an infant rat model of meningococcal infection . Region 8 encodes a putative siderophore receptor and a disulfide oxidoreductase . None of the deleted mutants was modified in its resistance to the bactericidal effect of serum . Neither were the mutant strains altered in their ability to interact with endothelial cells, suggesting that such interactions are not encoded by large genetic islands in N . meningitidis.

Infect Immun, 2000 Apr, 68(4), 1871 - 8
Functional activities and immunoglobulin variable regions of human and murine monoclonal antibodies specific for the P1.7 PorA protein loop of Neisseria meningitidis; Wang J et al.; The meningococcal PorA protein is considered a promising vaccine candidate . Although much is understood regarding the structure of PorA proteins, little is known about the structure-function relationships of PorA antibodies . The aim of this study was to compare the functional and molecular characteristics of a human monoclonal antibody (MAb) and three murine MAbs specific for the PorA P1.7 serosubtype . Murine MAbs 207,B-4 (immunoglobulin G2a {IgG2a}) and MN14C11.6 (IgG2a) were both bactericidal and opsonophagocytic for P1.7-expressing meningococci, whereas human MAb SS269 (IgG3) and murine MAb 208,D-5 (IgA) initiated neither effector function . Epitope mapping with synthetic peptides revealed that MAbs 207,B-4 and 208,D-5 recognized the sequence ASGQ, which is the same specificity motif that a previous study had established for SS269 and MN14C11.6 . Nucleotide and amino acid sequence analyses of the variable regions of the four MAbs showed that the SS269 V(H) region belonged to the VH3 family and was approximately 70% homologous to those of the murine MAbs which were all from the 7183 family, whereas the SS269 V(L) region belonged to the Vlambda1-b family and was less than 40% homologous to those of the murine MAbs which were all members of the Vkappa1 family . The Fab fragment of SS269 was cloned and expressed in Escherichia coli and was shown by enzyme-linked immunosorbent assay analyses to bind as well as intact SS269 MAb to P1.7,16 serosubtype group B strain 44/76 . We conclude that distinct differences exist in the effector function activities and variable region gene sequences of human and murine P1.7-specific MAbs despite their recognition of similar epitopes.

Epidemiol Infect, 2000 Feb, 124(1), 75 - 81
Management of an outbreak of meningococcal meningitis in a Sudanese refugee camp in Northern Uganda; Santaniello-Newton A et al.; We describe an outbreak of meningitis at a Sudanese refugee camp in Northern Uganda that lasted over a year from February 1994 . Some 291 cases occurred in a refugee population of 96860 (averaged over the year), an attack rate of 0.30% . The case fatality rate was 13.3% . From a small number of samples taken for culture N . meningitidis serogroup A, serotype 21:P1.9, clone III-1 was identified as the causative organism . The outbreak started in the camp's reception centre which had the highest attack rate . Spread from the reception centre was rapid and the epidemic reached its peak within 3 weeks . All of the cases amongst residents of the reception centre reported having had meningococcal vaccine before arriving at the camp and so were not immunized on arrival as would normally have been the case . Some 37 547 doses of meningococcal vaccine were used in a mass immunization campaign in February and March 1994 . Following this the outbreak was declared over in August 1994 when no cases were registered for 2 consecutive weeks . However, following a massive and sudden influx of refugees a new epidemic peak occurred during February 1995 . Many of these new refugees were also not immunized on arrival due to pressures of numbers . A follow-up immunization campaign then brought an end to the outbreak . Our experience confirms the effectiveness of timely and high-coverage immunization campaigns in controlling group A meningitis outbreaks amongst refugees in Africa.

Epidemiol Infect, 2000 Feb, 124(1), 69 - 73
Serogroup C meningococcal disease outbreak associated with discotheque attendance during carnival; Hauri AM et al.; In the week following a carnival during 19-24 February 1998, an outbreak of meningococcal disease occurred in a rural German county . The available isolates belonged to phenotype C:2a:P1.2,5 and were clonally related by pulsed-field gel electrophoresis . A case-control study was done to identify risk factors for the outbreak and to define possible vaccination target groups . Five persons aged 13-16 years who fell ill during 24-27 February were included in the study . Four of 5 cases and 10 of 32 controls visited local discotheques (OR = 8.8; P = 0.06) . Cases also visited discotheques more frequently than controls (chi2 for trend, P = 0.0002) . Multiple discotheques during the carnival may have been predominant locations of transmission in this outbreak . Because this risk factor was limited in time, a mass community vaccination campaign was not initiated.

J Infect Dis, 2000 Mar, 181(3), 1172 - 5
Lack of immunity in university students before an outbreak of serogroup C meningococcal infection; Jones GR et al.; Immunity to meningococci was determined in infected and uninfected students before and during an outbreak of serogroup C meningococcal infection at a university in the United Kingdom . No immunity against the outbreak strain was detected in serum taken from infected students prior to the outbreak or at the time of admission; bactericidal activity developed during convalescence . Carriage of all strains of serogroup C meningococci in asymptomatic students was low (0.9%), and no carriage of the outbreak strain could be detected . Immunity in the at-risk student population before the outbreak was low: 90% of students had no significant bactericidal activity against the outbreak strain . A low prevalence of carriage of the outbreak strain, together with a low prevalence of protective immunity within the student population, was associated with a high incidence of invasive disease in those who acquired the outbreak strain.

Scand J Immunol, 2000 Feb, 51(2), 176 - 85
Human T-cell response to meningococcal immunoglobulin A1 protease associated alpha-proteins; Jose J et al.; A unique feature of the immunoglobulin A1 (IgA1) protease from pathogenic Neisseriae, i.e . N . meningitidis and N . gonorrhoeae, is its co-secretion with an amphipathic a-protein . Polymerase chain reaction (PCR) analysis of the respective iga(alpha) . gene region in 48 meningococcal strains revealed that this protein domain is conserved throughout all isolates in four different principal variants . Despite strain-dependent size and sequence variations, sequence analysis showed common structural characteristics . More than 80% of the amino acid sequence of all a-proteins is dependent on the five amino acids Q, E, A, K and R, resulting in a pI> 10 . The sequences are highly conserved at the N-terminus and the C-terminus and contain long amphipathic alpha-helical stretches . These stretches have a strong probability of forming coiled coil conformations and comprise short repetitive sequence modules with pronounced similarities to T-cell epitopes . We therefore analyzed the T-cell response of 20 volunteer blood donors to four peptides, representing such predicted epitopes, and a recombinant meningococcal alpha-protein . Sixteen donors reacted against at least one peptide after culture of peripheral blood mononuclear cells in interleukin (IL)-2-rich medium, while two individuals showed a positive reaction only against an IgA1 protease-derived control peptide . From one donor, we established and maintained T-cell clones specific for purified alpha-protein . Characterization of the T-cell clones revealed a CD3- and a CD4-positive phenotype and the secretion of IL-2 and interferon-gamma (IFN-gamma),

Science, 2000 Mar 10, 287(5459), 1816 - 20
Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing; Pizza M et al.; Neisseria meningitidis is a major cause of bacterial septicemia and meningitis . Sequence variation of surface-exposed proteins and cross-reactivity of the serogroup B capsular polysaccharide with human tissues have hampered efforts to develop a successful vaccine . To overcome these obstacles, the entire genome sequence of a virulent serogroup B strain (MC58) was used to identify vaccine candidates . A total of 350 candidate antigens were expressed in Escherichia coli, purified, and used to immunize mice . The sera allowed the identification of proteins that are surface exposed, that are conserved in sequence across a range of strains, and that induce a bactericidal antibody response, a property known to correlate with vaccine efficacy in humans.

Nervenarzt, 2000 Feb, 71(2), 134 - 7
{Prevention of meningococcal meningitis}; Kastenbauer S et al.; In Germany, the incidence of meningococcal disease is approximately 1/100,000 and has not risen during recent years . Transmission occurs by direct contact with respiratory droplets, mostly from asymptomatic carriers and less frequently from patients with meningococal disease . The incubation period can vary from 2-10 days but usually is 3-4 days . Incidence is highest in children and decreases with age . The mortality from meningococcal disease is approximately 10% . In case meningococcal meningitis is clinically suspected antibiotic treatment (in Germany with penicillin G or a cephalosporin) should not be delayed . Patients must be isolated for at least 24 hours after the institution of antibiotic therapy . For early detection of local outbreaks, public health authorities should be quickly informed of suspected cases . Persons in close contact should be treated with antimicrobial chemoprophylaxis . In addition to rifampin, ciprofloxacin or ceftriaxone can be used for chemoprophylaxis . For control of local outbreaks of serogroup C meningococcal disease, the meningococcal vaccine can be used.

Anaesth Intensive Care, 2000 Feb, 28(1), 54 - 7
Generic polymerase chain reaction followed by DNA sequencing as a means of diagnosing bacteraemia; Sleigh JW et al.; There is increasing use of polymerase chain reaction techniques to diagnose infection . We report the use of polymerase chain reaction using a generic section of the bacterial 16S rDNA gene--followed by nucleotide sequencing--to determine the species of the infecting bacteria . In the first case, the clinical and microbiological diagnosis of meningococcal septicaemia was in agreement with the results from polymerase chain reaction technique . In the second case, a Yersinia enterocolitica bacteremia was detected by the polymerase chain reaction technique, but missed with conventional blood culture techniques.

Vaccine, 2000 Mar 17, 18(18), 1910 - 9
Inactivated meningococci and pertussis bacteria are immunogenic and act as mucosal adjuvants for a nasal inactivated influenza virus vaccine; Berstad AK et al.; Whole killed meningococci (Nm) and pertussis bacteria (Bp) were tested for mucosal immunogenicity and as mucosal adjuvants for an inactivated influenza virus vaccine given intranasally to unanaesthetized mice . Virus was given alone, or simply mixed with one of the bacterial preparations, in four doses at weekly intervals . The virus alone induced low but significant increases of influenza-specific IgG antibodies in serum measured by ELISA, whereas IgA responses in serum and saliva were insignificant compared to non-immunized controls . With Bp or Nm admixed, serum IgG and IgA and salivary IgA responses to the influenza virus were substantially augmented (P<0.005) . However, this adjuvant effect of the bacterial preparations was not significant for responses in the intestine as measured by antibodies in faeces . Antibody responses to Bp itself, but not to Nm, were inhibited by the admixture of the virus vaccine . Moreover, the pertussis preparation induced salivary antibodies which cross-reacted with Nm . Whole-cell bacteria with inherent strong mucosal immunogenicity may also possess mucosal adjuvanticity for admixed particulate antigens which are weakly immunogenic by the nasal route.

EMBO J, 2000 Mar 1, 19(5), 1068 - 78
Intimate adhesion of Neisseria meningitidis to human epithelial cells is under the control of the crgA gene, a novel LysR-type transcriptional regulator; Deghmane AE et al.; PilC1, a pilus-associated protein in Neisseria menin- gitidis, is a key element in initial meningococcal adhesion to target cells . A promoter element (CREN, contact regulatory element of Neisseria) is responsible for the transient induction of this gene upon cell contact . crgA (contact-regulated gene A) encodes a transcriptional regulator whose expression is also induced upon cell contact from a promoter region similar to the CREN of pilC1 . CrgA shows significant sequence homologies to LysR-type transcriptional regulators . Its inactivation in meningococci provokes a dramatic reduction in bacterial adhesion to epithelial cells . Moreover, this mutant is unable to undergo intimate adhesion to epithelial cells or to provoke effacing of microvilli on infected cells . Purified CrgA is able to bind to pilC1 and crgA promoters, and CrgA seems to repress the expression of pilC1 and crgA . Our results support a dynamic model of bacteria-cell interaction involving a network of regulators acting in cascade . CrgA could be an intermediate regulator in such a network.

Mol Immunol, 1999 Sep-Oct, 36(13-14), 915 - 28
The contrasting mechanisms of serum resistance of Neisseria gonorrhoeae and group B Neisseria meningitidis; Ram S et al.; Neisseria gonorrhoeae and Neisseria meningitidis have evolved intricate mechanisms to evade complement-mediated killing . Sialylation of gonococcal lipooligosaccharide (LOS) results in conversion of previously serum sensitive strains to unstable serum resistance, which is mediated by factor H binding . Porin (Por) is also instrumental in mediating stable serum resistance in gonococci . The 5th loop of certain gonococcal PorlAs binds factor H, which efficiently inactivates C3b to iC3b . Factor H glycan residues may be essential for factor H binding to certain Por1A strains . Por1A strains can also regulate the classical pathway by binding to C4b-binding protein (C4bp) probably via the 1st loop of the Por molecule . Certain serum resistant Por1 B strains can also regulate complement by binding C4bp through a loop other than loop 1 . Purified C4b can inhibit binding of C4bp to Por 1B, but not Por1A, suggesting different binding sites on C4bp for the two Por types . Unlike serum resistant gonococci, resistant meningococci have abundant C3b on their surface, which is only partially processed to iC3b . The main mechanism of complement evasion by group B meningococci is inhibition of membrane attack complex (MAC) insertion by their polysaccharide capsule . LOS structure may act in concert with capsule to prevent MAC insertion . Meningococcal strains with Class 3 Por preferentially bind factor H, suggesting Class 3 Por acts as a receptor for factor H.

Pediatr Emerg Care, 2000 Feb, 16(1), 33 - 8
Non-Q wave acute myocardial infarction in acute meningococcemia in a 10-year-old girl; Briassoulis G et al.; INTRODUCTION: Children with acute meningococcemia may have impaired myocardial function resulting in low cardiac output despite normal intravascular volume . Severe meningococcal infection has been associated with acute interstitial myocarditis, endocarditis, and pericarditis, but not with myocardial infarction . CASE: We present the case of a 10-year-old girl with positive family history for premature myocardial infarction who sustained an acute myocardial infarction temporally related to meningococcemia . DISCUSSION: This is the first pediatric case of non-Q wave acute myocardial infarction associated with purpura fulminans in meningococcemia . Similarly, the association of high troponin I levels and meningococcemia has not been described previously . Although, the patient's genetic predisposition for myocardial infarction might have been a potential contributing factor, there was no angiographic evidence of coronary artery disease in this patient . Thereby, other factors related to shock, endotoxin, microthrombi of meningococcemia, and their treatment might have been also contributing . We propose possible mechanisms for this rare but serious complication of meningococcemia and review the literature.

Can J Microbiol, 1999 Dec, 45(12), 1050 - 4
Antigenic and genetic characterization of a putative hybrid transferrin-binding protein B from Neisseria meningitidis; Menendez T et al.; The transferrin-binding protein Bs (TbpBs) from the bacterium Neisseria meningitidis have been divided into two families according to genetic and antigenic features . TbpB from meningococcal strain B385 showed a molecular mass similar to that exhibited by TbpBs belonging to the high molecular mass family of TbpBs . TbpB was recognized by immunoassay using a specific serum directed against the TbpB of the reference strain for this family (strain M982) . It was also recognized by a serum elicited against the TbpB of the reference strain for the low molecular mass family (strain B16B6) . The tbpB gene from strain B385 was cloned and sequenced . The highest degree of sequence homology was found to be with the TbpBs belonging to the high molecular mass family, although a region of 14 amino acids that is only present in the TbpB from strain B16B6 was also found . This report illustrates a TbpB that shows hybrid antigenic and genetic behaviour.

Epidemiol Infect, 1999 Dec, 123(3), 507 - 9
Seven-week interval between acquisition of a meningococcus and the onset of invasive disease . A case report; Neal KR et al.; Invasive meningococcal disease (IMD) is thought to occur within a few days of pharyngeal acquisition of Neisseria meningitidis . During a longitudinal study of carriage and acquisition among 2453 first-year undergraduates we identified a male student from whom N . lactamica was isolated in October 1997 followed by N . meningitidis in December 1997 . In mid-January 1998 this student suffered a mild episode of IMD (meningitis) during which N . meningitidis was isolated from his CSF . The meningococcus carried in December 1997 was phenotypically and genotypically indistinguishable from the invading organism, suggesting the possibility that the organism may have been carried for 7 weeks prior to the onset of invasive disease . Further studies are needed to assess more accurately the range of asymptomatic carriage prior to disease onset.

Epidemiol Infect, 1999 Dec, 123(3), 373 - 82
Outbreak of meningococcal disease in western Norway due to a new serogroup C variant of the ET-5 clone: effect of vaccination and selective carriage eradication; Smith I et al.; A new sulphonamide resistant (SR) C: 15:P1.7,16 meningococcal strain, a variant of the ET-5 clone, dominated in an outbreak of 22 cases in western Norway commencing in 1995 . The first eight patients were 15-21 years old from the Nordhordland area, initiating a carrier study in the local high schools . Carriage of SR serogroup C meningococci was detected by routine methods and treated with a single dose of ofloxacin 400 mg . Of 20 treated carriers, 14 harboured the outbreak strain C: 15:P1.7,16 . Vaccination of 4000 children, adolescents and close contacts of patients was also performed . After the intervention, 14 additional cases of meningococcal disease occurred, 8 due to the outbreak strain . However, incidence rates dropped from 180 to 30 per 100000 per year in the student population, but increased from 0 to 13 in the rest of the population in Nordhordland . Carriage eradication is not generally recommended in Norway . However, tracing and treating meningococcal carriage may have reduced transmission and disease in this outbreak situation.

Epidemiol Infect, 1999 Dec, 123(3), 359 - 71
Predicting the course of meningococcal disease outbreaks in closed subpopulations; Ranta J et al.; A stochastic epidemic model was applied to meningococcal disease outbreaks in defined small populations such as military garrisons and schools . Meningococci are spread primarily by asymptomatic carriers and only a small proportion of those infected develop invasive disease . Bayesian predictions of numbers of invasive cases were developed, based on observed data using a stochastic epidemic model . We used additional data sets to model both disease probability and duration of carriage . Markov chain Monte Carlo sampling techniques were used to compute the full posterior distribution which summarized all information drawn together from multiple sources.

Epidemiol Infect, 1999 Dec, 123(3), 349 - 57
Carriage of a new epidemic strain of Neisseria meningitidis and its relationship with the incidence of meningococcal disease in Galicia, Spain; Fernandez S et al.; In Galicia, Spain, a dramatic increase in the incidence of meningococcal disease was seen in the 1995-6 . The annual incidence rose to 11 per 10(5) inhabitants, and 80% of identified strains were C:2b:P1.2,5 . This led to the implementation of an intensive A+C vaccination campaign for the population aged 18 months to 19 years . During this campaign the prevalence of carriage in areas with high and low incidence was studied . Nasopharyngeal swabs were taken from 9796 subjects immediately before the administration of meningococcal vaccine, plated onto Thayer-Martin plates, incubated and sent for analysis to the Reference Laboratory for Neisseria in Spain . The prevalence of the C:2b: P1.2,5 strains was 0.6% (95% CI 0.29-0.88) in the high incidence area, and 0.41% (95 % CI 0.00-1.04) in the low incidence area, and that of serogroup C (all strains) 1.36% (95% CI 0.80-1.80) and 0.89% (95% CI 0.09-1.69) respectively . The prevalence of N . meningitidis (all strains) was almost the same in both areas (8%) . Carriers of the epidemic strain were not found in the 2-4 year age group, that most affected by the disease . Our data showed a wide distribution but a low carriage rate of the epidemic strain C:2b:P1.2,5 in the high and low disease incidence areas studied; the difference in the carriage rates between the two areas was not statistically significant.

Ann Trop Med Parasitol, 1999 Jul, 93(5), 505 - 10
Preventive immunisation could reduce the risk of meningococcal epidemics in the African meningitis belt; Chippaux JP et al.; Control of meningitis epidemics is based on early case detection followed by mass campaigns of immunisation . However, this strategy showed severe inadequacies during recent outbreaks in Africa . In Niamey, Niger, meningococcal vaccinations began in 1978 and detailed bacteriological and epidemiological surveillance of meningitis started in 1981 . When vaccine coverage rates were higher than 50%, the prevalences of Neisseria meningitidis A meningitis were low in Niamey, although there was a concurrent epidemic in rural Niger . A massive outbreak of meningitis in Niamey in 1994-1995 followed a 6-year period during which the mean rate of vaccine coverage remained < 25% . The data indicate that, in the meningitis belt, preventive immunization should avoid a great number of deaths and be less expensive than mass immunisation campaigns performed after epidemics have begun.

FEMS Immunol Med Microbiol, 2000 Mar, 27(3), 227 - 33
Immunogenicity of in vitro folded outer membrane protein PorA of Neisseria meningitidis; Jansen C et al.; In vitro folded and the denatured form of PorA P1.6 from Neisseria meningitidis strain M990 were used for immunization studies in mice . Previously, the antigen was isolated from cytoplasmic inclusion bodies, folded and purified . Its immunogenicity without adjuvant appeared to be low . The addition of the adjuvant QuilA, but not of galE lipooligosaccharide, considerably enhanced the immunogenicity . Moreover, when immunized with folded PorA P1.6 plus QuilA, a clear switch towards the IgG2a subclass of antibodies and concomitantly, the appearance of serum bactericidal activity, which is believed to be important for protective immunity, was observed . Hence, a tool for preparing vaccines against serogroup B meningococci devoid of endotoxin is available.

Trans R Soc Trop Med Hyg, 1999 Jul-Aug, 93(4), 341 - 53
Manson Lecture . Meningococcal meningitis in Africa; Greenwood B; This review covers the history of meningococcal meningitis in Africa since epidemics of the infection were first described around 100 years ago . It is possible that an epidemic strain of the meningococcus was introduced into West Africa from the Sudan by pilgrims returning from the Haj around the turn of the century . Since 1905 major epidemics of meningococcal meningitis have occurred in countries of the Sahel and sub-Sahel every few years, culminating in a massive epidemic in which nearly 200,000 cases were reported in 1996 . Attempts to control epidemic meningococcal meningitis in Africa by vaccination with meningococcal polysaccharide vaccines have met with only modest success because epidemics can progress with great rapidity and vaccination is often started too late . This situation should be improved as a result of a recent initiative, the International Coordinating Group (ICG), which is contributing to better surveillance in countries at risk and ensuring that vaccine is available when needed . However, in the medium term, the best prospect for the control of meningococcal meningitis in Africa lies in the recent development of polysaccharide-protein conjugate vaccines which, unlike polysaccharide vaccines, are immunogenic in the very young, induce immunological memory and are likely to give long-lasting protection.

J Bacteriol, 2000 Mar, 182(5), 1296 - 303
Differential distribution of novel restriction-modification systems in clonal lineages of Neisseria meningitidis; Claus H et al.; Using representational difference analysis, we isolated novel meningococcal restriction-modification (R-M) systems . NmeBI, which is a homologue of the R-M system HgaI of Pasteurella volantium, was present in meningococci of the ET-5 complex and of lineage III . NmeAI was found in serogroup A, ET-37 complex, and cluster A4 meningococci . NmeDI was harbored by meningococci of the ET-37 complex and of cluster A4, but not by serogroup A meningococci . Two of the R-M systems, NmeBI and NmeDI, were located at homologous positions between the phenylalanyl-tRNA synthetase genes pheS and pheT, which appeared to be a preferential target for the insertion of foreign DNA in meningococci . The distribution of the three R-M systems was tested with 103 meningococcal strains comprising 49 sequence types . The vast majority of the strains had either NmeBI, NmeAI, or both NmeAI and NmeDI . Using cocultivation experiments, we could demonstrate that NmeBI, which was present in ET-5 complex meningococci, was responsible for a partial restriction of DNA transfer from meningococci of the ET-37 complex to meningococci of the ET-5 complex.

J Med Microbiol, 2000 Feb, 49(2), 157 - 63
A nasal whole-cell pertussis vaccine induces specific systemic and cross-reactive mucosal antibody responses in human volunteers; Berstad AK et al.; A whole-cell pertussis vaccine, each dose consisting of 250 microg of protein, was given intranasally four times at weekly intervals to six adult volunteers . All vaccinees responded with increases in nasal fluid IgA antibodies to Bordetella pertussis whole-cell antigen . Three vaccinees with high nasal antibody responses also developed increased serum IgA and IgG antibodies to this antigen . Salivary antibody responses to the whole-cell antigen, as well as antibodies in serum and secretions to pertussis toxin (PT) and filamentous haemagglutinin (FHA) were negligible, except for a moderate increase in nasal fluid antibodies to FHA . Unexpectedly, the same vaccinees developed significant rises in nasal and salivary IgA antibodies to meningococcal outer-membrane antigens, whereas corresponding serum IgA and IgG antibodies were unchanged . Thus it appears that mucosal immunisation may induce secretory antibodies with broader specificities than can be found in serum.

J Infect Dis, 2000 Feb, 181(2), 761 - 4
Meningococcal C polysaccharide vaccine induces immunologic hyporesponsiveness in adults that is overcome by meningococcal C conjugate vaccine; Richmond P et al.; Widespread use of meningococcal AC polysaccharide (MACP) vaccines has raised concerns about induction of hyporesponsiveness to C polysaccharide . Whether meningococcal C conjugate (MCC) vaccine overcomes any immunologic refractoriness following MACP vaccination in adults was investigated . University students vaccinated 6 months previously with MACP vaccine were randomized to receive MACP or MCC vaccine, and antibody responses were compared with those of previously unvaccinated students receiving MACP or MCC vaccine . In students primed with MACP vaccine, MCC vaccine induced significantly higher IgG and serum bactericidal antibody levels than did a second dose of MACP vaccine . Responses to a second dose of MACP vaccine were significantly lower than to the first dose . Previous receipt of MACP vaccine reduced serum bactericidal antibody but not IgG responses to MCC vaccine compared with those in previously unvaccinated students . This confirms that MACP vaccine induces immunologic hyporesponsiveness to C polysaccharide in adults, but this can be overcome with MCC vaccine . Repeated vaccination with MACP vaccine may be ineffective, and MCC vaccines should provide better long-term protection.

Epidemiol Mikrobiol Imunol, 1999 Nov, 48(4), 140 - 52
{Factors affecting the occurrence and development of invasive meningococcal disease and development of Neisseria meningitis carrier state--results of a nationwide prospective questionnaire survey of cases and controls}; Krizova P et al.; The nationwide prospective questionnaire study of cases and controls was implemented during the period from October 1996 till May 1998 . Thirty-nine districts participated (= 54.2% of district hygiene stations) and 107 invasive meningococcal diseases were included in the study (= 76.9% of diseases recorded during the given period in the Czech Republic by active surveillance) . A total of 390 subjects were included in the study-107 with invasive meningococcal diseases, 211 healthy controls and 72 healthy carriers of Neisseria meningitidis . This is the first study in the Czech Republic which analyzes comprehensively socioeconomic, health and stress factors in relation to the genesis and development of invasive meningococcal disease or carriership of N . meningitidis . The relationship between these factors and meningococcal disease or carriership was evaluated by the chi square test: odds ratio (OR) and statistical significance (p for chi square-Yates correction or Fischer's exact test) . For the development of invasive meningococcal disease in particular, risk factors are significant (p < 0.05) which at the time weaken the overall resistance of the organism: febrile diseases, respiratory diseases, other diseases, exertion, exposure to cold, mental stress, other stress, injury, staying in places outside the home on brigades, training courses, stay in crowded premises . As to long-term factors the development of the disease is influenced by a contaminated environment, passive smoking and lower education of the mother which indicates a different lifestyle . Conversely, factors negatively correlated with the development of the disease are active participation in sports and favourable economic conditions . For death: significant risk factors (p < 0.05) are also factors which weaken the resistance of the organism: exertion, mental stress, other stress (= alcohol consumption), staying outside the home on brigades, training courses etc . For carriership risk factors are significant (p < 0.05) when the mucosal membranes of the upper airways are impaired (staying in a dusty environment, in smoke-filled rooms, contaminated atmosphere, active smoking, passive smoking) and factors where contact with other people is frequent (overcrowded rooms, multi-generation housing, use of public transport, staying outside the home on brigades, training courses etc.) . A risk factor is also lower education of parents which indicates a different lifestyle . Conversely, factors negatively correlated with carriership are favourable economic conditions, frequent outdoor stay and active participation in sports . By comparison of factors significantly associated with the development of invasive meningococcal disease or carriership data are assembled for the implementation of effective preventive measures.

J Clin Microbiol, 2000 Feb, 38(2), 855 - 7
Simultaneous approach for nonculture PCR-based identification and serogroup prediction of Neisseria meningitidis; Taha MK; A nonculture PCR-based method to characterize Neisseria meningitidis was used to test 225 clinical specimens . PCR correctly identified and predicted the serogroups of N . meningitidis of culture-proven meningococcal diseases and confirmed this diagnosis in 35% of suspected samples . This approach could be useful when culture fails to isolate N . meningitidis.

Emerg Infect Dis, 2000 Jan-Feb, 6(1), 65 - 9
Risk factors for carriage of Neisseria meningitidis during an outbreak in Wales; Fitzpatrick PE et al.; In a school outbreak of meningococcal disease in Wales, we compared risk factors for the carriage of Neisseria meningitidis B15 P1.16 with carriage of any meningococci . Students had throat swabs and completed a questionnaire . Sixty (7.9%) carried meningococci; risk for carriage was higher in those >14 years of age.

Vaccine, 2000 Jan 18, 18(13), 1253 - 63
Selection of an immunogenic peptide mimic of the capsular polysaccharide of Neisseria meningitidis serogroup A using a peptide display library; Grothaus MC et al.; The presently available meningococcal vaccine is poorly immunogenic in infants and fails to induce long-lasting immunity in adults . Efforts to convert this TI-2 type vaccine into a T dependent vaccine are being actively pursued and include conjugate vaccine development . Alternatively, the meningococcal polysaccharide can be rendered into a T dependent antigen through the use of peptides which mimic the capsular polysaccharide complexed or conjugated to potent protein carrier molecules . We have previously developed an anti-idiotypic monoclonal antibody (mAb) based peptide mimic of meningococcal group C polysaccharide (MCPS) . A direct approach to identification of peptide mimics of antigen is through the use of peptide display libraries . We have utilized a phage library and a mAb with specificity for meningococcal group A polysaccharide (MAPS) to screen for a peptide mimic of MAPS . Six different peptide motifs were selected with the use of the mAb . Thirty-eight of the 60 sequenced phage clones were represented by motif 1 and 2 which differed only in three amino acids at the carboxy terminus . Immunological assays were performed . Phage clones with motif 1 and 2 were capable of binding human hyperimmune sera and inhibiting the binding of human hyperimmune sera to nominal antigen . Immunization with motif 1 peptide complexed to proteosomes resulted in an anti-MAPS antibody response . Priming with the peptide proteosome complex induced an anamnestic response indicating the formation of immunological memory.

Blood, 2000 Feb 1, 95(3), 930 - 5
Cellular origin and procoagulant properties of microparticles in meningococcal sepsis; Nieuwland R et al.; Patients with meningococcal sepsis generally suffer from disseminated intravascular coagulation (DIC) . The aim of this study was to address whether these patients have elevated numbers of circulating microparticles that contribute to the development of DIC . Plasma samples from 5 survivors, 2 nonsurvivors, and 5 healthy volunteers were analyzed for the presence of microparticles by flow cytometry . Ongoing coagulation activation in vivo was quantified by enzyme-linked immunosorbent assay of plasma prothrombin fragment F(1 + 2), and procoagulant properties of microparticles in vitro were estimated by thrombin-generation assay . On admission, all patients had increased numbers of microparticles originating from platelets or granulocytes when compared with controls (P =.004 and P =.008, respectively) . Patients had elevated levels of F(1 + 2) (P =.004), and their microparticles supported thrombin generation more strongly in vitro (P =.003) than those of controls . Plasma from the patient with the most fulminant disease course and severe DIC contained microparticles that expressed both CD14 and tissue factor, and these microparticles demonstrated extreme thrombin generation in vitro . We conclude that patients with meningococcal sepsis have elevated numbers of circulating microparticles that are procoagulant . These findings may suggest a novel therapeutic approach to combat clinical conditions with excessive coagulation activation.

Eur J Pediatr, 1999 Dec, 158 Suppl 3, S192 - 6
Systemic meningococcal infection: which children may benefit from adjuvant haemostatic therapy? Results from an observational study; Nurnberger W et al.; The potential benefits of haemostatic therapy (heparin, antithrombin (AT) concentrate, fresh frozen plasma (FFP)) in severe systemic meningococcal infections (SMI) are controversial . A reduction of the still high case fatality rate would be an important indicator for potential benefits of adjuvant haemostatic therapy in children with SMI . Observational data from nationwide, active surveillance for SMI in children under 16 years in all German paediatric hospitals over a one-year period were used to assess whether potentially beneficial effects of haemostatic therapy are related to the severity of disease . The Neisseria sepsis index (NESI), which grades the severity of SMI from 0 to 8 and has proven to be a reliable tool for predicting the outcome of children with SMI, was used as an indicator of the severity of SMI . During the study period from July 1994 to June 1995, 305 children met the case definition; for 176 of these, complete data sets providing information on parameters underlying the NESI index and regarding the specific haemostatic therapy were available . As all recorded children with NESI 0-2 (n = 129; 73%) survived, a potential impact of haemostatic therapy (given to 45 of them) on survival would be undetectable in this group . A NESI between 3 and 8 was found in 47/176 patients (24%), 35 of whom received some kind of haemostatic therapy . The survival rates were 80% in children with haemostatic therapy (n = 35) and 50% in those without (n = 12) (odds ratio 0.25; 95% confidence interval 0.06-0.98) . A subgroup analysis of patients with NESI 3-5 versus those with NESI scores above 5 showed that the beneficial effect of haemostatic therapy was almost confined to children in the NESI 3-5 subgroup . In this subgroup there were 28/31 (90%) survivors with, and 6/11 (55%) survivors without adjuvant haemostatic therapy, whereas none of the patients (n = 5) with a NESI of 6-8 survived, although 4 had received adjuvant haemostatic therapy . CONCLUSION: Studies on the impact of adjuvant haemostatic therapy on survival in children with SMI should focus on those with NESI scores 3-5 . The data from this population-based, observational study suggests that haemostatic therapy might reduce the case fatality rate in these children . The optimal dosage and choice of preparations remains to be established . Alternative adjuvant therapeutic strategies may be required in children with SMI and NESI scores > 5.

Microb Pathog, 2000 Feb, 28(2), 81 - 8
A comparative analysis of pilin genes from pathogenic and nonpathogenic Neisseria species; Aho EL et al.; Pathogenic Neisseria species elaborate type IV pili, which are considered important for virulence . In this study, we examined pilin-encoding expression loci (pilE) in nonpathogenic Neisseria species . PCR based screening detected homology to a conserved N-terminal region of pilE in 12 of 15 Neisseria species, including all human commensal isolates . The three species failing to display homology were isolated from nonhuman sources . We have also characterized complete pilE loci from the human commensal species N . lactamica and N . cinerea . As anticipated, the predicted protein sequences from these species display features typical of all type IV pilins . In addition, these commensal pilins possess two highly conserved regions, SV2 and CYS2, which are shared among all neisserial pilins . However, a comparative analysis of pilE loci from pathogenic and nonpathogenic Neisseria species reveals two distinct structural groups, one composed of the pilin genes from N . lactamica, N . cinerea, and the class II pilin-producing subset of N . meningitidis isolates, the other of gonococcal and meningococcal class I pilin-encoding genes . Since both class I and class II pilin-producing meningococci can act as pathogens, structural relationships among neisserial pilin genes do not obviously reflect either species membership or ability to cause human disease .

FEMS Immunol Med Microbiol, 2000 Feb, 27(2), 103 - 9
Antigenic cross-reactivity between outer membrane proteins of Neisseria meningitidis and commensal Neisseria species; Troncoso G et al.; Two mouse sera against outer membrane proteins from a pathogenic Neisseria meningitidis strain and a commensal N . lactamica strain and two human sera from patients recovering from meningococcal meningitis were used to identify antigens common to pathogenic and commensal Neisseria species . Two major antigens of 55 kDa and 32 kDa, present in all N . meningitidis and N . lactamica strains tested, were demonstrable with all the sera used; the 55-kDa protein was iron-regulated . Demonstration of other common antigens was dependent on the serum used: a 65-kDa antigen was visualised with the human and the mouse anti-N . lactamica sera; a 37-kDa antigen identified as the meningococcal ferric binding protein (FbpA) was only detected with the mouse sera, and two antigens of 83 kDa and 15 kDa were only shown with the mouse anti-N . meningitidis serum . The results demonstrate the existence of several outer membrane antigens common to N . lactamica and N . meningitidis strains, in agreement with the hypothesis that natural immunity against meningitis is partially acquired through colonisation by commensal species, and open new perspectives for the design of vaccine formulations and the development of strategies for vaccination against meningitis.

Infect Immun, 2000 Feb, 68(2), 550 - 7
Neisseria meningitidis expressing transferrin binding proteins of Actinobacillus pleuropneumoniae can utilize porcine transferrin for growth; Litt DJ et al.; Homologous recombination was used to generate a number of mutants of serogroup B Neisseria meningitidis B16B6 with the following characteristics: (i) an inability to bind human or porcine transferrin because of loss of both transferrin binding proteins (Tbp) A and B {strain B16B6(Str(r))/tbpA(-)B(-)} and (ii) an ability to bind porcine transferrin but not human transferrin {strain B16B6(Str(r))/tbpA(ap)B(ap)} due to replacement of the meningococcal Tbp with the Tbp of Actinobacillus pleuropneumoniae . During construction of the B16B6(Str(r))/tbpA(ap)B(ap) strain, transformants expressing only TbpA or TbpB of A . pleuropneumoniae were isolated {strains B16B6(Str(r))/tbpA(ap)B(-) and B16B6(Str(r))/tbpA(-)B(ap)} . Expression of the A . pleuropneumoniae Tbp in N . meningitidis B16B6 was iron regulated and expressed under the control of the meningococcal promoter . The relative abilities of the meningococcal transformants to bind porcine transferrin were in the order B16B6(Str(r))/tbpA(ap)B(ap) > B16B6(Str(r))/tbpA(ap)B(-) > B16B6(Str(r))/tbpA(-)B(ap) . Of these transformants, only B16B6(Str(r))/tbpA(ap)B(ap) could grow in the presence of porcine transferrin as the sole iron source, achieving a growth rate similar to that of the B16B6 parent strain in the presence of human transferrin.

Vestn Ross Akad Med Nauk, 1999, (11), 48 - 54
{Impact of stressors on serogroup B neisseria meningitidis outer membrane proteins during cultivation in bioreactor}; Aleksakhina NN et al.; The authors examined the antigenic complexes obtained from serogroup B Neisseria meningitidis strain 125 cells grown in the bioreactor to different phases of growth in the reaction of gel precipitation and counter immunophoresis in a periodical fashion . A set of serotypic antigens was shown to increase from 3 to 9 with cultural growth . Their largest quantities were seen in the cells grown till the end of the stationary growth phase, the concentration of high-molecular weight peptides rising from 19% (in the exponential growth phase cells) to 54% (in the stationary growth phase ones) . The revealed regularities were evidenced by gel precipitation examinations of the sera from rabbits immunized with meningococci grown till different growth phases . At the same time, there were the largest quantities of serotypic antigenic precipitation bands when the sera obtained in the culture grown till the end of the stationary growth phase were used . It cannot be excluded that the results depend on the combined effects of several stressors on Neisseria meningitidis in the transition from the exponential to stationary growth phase, as resulted from the increased synthesis of high-molecular weight proteins that seem to act as protectors.

Clin Exp Immunol, 2000 Feb, 119(2), 311 - 6
Development of antibodies against tetravalent meningococcal polysaccharides in revaccinated complement-deficient patients; Drogari-Apiranthitou M et al.; Individuals deficient in C3 or a late complement component are susceptible to recurrent meningococcal infections . Since they experience meningococcal episodes mostly with uncommon meningococcal serogroups, vaccination with a tetravalent vaccine containing A, C, Y and W135 polysaccharides has been suggested . We vaccinated a cohort of two C3 and 17 late complement component-deficient (LCCD) patients, revaccinated them 7 years later and investigated the development of their IgG antibodies to the capsular polysaccharides of the meningococcal vaccine . Seven years after the first vaccination levels of IgG antibodies declined compared with the levels present at 6 months after the first vaccination, but were still at least four times higher than before vaccination . Levels of antibodies to Y polysaccharide in serum of complement-deficient patients were rather low but they did not differ significantly from those in serum of healthy non-related controls (P = 0.07) . Three months after the second vaccination IgG antibodies against all polysaccharides increased, exceeding those measured at 6 months after the first vaccination . In the 8 years of observation after the first vaccination two new meningococcal infections with strains related to the vaccine (serogroup Y strains) occurred in two patients, 3.5 and 5 years after the first vaccination . Our findings show that high IgG antibody levels against the tetravalent meningococcal polysaccharide vaccine were reached after revaccination of two C3 and 17 LCCD individuals 7 years after the first vaccination . Whether revaccination should be required within a period shorter than 7 years is discussed, since two vaccinees developed meningococcal disease to vaccine serogroup Y.

Clin Exp Immunol, 2000 Feb, 119(2), 305 - 10
High prevalence of complement component C6 deficiency among African-Americans in the south-eastern USA; Zhu Z et al.; Complement component C6 is a part of the membrane attack complex that forms a pore-like structure in cell membranes following complement activation . Deficiency of terminal complement components including C6 predisposes individuals to infection with Neisseriae . Using polymerase chain reaction/single-strand conformation polymorphism analysis followed by DNA sequencing, we screened genomic DNA from 200 randomly chosen blacks and an equal number from whites for three loss-of-function C6 mutations . Ten blacks and two whites were found to be heterozygous for one of the mutations . Two of the mutations, 1195delC and 1936delG, were found exclusively in black individuals . A third previously undescribed mutation, 878delA, was found at equal frequency among the two groups . The difference between the two groups was significant (P = 0.027), indicating that C6 deficiency due to these three mutations is more common among blacks than whites in the local area, principally Jefferson County, Alabama . In addition, three previously undescribed point mutations, two of which result in amino acid substitutions, were identified within exon 6 . A review of the county health department records over the past 6 years revealed a higher incidence of meningococcal meningitis in blacks due to serogroups Y and W-135 which paralleled the difference in the estimated prevalence of C6 deficiency . Among black residents of the county (n = 235 598) there were 15 cases of meningitis due to these two serogroups, compared with two cases in the white population (n = 422 604) (P = 0.002) . We conclude that C6 deficiency is more common among blacks than whites in the south-eastern United States, with a frequency approaching 1 in 1600 black individuals.

Semin Thromb Hemost, 1999, 25(6), 537 - 41
Replacement therapy with protein C concentrate in infants and adolescents with meningococcal sepsis and purpura fulminans; Ettingshausen CE et al.; We report the effects of substitution with a virus-inactivated protein C (PC) concentrate in disseminated intravascular coagulation (DIC) in infants and children with meningococcal sepsis associated with purpura fulminans . It was a prospective open-label study . Eight pediatric and adolescent patients age 0.2 to 18.25 years with DIC associated with severe acquired PC deficiency (range 0.02 to 0.48 IU/mL; median, 0.22 IU/mL) in meningococcal septic shock and purpura fulminans were studied . Replacement therapy was initiated with a virus-inactivated PC concentrate with an initial intravenous bolus of 80 to 120 IU/kg followed by 50 IU/kg up to six times per day as an adjunctive therapeutic regimen to otherwise optimal intensive care treatment . After initial PC administration, plasma PC levels rose to normal ranges and were maintained under PC replacement therapy . Improving or even normalizing global hemostatic parameters were assessed in all patients . Markedly elevated plasminogen activator inhibitor type 1 (PAI-1) levels prior to treatment, reflecting a reduced fibrinolytic potential, decreased rapidly under PC substitution . Concomitantly improving signs of purpura fulminans reflected by decreasing size of skin lesions, demonstrated a restoring microcirculation . Six of the eight patients survived . One patient required limb amputation; two patients died because of multiorgan failure . Both presented with a severely low plasma PC activity of 0.02 IU/mL on admission to the hospital . No adverse effects were observed with the PC concentrate administration . It can be concluded that the administration of PC concentrate had a marked benefit on the deranged coagulation status of patients with purpura fulminans and meningococcal septicemia . Normalization or even partial correction of hemostasis as well as improvement of microcirculation accompanied by improving signs of purpura fulminans were demonstrated in all patients.

Mayo Clin Proc, 2000 Jan, 75(1), 98 - 109
Antimicrobial prophylaxis in adults; Osmon DR; Antimicrobial prophylaxis is used by clinicians for the prevention of numerous infections, including sexually transmitted diseases, human immunodeficiency virus infection, tuberculosis, rheumatic fever, recurrent cellulitis, meningococcal disease, recurrent uncomplicated urinary tract infections in women, spontaneous bacterial peritonitis in patients with cirrhosis, influenza, malaria, infective endocarditis, pertussis, plague, anthrax, early-onset group B streptococcal disease in neonates, and animal bite wounds . Certain opportunistic infections such as Pneumocystis carinii pneumonia in immunocompromised patients also can be effectively prevented with primary antimicrobial prophylaxis . Perioperative antimicrobial prophylaxis is recommended for various surgical procedures to prevent surgical site infection . Optimal antimicrobial agents for prophylaxis are bactericidal, nontoxic, inexpensive, and active against the typical pathogens that cause surgical site infection postoperatively . To maximize its effectiveness, intravenous perioperative prophylaxis should be given within 30 to 60 minutes before the time of surgical incision . Antibiotic prophylaxis should be of short duration to decrease toxicity, antimicrobial resistance, and excess cost.

Pediatr Clin North Am, 1999 Dec, 46(6), 1073 - 109
Occult bacteremia in young febrile children; Kuppermann N; The evaluation of nontoxic-appearing, young, febrile children has been a subject of considerable debate . Of young, nontoxic-appearing children aged 3 to 36 months with temperatures of 39 degrees C or more and no clear source, approximately 2% to 3% have occult bacteremia . Of these bacteremias, approximately 90% are caused by S . pneumoniae, 5% by nontyphoidal Salmonella sp., and 1% by N . meningitidis . Most children with occult pneumococcal bacteremia improve spontaneously, but approximately 25% of untreated patients have persistent bacteremia or develop new focal infections, including 3% to 6% who develop meningitis . Occult meningococcal bacteremia, although rare, has frequent complications, including meningitis in approximately 40% and death in approximately 4% . Less is known about the natural history of untreated occult nontyphoidal Salmonella bacteremia . Empiric antibiotic treatment of children with occult bacteremia decreases the rate of complications, including meningitis . Few disagree that febrile, young children at risk for occult bacteremia require a careful clinical evaluation and close follow-up . The benefits of laboratory screening and selective empiric antibiotic treatment of febrile children at risk for occult bacteremia have to be weighed against the costs of screening tests and blood cultures, inconvenience, temporary discomfort to patients, risk for side effects of antibiotics, and the role of antibiotics in the development of bacterial resistance . Although great debate exists concerning the role of empiric antibiotics, a strategy for obtaining blood cultures and empirically administering antibiotics on the basis of an increased ANC, in addition to close clinical follow-up, may be effective in reducing the frequency and severity of uncommon but adverse sequelae . A highly effective S . pneumoniae bacterial conjugate vaccine will soon be available, which will benefit all children, and will alter the ways that clinicians evaluate fully immunized young, febrile children.

J Allergy Clin Immunol, 2000 Jan, 105(1 Pt 1), 170 - 5
Effect of acellular pertussis vaccine on the development of allergic sensitization to environmental allergens in adults; Assa'ad A et al.; BACKGROUND: Exposure of children to pertussis antigens caused by infection or vaccination with whole-cell pertussis vaccine may increase the serum IgE level and predispose to sensitization to the prevalent environmental allergens . Acellular pertussis vaccine (APV) that may be given to adults may have a similar effect . OBJECTIVE: The purpose of this study was to determine whether APV will cause an increase in environmental sensitization measured by an increase of serum-specific IgE to the allergens to which adults are exposed during the vaccination period . METHODS: One hundred adult hospital employees were randomized to receive either a 2-component APV composed of pertussis toxin and filamentous hemagglutinin or a meningococcal vaccine as a control . Serum-specific IgE level to 2 indoor allergens, cat and dust mite, and 2 outdoor allergens prevalent during the immunization season, Alternaria species and ragweed, was measured by an RIA on sera collected before and 1 month after vaccination . RESULTS: The group that received the APV had no significant change in their serum-specific IgE levels to cat, dust, Alternaria species, or ragweed 1 month after vaccination . CONCLUSION: A 2-component APV did not predispose to an increase of allergen-specific IgE in an adult population.

Pediatrics, 2000 Dec, 106(6), 1500 - 4
Meningococcal disease prevention and control strategies for practice-based physicians (Addendum: recommendations for college students) . Committee on Infectious Diseases; Update on meningococcal disease with emphasis on pathogenesis and clinical management; Department of Internal Medicine, University Hospital Nijmegen, Nijmegen, The Netherlands . M.vanDeuren@aig.azn.nl

The only natural reservoir of Neisseria meningitidis is the human nasopharyngeal mucosa . Depending on age, climate, country, socioeconomic status, and other factors, approximately 10% of the human population harbors meningococci in the nose . However, invasive disease is relatively rare, as it occurs only when the following conditions are fulfilled: (i) contact with a virulent strain, (ii) colonization by that strain, (iii) penetration of the bacterium through the mucosa, and (iv) survival and eventually outgrowth of the meningococcus in the bloodstream . When the meningococcus has reached the bloodstream and specific antibodies are absent, as is the case for young children or after introduction of a new strain in a population, the ultimate outgrowth depends on the efficacy of the innate immune response . Massive outgrowth leads within 12 h to fulminant meningococcal sepsis (FMS), characterized by high intravascular concentrations of endotoxin that set free high concentrations of proinflammatory mediators . These mediators belonging to the complement system, the contact system, the fibrinolytic system, and the cytokine system induce shock and diffuse intravascular coagulation . FMS can be fatal within 24 h, often before signs of meningitis have developed . In spite of the increasing possibilities for treatment in intensive care units, the mortality rate of FMS is still 30% . When the outgrowth of meningococci in the bloodstream is impeded, seeding of bacteria in the subarachnoidal compartment may lead to overt meningitis within 24 to 36 h . With appropriate antibiotics and good clinical surveillance, the mortality rate of this form of invasive disease is 1 to 2% . The overall mortality rate of meningococcal disease can only be reduced when patients without meningitis, i.e., those who may develop FMS, are recognized early . This means that the fundamental nature of the disease as a meningococcus septicemia deserves more attention.

Ter Arkh, 1999, 71(11), 14 - 8
{Clinical features of meningococcal infection in subjects with deficient terminal components of complement}; Platonov AE et al.; AIM: To evaluate clinical characteristics of meningococcal disease (MD) in individuals with terminal complement component deficiency (TCCD) who are thousands times more susceptible to MD than complement-sufficient persons . MATERIALS AND METHODS: 61 cases of MD in TCCD patients and 200 randomly selected cases of MD in complement-sufficient patients were analyzed . RESULTS: Meningitis without meningococcemia accounted for 17% of the MD episodes in the control group of complement-sufficient patients but none in individuals with TCCD who had meningococcemia (10%) or meningococcemia with meningitis (90%) . Moderate disease predominated in patients with TCCD (70%) and no episodes of fatal disease were noted, whereas severe disease was more common in the control group which had an 8% case fatality rate and frequent complications such as endotoxic shock (15% of episodes) and brain edema (26%) . The severity of the disease in TCCD patients did not differ between the first and subsequent episodes, between males and females, between episodes caused by serogroup A and B meningococci, etc . CONCLUSION: In comparison to complement-sufficient persons, the course of the disease in patients with TCCD is statistically less severe.

Cytokine, 2000 Jan, 12(1), 21 - 5
Neisseria meningitidis induces the expression of the TNF-alpha gene in endothelial cells; Taha MK; Pilus-mediated adhesion plays a prominent role in the pathogenesis of Neisseria meningitidis by allowing the initial localized adhesion to epithelial and endothelial cells . Non-piliated bacteria are not adherent . Moreover, cytokine production during infection is a key feature of meningococcal pathogenesis . Tumour necrosis factor alpha (TNF-alpha) is known to be produced early during meningococcal infections and experimental endotoxemia . Monocytic cells are thought to be responsible for this systemic production of TNF-alpha which is involved in many aspects of meningococcal pathogenesis such as coagulopathy and activation of endothelial cells . In this report, both adherent and non-adherent N . meningitidis were shown to induce the expression of TNF-alpha gene in monocytic cells, however, only adherent N . meningitidis was able to induce the expression of TNF-alpha gene in endothelial cells . This latter induction required the presence of monocytes . These data suggest that endothelial cells may be activated selectively and efficiently by adherent N . meningitidis and can locally produce TNF-alpha upon bacterial adhesion .

Gac Sanit, 1999 Nov-Dec, 13(6), 462 - 7
{Safety of meningococcal A and C vaccine . Data from the Spanish drug surveillance system . Meningococcal Vaccine Research Group of the Spanish System of Drug Surveillance}; de Abajo F et al.; OBJECTIVE: Data on meningococcal vaccines safety are scanty . In 1997 several vaccination campaign took place in Spain . Thus, this situation was used to improve our knowledge about the safety profile of this vaccine . METHODS: An inquiry was carried out to the Regional Centers of the Spanish Pharmacovigilance System to know the number of vaccinated people and the type and number of suspected cases of adverse reactions . RESULTS: There were 133 identified cases of suspected adverse reactions associated with meningococcal A and C vaccine until June 1st, 1998 . Most of them affected the skin (25,3%) or nervous system (similar proportion) . Those of allergic reactions accounted for 35,2% . Two cases were considered as severe, although they were resolved without secuelae . CONCLUSIONS: Serious risks were not detected . The Spanish Pharmacosurveillance System as an epidemiological surveillance resource has been useful to know the safety problems associated with antimeningococcal vaccine in the community.

Clin Infect Dis, 2000 Jan, 30(1), 87 - 94
Meningococcal pneumonia: characterization and review of cases seen over the past 25 years; Winstead JM et al.; Fifty-eight cases of meningococcal pneumonia were included in this review . Fifty cases previously described in the literature from 1974 through 1998 and 8 new cases were included in this series . The median age of patients was 57.5 years, and pleuritic chest pain was described in 21 (53.9%) of 39 cases . Blood cultures were positive in 42 (79.3%) of 53 cases for which results were mentioned . Despite the presence of bacteremia, patients did not develop the syndrome of meningococcemia with its associated complications . Serogroup Y meningococci were most commonly recovered and accounted for 44.2% of identified isolates . Therapy has dramatically changed over the past 25 years; prior to 1991, penicillin antibiotics were most often used . Since 1991, 12 (80%) of 15 patients received cephalosporin antibiotics . Only 5 (8.62%) of 58 patients died . Secondary cases of meningococcal infections following exposure to patients with meningococcal pneumonia were noted in 2 instances.

Clin Infect Dis, 2000 Jan, 30(1), 25 - 8
Association between FcgammaRIIa-R131 allotype and bacteremic pneumococcal pneumonia; Yee AM et al.; Human FcgammaRIIa has 2 codominantly expressed allotypes, which differ greatly in their ability to ligate immunoglobulin G2 (IgG2) . Whereas FcgammaRIIa-R131 binds only weakly to IgG2, FcgammaRIIa-H131 binds to it efficiently and might be primarily responsible for the phagocytosis of IgG2-opsonized bacteria . IgG2 plays a pivotal role in defense against pneumococcal infection . This prospective study showed that 50% of patients with bacteremic pneumococcal pneumonia were homozygous for FcgammaRIIa-R131, compared with 28% with nonbacteremic pneumococcal pneumonia and 29% of uninfected controls (P<.05) . The gene frequency of FcgammaRIIa-R131 was 0.67 in bacteremic patients, significantly higher than in the other groups (P<.05) . All bacteremic patients who died within 1 week of hospitalization were homozygous for FcgammaRIIa-R131 . Therefore, the severity of pneumococcal infection may, in part, be genetically mediated . Taken together with similar findings in cases of meningococcal disease, these results suggest that such genetic factors may be generalizable to infections caused by encapsulated bacteria.

Vaccine, 2000 Feb 14, 18(15), 1456 - 66
Immunogenicity and safety of a hexavalent meningococcal outer-membrane-vesicle vaccine in children of 2-3 and 7-8 years of age; de Kleijn ED et al.; To study the reactogenicity and immunogenicity of a hexavalent meningococcal outer-membrane-vesicle vaccine (OMV), two different dosages of this vaccine (7.5 and 15 microg of individual PorA proteins) consisting of vesicles expressing class 1 outer-membrane proteins (OMPs) of subtypes P1.7,16; P1.5,2; P1.19,15 and P1.5(c), 10; P1.12,13; P1.7(h),4 were administered to a group of 7-8 year (n=165) and a group of 2-3 year old children (n=172) . Control groups of children with similar ages were vaccinated against hepatitis B . All participants received three injections . Pre- and postimmunisation sera were tested for bactericidal antibodies against six isogenic meningococcal vaccine strains expressing different PorA proteins . Antibody titres against OMP of the two different vesicles (PL16215 and PL10124) were measured by ELISA . The meningococcal hexavalent OMV vaccine was well tolerated . No statistically significant differences were seen between the high and low dose of hexavalent meningococcal OMV vaccine . The percentage of children showing a fourfold increase of bactericidal antibody titres against the specific serosubtype varied in toddlers from 28 to 98% and in older children from 16 to 100% . Both ELISA antibody titres and bactericidal activity showed the highest level in the youngest age-group.

Vaccine, 2000 Jan 31, 18(14), 1334 - 43
Immunogenicity studies with a genetically engineered hexavalent PorA and a wild-type meningococcal group B outer membrane vesicle vaccine in infant cynomolgus monkeys; Rouppe van der Voort E et al.; The immunogenicity of two meningococcal outer membrane vesicle (OMV) vaccines, namely the Norwegian wild-type OMV vaccine and the Dutch hexavalent PorA OMV vaccine, were examined in infant cynomolgus monkeys . For the first time, a wild-type- and a recombinant OMV vaccine were compared . Furthermore, the induction of memory and the persistence of circulating antibodies were measured . The Norwegian vaccine contained all four classes of major outer membrane proteins (OMP) and wild-type L3/L8 lipopolysaccharide (LPS) . The Dutch vaccine consisted for 90% of class 1 OMPs, had low expression of class 4 and 5 OMP, and GalE LPS . Three infant monkeys were immunised with a human dose at the age of 1.5, 2.5 and 4.5 months . Two monkeys of each group received a fourth dose at the age of 11 months . In ELISA, both OMV vaccines were immunogenic and induced booster responses, particularly after the fourth immunisation . The Norwegian vaccine mostly induced sero-subtype P1.7,16 specific serum bactericidal antibodies (SBA), although some other SBA were induced as well . The antibody responses against P1.7,16, induced by the Norwegian vaccine, were generally higher than for the Dutch vaccine . However, the Dutch vaccine induced PorA specific SBA against all six sero-subtypes included in the vaccine showing differences in the magnitude of SBA responses to the various PorAs.

J Clin Microbiol, 2000 Jan, 38(1), 198 - 200
The 1998 Senegal epidemic of meningitis was due to the clonal expansion of A:4:P1.9, clone III-1, sequence type 5 Neisseria meningitidis strains; Nicolas P et al.; Between January and April 1998, a meningitis outbreak due to serogroup A meningococcus took place in Senegal . The outbreak began in Gandiaye, 165 km to the east of Dakar, and progressed towards the towns of Gossas, Niakkhar, Guinguineo, Fatik, Foundiougne, Dioffior, Sokone, Kaolack, and Nioro . At the same time, the outbreak reached regions of Kaffrine, Koungheul, and Tambacounda in the east of Senegal . A total of 1,350 cases and 200 deaths were reported . The WHO Collaborating Center in Marseilles received 24 strains for analysis . All were serogroup A Neisseria meningitidis, type 4 and subtype P1.9 . Multilocus enzyme electrophoresis, performed by Institut Pasteur Paris, showed that the strains belonged to clone III-1 . DNA restriction fragments generated by endonuclease BglII and analyzed by pulsed-field gel electrophoresis showed 24 indistinguishable fingerprint patterns similar to those of meningococcus strains isolated from African outbreaks since 1988 . Three strains were studied by multilocus sequence typing (MLST) with seven loci . The comparison between sequences and existing alleles on the MLST website () allowed us to assign these strains to sequence type 5 (ST5), as their sequences were identical to the consensus at seven loci . All 24 strains were susceptible to penicillin, amoxicillin, chloramphenicol, and rifampin . Subgroup III is finishing its spread towards west of the meningitis belt of Africa . To our knowledge, this is the first time subgroup III, and more precisely ST5, strains are reported as being responsible for a meningitis outbreak in Senegal.

Pediatrics, 2000 Jan, 105(1 Pt 3), 260 - 6
Fever in pediatric primary care: occurrence, management, and outcomes; Finkelstein JA et al.; OBJECTIVE . To describe the epidemiology, management, and outcomes of children with fever in pediatric primary care practice . PATIENTS . A cohort of 20 585 children 3 to 36 months of age cared for in 11 pediatric offices of a health maintenance organization between 1991 and 1994 . METHODS . Using automated medical records we identified all office visits with temperatures >/=38 degrees C for a random sample of 5000 children, and analyzed diagnoses conferred, laboratory tests performed, and antibiotics prescribed . We also determined the frequency of in-person and telephone follow-up after initial visits for fever . Finally, we reviewed hospital claims data for the entire cohort of 20 585 to identify cases of meningitis, meningococcal sepsis, and death from infection . RESULTS . Among 3819 initial visits of an illness episode, 41% of children had no diagnosed bacterial or specific viral source . Of these, 13% with a temperature of 38 degrees C to 39 degrees C and 36% with a temperature of >/=39 degrees C received laboratory testing . Almost half (43%) received some documented follow-up care in the subsequent 7 days . Among the 26 970 child-years of observation in the entire cohort, 15 children (56 per 100 000 child-years) were treated for bacterial meningitis or meningococcal sepsis . Five had an office visit for fever in the week before hospitalization, but only 1 had documented fever >/=39 degrees C and received neither laboratory testing for occult bacteremia nor treatment with an antibiotic . CONCLUSION . The majority of febrile children in ambulatory settings were diagnosed with a bacterial infection and treated with an antibiotic . Of highly febrile children without a source, 36% received laboratory testing consistent with published expert recommendations, and short-term follow-up was common . Meningitis or death after an office visit for fever without a source was predictably rare . These data suggest that increased testing and/or treatment of febrile children beyond the rates observed here are unlikely to affect population rates of meningitis substantially.

Lancet, 2000 Jan 1, 355(9197), 30 - 3
Emergency vaccination against epidemic meningitis in Ghana: implications for the control of meningococcal disease in West Africa; Woods CW et al.; BACKGROUND: Recurrent epidemics of meningococcal disease have been reported throughout the African meningitis belt since description of the disease in 1912 . Meningooccal polysaccharide vaccines can effectively prevent disease but the optimum strategy for their use in this setting has been controversial . We used data from an outbreak of meningococcal disease in northern Ghana in 1997 to assess the potential effect of different vaccination strategies . METHODS: We identified all reported cases of meningococcal meningitis and estimated the number of cases and deaths that could have been prevented by vaccination through use of a simple mathematical model . We then assessed the potential effect of different vaccination strategies and the burden of these strategies on the public-health system . FINDINGS: In the three affected regions in northern Ghana there were 18703 cases and 1356 deaths reported between November, 1996, and May, 1997 . Vaccination began in the third week of February and continued to April, reaching 72% of the at-risk population and preventing an estimated 23% of cases and 18% of deaths . A strategy of routine childhood and adult immunisation would have prevented 61% of cases had this same rate of vaccine coverage been achieved and maintained before the epidemic . If vaccination had started after the onset of the epidemic in January, as currently advocated by WHO guidelines, a similar proportion (61%) of cases could have been prevented . INTERPRETATION: Prevention of epidemics of meningococal disease in west Africa will be difficult until long-lasting conjugate vaccines capable of interrupting transmission of Neisseria meningitidis can be incorporated into routine infant-immunisation schedules . Until then, the strategy of surveillance and response advocated by WHO is as effective and more practical than a strategy of routine childhood and adult vaccination with currently available polysaccharide vaccinesPIP: This study assessed the potential effects of different vaccination strategies using data from the 1997 meningococcal outbreak in northern Ghana . Since the description of the disease in 1912, recurrent epidemics of meningococcal disease have been reported throughout the African meningitis belt . The use of meningococcal polysaccharide vaccines has been proven to effectively prevent the disease, although the method of vaccine distribution was disputable . Using a simple mathematical model, meningococcal meningitis cases and deaths, which could have been forestalled by vaccination, were identified, and the effect of developed vaccination strategies on the public health system was analyzed . About 18,703 cases and 1356 deaths were reported in 3 regions of northern Ghana between November 1996 and May 1997 . Vaccination was conducted between February and April, which covered 72% of the high-risk population and prevented approximately 23% of cases and 18% of deaths . Routine childhood and adult immunization would have prevented 61% of cases had this same rate of vaccine coverage been achieved and maintained before the epidemic . This study suggests that the prevention of the meningococcal disease epidemic in West Africa would be difficult unless long-lasting conjugate vaccines are incorporated into routine infant immunization schedules . For now, the surveillance and response strategies advocated by the WHO serve as an effective and practical intervention .

Lancet . 2000 Jan 1;355(9197):3.
Emergency or routine vaccination against meningococcal disease in Africa?
Peltola H.
PIP: The spread of meningococcal disease in sub-Saharan Africa, which extends from Senegal to Ethiopia, has already affected thousands of people in the region and is urgently in need of an intervention . The meningococcal epidemic in Africa is usually caused by serogroup A and sweeps over the region within several weeks; it then disappears and reappears 5-10 years later . Although vaccination against serogroup A and C meningococci may have its limitations, it is still capable of eliminating the disease . In Ghana, the Ministry of Health launched a vaccination campaign which covered 72% of the population and prevented 23% of cases and 18% of deaths . A simple method of identifying an impending epidemic followed by the development of various vaccination strategies is necessary among less developed countries . WHO recommends that emergency vaccination be implemented, while continuous and improved surveillance systems must be used to confront the epidemic . In conclusion, this paper suggests that the meningococcal disease in sub-Saharan Africa would be better dealt with by well organized campaigns rather than by repeated vaccinations of the entire population .

Commun Dis Intell, 1999 Nov 25, 23(12), 317 - 23
Annual report of the Australian Meningococcal Surveillance Programme, 1998 . The Australian Meningococcal Surveillance Programme; Infection with uncommon subgroup Y Neisseria meningitidis in patients with systemic lupus erythematosus; Rheumatology Section, University of Illinois, Chicago College of Medicine, USAThe association of Neisseria meningitidis infection and systemic lupus erythematosus (SLE) is uncommon . We describe here three patients with SLE who developed disseminated meningococcal disease . Each patient had long-standing SLE and was receiving treatment with prednisone . Furthermore, each patient showed serum hypocomplementemia at the time of the infection . N . meningitidis Group Y, considered to be an organism of relatively low virulence, was isolated from the blood or cerebrospinal fluid in each case . The patients presented with diverse clinical manifestations of meningococcal disease . The relationship of disseminated meningococcal infections to hypocomplementemia in patients with SLE is discussed in light of a review of the literature.

Pediatr Infect Dis J, 1999 Dec, 18(12), 1051 - 9
Evaluation of meningococcal meningitis vaccination strategies for the meningitis belt in Africa; Miller MA et al.; BACKGROUND: Although the meningococcal polysaccharide vaccine has contributed to the control of Group A meningitis in the "meningitis belt" of Africa, recurrent large outbreaks have led to questions regarding vaccination strategy . We evaluated current and hypothetical vaccination strategies for the region . METHODS: A model was formulated to analyze the effectiveness and costs of vaccine campaigns in response to outbreaks based on 7 years of weekly incidence data from Burkina Faso . Additional models analyzed the potential impact and costs of either a 1- or 4-dose routine scheduled delivery of meningococcal polysaccharide vaccine based on data reported to the World Health Organization from 16 countries during 1948 through 1996 . Vaccine efficacy, vaccination coverage and economic data from literature reviews provided model assumptions . RESULTS: For Burkina Faso neither 1- nor 4-dose vaccination schedules would prevent >30% of meningitis cases compared with the 42% prevented through an outbreak response program of vaccinating districts, which reach an incidence of 15 per 100000 persons for 2 weeks . For the entire meningitis belt, routine coverage with the 1- or 4-dose schedule meningococcal vaccine would require 4.9 and 19.6 million doses annually, respectively, for an annual net cost of $4.4 to $12.3 million and prevent an average 10300 to 12600 cases (23 to 28%), assuming a long term vaccine efficacy of 50% . In addition an initial "catch-up" campaign costing up to $72 million to vaccinate the population from 1 to 30 years of age would be required before achieving that level of effectiveness . CONCLUSION: Given the relatively poor routine vaccination coverage in this region, current strategies of vaccination campaigns that achieve higher coverage would generally be more effective and less costly than the modeled routine scheduled programs, assuming that campaigns can be rapidly implemented . Until a better vaccine is available, countries in this region would be more efficient in improving the response times to outbreaks, perhaps through improved surveillance, and in bolstering existing vaccination infrastructures rather than embarking on strategies of questionable effectiveness.

Med Klin (Munich), 1999 Nov 15, 94(11), 633 - 7
{Clinical course and complications of meningococcal septicemia}; Gradaus F et al.; BACKGROUND: Meningococcal septicemia is still associated with high mortality with most deaths occurring within the first 24 hours . CASE REPORT: We report on 3 patients with severe meningiococcemia . All patients had an aprupt onset of clinical illness with fever and unspecific prodomi like arthralgias, myalgias and abdominal pain . On admission all patients had severe prostration, hypotension and tachycardia . Two patients presented purpuric rash and petechiae, meningitis was found in only 1 patient . Gram-negative diplococci were demonstrated in spinal fluid primarily in 2 patients, in all patients meningococcae could be cultured in serial blood specimens . Because of severe cardiorespiratory distress all patients required mechanical ventilation and catecholamine support within 24 hours of diagnosis . Complications of meningococcemia demonstrated by these patients were coagulopathy, meningitis, myocarditis with alterations of echocardiographic and ECG records and elevations of CK levels and surgical relevant peripheral gangrene . Antibiotic therapy was initiated with penicillin on the day of admission, which resulted in stabilisation and recuperation in all patients . CONCLUSIONS: In patients with aprupt onset of acute illness, which include fever and sudden petechial rash, severe meningococcal septicemia has to be taken in consideration without clinical signs of meningitis . The prompt diagnosis, the use of parenteral antiobiotics in suspected meningococcal disease as well as the management of meningococcemia and its complications in intensive care units is crucial for the prognosis of the individual patient.

Commun Dis Public Health, 1999 Dec, 2(4), 293 - 4
Cases of meningococcal infection and bacterial meningitis occur every day and require an 'out of hours' public health response; Howell F et al.; Analysis of hospital admissions data over three years in Ireland showed that the 1478 cases of meningococcal disease and meningitis were admitted at the same frequency every day of the week . The need for and the cost effectiveness of an 'out of hours' service in order to manage the community aspects of meningococcal disease/meningitis requires further attention.

Adv Exp Med Biol, 1999, 455, 201 - 6
Reactive arthritis; Keat A; Reactive arthritis is one of the spondyloarthropathy family of clinical syndromes . The clinical features are those shared by other members of the spondyloarthritis family, though it is distinguished by a clear relationship with a precipitating infection . Susceptibility to reactive arthritis is closely linked with the class 1 HLA allele B27; it is likely that all sub-types pre-dispose to this condition . The link between HLA B27 and infection is mirrored by the development of arthritis in HLA B27-transgenic rats . In this model, arthritis does not develop in animals maintained in a germ-free environment . Infections of the gastrointestinal, genitourinary and respiratory tract appear to provoke reactive arthritis and a wide range of pathogens has now been implicated . Although mechanistic parallels may exist, reactive arthritis is distinguished from Lyme disease, rheumatic fever and Whipple's disease by virtue of the distinct clinical features and the link with HLA B27 . As in these conditions both antigens and DNA of several micro-organisms have been detected in joint material from patients with reactive arthritis . The role of such disseminated microbial elements in the provocation or maintenance of arthritis remains unclear . HLA B27-restricted T-cell responses to microbial antigens have been demonstrated and these may be important in disease pathogenesis . The importance of dissemination of bacteria from sites of mucosal infection and their deposition in joints has yet to be fully understood . The role of antibiotic therapy in the treatment of reactive arthritis is being explored; in some circumstances, both the anti-inflammatory and anti-microbial effects of certain antibiotics appear to be valuable . The term reactive arthritis should be seen as a transitory one, reflecting a concept which may itself be on the verge of replacement, as our understanding of the condition develops . Nevertheless it appropriately describes arthritis that is associated with demonstrable infection at a distant site without traditional evidence of sepsis at the affected joint(s) . Although several forms of disease could be described as "reactive", particularly acute rheumatic fever, post-meningococcal septicaemia arthritis and Lyme disease, in clinical practice the term is restricted to an acute spondyloarthritis, usually, but not exclusively, linked to acute genitourinary or gastrointestinal infection . A proportion of patients fulfil criteria for Reiter's Syndrome {1}.

APMIS, 1999 Nov, 107(11), 1023 - 33
Functional differentiation of acute myeloid leukaemia blast cells; Bassoe CF et al.; Little is known of the functional status of blast cells from patients with acute myeloid leukaemia (AML) . We have studied phagocytosis and membrane receptors by flow cytometry (FCM), and secretory activities in blast cells from 24 AML patients prior to treatment . Blast cells from 11/16 patients attached N . meningitidis, and internalization occurred in 7/14 . The phagocytosis of zymosan particles and N . meningitidis correlated linearly (r = 0.9, p<0.01, n = 11) . Surface membrane expression of CD32 and CD11b was sufficient to account for opsonin-dependent attachment in all except one patient . A significant fraction of the blast cells attached, but did not internalize meningococci . CD32 and CD11b were non-functional in all the blasts from five patients, and in a subpopulation from seven additional patients . Significantly more large than small blasts expressed CD32, CD35 and CD11b (p<0.001) . Phagocytosis was unrelated to the secretion of IL-1alpha, IL-1beta, and TNFalpha . In conclusion, AML blast cell function is related to receptor expression, cell size and granularity, and to FAB-type.

Commun Dis Public Health, 1999 Dec, 2(4), 269 - 72
Enhanced surveillance of meningococcal disease in the West Midlands: 1996 to 1998; Hawker JI et al.; Surveillance of meningococcal disease is vital if we are to respond to a changing burden of disease, but current sources of routine data suggest different trends . A scheme for enhanced surveillance of meningococcal disease began in the West Midlands in January 1996 using several data sources, including case reporting from consultants in communicable disease control, data from the PHLS Meningococcal Reference Unit, and monitoring of statutory notifications and laboratory reports . One thousand two hundred and twenty-eight cases of probable meningococcal infection were identified in three years (1996-1998), 594 of which were laboratory confirmed . Routine data for the same period yielded smaller totals--920 notifications and 412 laboratory reports--suggesting that these sources underestimate incidence by 25% to 30% . Diagnosis by polymerase chain reaction became increasingly important, and accounted for 38% of confirmed cases in 1998 . A significant excess of male cases was observed (p < 0.01), most obvious in children under 5 years of age . There was no increase in N . meningitidis C2a strains, which had been identified as a threat nationally . A national system of enhanced surveillance has now been set up to inform programmes that aim to reduce the burden of meningococcal infection.

Gesundheitswesen, 1999 Oct, 61 Spec No 1, S41 - 5
{Meningococcal infections: aspects of microbiology, epidemiology and prevention}; Ehrhard I et al.; Neisseria meningitidis (meningococcus) is responsible for an average of 40% of all cases of bacterial meningitis in Germany . Cerebrospinal fluids, blood cultures, throat swabs and scratches, aspirations and biopsies of the skin rash are appropriate materials for the diagnosis of meningococcal disease . The materials should reach the laboratory without delay . Since 1993, the incidence of meningococcal disease in Germany is less than 1 case per 100,000 inhabitants . The case fatality rate is about 10% . Most cases of meningococcal disease occur in the first quarter of the year . Almost half of all invasive N . meningitidis isolates are from children under five years of age . In the period 1990-1998, in Germany an average of 74% of cases were caused by serogroup B and 21% by serogroup C . In serogroup B disease, isolates of serotype 15, in group C disease strains of serotype 2a are predominating . Chemoprophylaxis should be given to all household members and all contacts living in institutions with household-like character, contacts in institutions for children under six years of age and all persons who had contact with the oropharyngeal secretions of the patient . At present, only capsular polysaccharide vaccines against serogroups A, C, Y and W135 are available for immunoprophylaxis in Germany.

J Med Microbiol, 1999 Dec, 48(12), 1055 - 64
Molecular typing methods for Neisseria meningitidis; Yakubu DE et al.; Neisseria meningitidis is an important pathogen because it causes life-threatening infections . The rapid course of meningococcal disease and the capacity of some serogroups to cause large-scale epidemics necessitates the use of sensitive, reliable and rapid typing methods to characterise strains . Molecular typing techniques for N . meningitidis are used for epidemiological purposes to investigate outbreaks and the spread of organisms and to examine the population genetic structure of the organism to understand better its variation and evolution . Many investigators have employed molecular typing methods and shown that meningococcal disease is associated with a variety of different epidemiological patterns . The choice of a typing method is dependent upon the epidemiological questions to be answered and on the population genetics of the organism under investigation . With highly clonal populations comprising independent non-recombining lineages such as serogroup A meningococci, ribotyping, multilocus enzyme electrophoresis (MLEE), pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), PCR with arbitrary primers (RAPD) or with other gene-based primers each provides a constant measure of the relationship between strains . A more restricted portfolio of molecular methods - PFGE, MLEE and MLST - is appropriate for the investigation of less clonal serogroup B and C meningococci from localised outbreaks . If a thorough evaluation of the overall population is sought to determine the relationship between new isolates and members of hyper-endemic clonal complexes then quantitative methods such as MLEE and MLST are necessary . Several PCR-based methods are used for the detection and typing of meningococcal strains, many requiring rigorous standardisation before they can be considered suitable for rapid and reliable differentiation between clones . This review examines strain characterisation by molecular techniques and non-culture-based subtyping of meningococci in clinical specimens . It assesses the importance of these techniques and examines the epidemiological questions that they answer and also their limitations.

Microbiology, 1999 Nov, 145 ( Pt 11), 3013 - 21
The genetic basis of the phase variation repertoire of lipopolysaccharide immunotypes in Neisseria meningitidis; Jennings MP et al.; Neisseria meningitidis strains express a diverse range of lipopolysaccharide (LPS) structures that have been classified into 12 immunotypes . A feature of meningococcal LPS is the reversible, high-frequency switching of expression (phase variation) of terminal LPS structures . A number of studies are strongly suggestive of a key role for these terminal structures, and their phase-variable expression, in pathogenesis . In a previous study, a locus of three LPS biosynthetic genes, IgtABE, involved in the biosynthesis of one of these terminal structures, lacto-N-neotetraose, was described . The molecular mechanism of phase-variable expression of this structure is by high-frequency mutation in a homopolymeric tract of G residues in the IgtA gene . To investigate the genetic basis of the structural differences between the immunotypes, and the potential for strains to express alternative immunotypes, this locus was examined in all of the immunotype strains . Initially, the Igt locus of strain 126E, an L1 immunotype strain, was cloned and sequenced, revealing two active genes, IgtC and IgtE . The remnants of the IgtA and IgtB genes and an inactive IgtD gene were also present, indicating that the locus may have once contained five active genes, similar to a locus previously reported in Neisseria gonorrhoeae strain F62 . Probes based on each of the Igt genes (ABCDE), and the recently reported IgtG gene, were used to determine the presence or absence of Igt genes within individual strains, allowing the prediction of the phase variation repertoire of these strains . Sequencing to determine the nature of homopolymeric tract regions within the Igt genes was carried out to establish the potential for LPS switching . In general, the set of strains examined could be sorted into two distinct groups: one group which phase-vary the alpha-chain extension via IgtA or IgtC but cannot make beta-chain; the second group phase-vary the beta-chain extension via IgtG but do not vary alpha-chain (lacto-N-neotetraose).

Nurs N Z, 1998 Apr, 4(3), 14 - 6
Combating meningococcal disease; Brown J; A thorough knowledge of the community and its networks are essential tools for a public health nurse following up contacts of someone infected with meningococcal disease.

Commun Dis Intell, 1999 Sep 30, 23(10), 261 - 4
Unusual cluster of mild invasive serogroup C meningococcal infection in a university college; Ferson M et al.; The objective of this study was to describe the epidemiology and public health response to an apparent cluster of Neisseria meningitidis serogroup C infection in university students in a residential college . A conventional epidemiological approach was taken, supported by routine and novel diagnostic techniques . Over the two days of 21-22 August 1997, three cases of suspected meningococcal infection were notified from a residential college complex at a university campus in the Sydney metropolitan area . Neisseria meningitidis was grown from throat swabs of all three cases, and was isolated from the blood of one case only . All three isolates were typed as C:2a:P1.5,2 . Seroconversion was demonstrated by a novel method in the three cases . Rifampicin was given to all identified contacts . Forty-seven days after the index case, a 19 year old female living in the same complex was diagnosed with bacterial meningitis, and identified contacts given rifampicin . When this isolate was found to be group C, it was decided to vaccinate residents of the college complex . Genotyping and serotyping (C:2a:P1.5) later revealed the fourth isolate to be distinct from isolates from Cases 1-3 . In conclusion the authors note that Australia's increasing capacity to type meningococcal strains is essential to understanding the epidemiology of this disease . Furthermore, typing information is of critical importance when decisions are made regarding mass vaccination . As early antibiotic treatment may inhibit isolation of the organism, development of novel approaches to diagnosis and typing should be supported.

Epidemiol Infect, 1999 Oct, 123(2), 201 - 8
Salivary antibodies following parenteral immunization of infants with a meningococcal serogroup A and C conjugated vaccine; Borrow R et al.; Bacterial and viral salivary antibody testing is proving sensitive and specific, useful for epidemiological studies, and is simple and non-invasive . Salivary serogroup C polysaccharide-specific (SC PS-S) IgA and IgG were determined as a proportion of total salivary IgA and IgG in a group of UK infants who were recipients of a conjugated A/C meningococcal PS vaccine . Geometric mean concentrations (GMCs) of salivary SC PS-S IgG per mg of total IgG (microg/mg) were 0.1 pre-vaccination, rising to 8.2 post first, 16.1 post second and 29.3 post third dose of vaccine . For IgA, the corresponding GMCs in ng/mg were 0.1, 82.8, 69.6 and 91.2 . Significant correlations (P < 0.0001) were found between serum Ig and salivary IgG SC PS-S antibody for pre-vaccine and 1 month post each dose of vaccine suggesting that SC PS-S IgG in saliva was largely derived from serum . Of the five infants whose sera were analysed for isotype-specific responses, only traces of IgM and IgA were measurable suggesting that the SC PS-S IgA was locally produced . These findings suggests that the widespread use of meningococcal conjugate vaccines is likely to reduce nasopharyngeal carriage and may thereby induce herd immunity in the vaccinated population.

Epidemiol Infect, 1999 Oct, 123(2), 193 - 200
Antimeningococcal herd immunity in the Czech Republic--influence of an emerging clone, Neisseria meningitidis ET-15/37; Kriz P et al.; For many years, invasive meningococcal disease in the Czech Republic occurred sporadically and was caused mainly by meningococci of serogroup B . In 1993, when a new clone (ET-15/37) emerged, the only phenotype found was C:2a:P1.2,5 . In 1995, an antigenic variation of the ET-15/37 clone, B:2a:P1.2,5, occurred . The results of immunological surveys conducted in 1989 and 1996 were compared . A significantly higher proportion of 1996 sera than those collected in 1989 showed bactericidal antibodies against N . meningitidis B:2a:P1.2,5 (19.7 vs . 5.1%) and N . meningitidis C:2a:P1.2,5 (15.9 vs . 7.4%), consistent with increased herd immunity due to the spread of the new clone in the Czech Republic . There were differences in the age distribution of the positive sera.

Epidemiol Infect, 1999 Oct, 123(2), 185 - 92
Meningococcal disease at the University of Southampton: outbreak investigation; Gilmore A et al.; In October 1997, an outbreak of meningococcal disease occurred at the University of Southampton . All six cases were first year students living in halls of residence . Microbiological characterization of case and carrier strains, case interviews, and a meningococcal carriage prevalence survey were used to investigate the outbreak . Five cases were due to serogroup C strains, one case was unconfirmed . Serotyping did not distinguish between the strains but gene sequencing permitted identification of two distinct strains in the outbreak . Although none of the cases was known to each other, three had attended the same nightclub one evening 3-4 days before illness . Meningococcal carriage rates in undergraduates were within the range expected (147/587, 25%), but no carriers of outbreak strains were identified in this sample . The findings suggest that in communities with a high degree of social interaction, the introduction of highly virulent meningococcal strains may result in enhanced transmission with clustering of cases.

Scand J Infect Dis, 1999, 31(5), 481 - 3
PCR identification of the group A Neisseria meningitidis gene in cerebrospinal fluid; Orvelid P et al.; The aim of this study was to develop a PCR method for direct identification of Neisseria meningitidis serogroup A in cerebrospinal fluid . The assay makes use of unique sites within the gene cassette responsible for expression of the (alpha1 --> 6)-linked N-acetyl-D-mannosamine-1-phosphate serogroup A capsule . A total of 67 different N . meningitidis strains and 12 clinical samples of CSF, culture positive for N . meningitidis, were examined . All the strains and samples of N . meningitidis serogroup A were correctly identified by an amplified PCR product of 519 bp . The PCR method for identification is specific for the group A gene of N . meningitidis . The assay may contribute to reducing recurrent, devastating epidemics of meningococcal infection by providing a diagnostic tool for grouping in developing countries where problems with false negative cultures are common and vaccination against serogroup A meningococci may be required.

FEMS Immunol Med Microbiol, 1999 Dec, 26(3-4), 209 - 26
Molecular mimetics of polysaccharide epitopes as vaccine candidates for prevention of Neisseria meningitidis serogroup B disease; Moe GR et al.; Neisseria meningitidis is a major cause of meningitis and sepsis . Despite nearly 25 years of work, there is no promising vaccine candidate for prevention of disease caused by meningococcal B strains . This review summarizes newer approaches for eliciting protective meningococcal B immune responses, including the use of molecular mimetics of group B polysaccharide and conserved membrane proteins as immunogens . The capsular polysaccharide of this organism is conserved and serum antibody to this capsule confers protection against disease . However, the immunogenicity of meningococcal B polysaccharide-based vaccines is poor . Further, a portion of the antibody elicited has autoantibody activity . Recently, our laboratory produced a panel of murine monoclonal antibodies (Mabs) that react specifically with capsular polysaccharide epitopes on meningococcal B that are distinct from host polysialic acid . These Mabs elicit complement-mediated bactericidal activity and confer passive protection in animal models . The anti-capsular Mabs were used to identify molecular mimetics from phage display peptide libraries . The resulting peptides were antigenic mimetics as defined by binding to the Mabs used to select them but, to date, are poor immunogenic mimetics in failing to elicit anti-capsular antibodies.

J Infect Dis, 1999 Dec, 180(6), 1894 - 901
The changing epidemiology of meningococcal disease in the United States, 1992-1996; Rosenstein NE et al.; New meningococcal vaccines are undergoing clinical trials, and changes in the epidemiologic features of meningococcal disease will affect their use . Active laboratory-based, population-based US surveillance for meningococcal disease during 1992-1996 was used to project that 2400 cases of meningococcal disease occurred annually . Incidence was highest in infants; however, 32% of cases occurred in persons >/=30 years of age . Serogroup C caused 35% of cases; serogroup B, 32%; and serogroup Y, 26% . Increasing age (relative risk {RR}, 1.01 per year), having an isolate obtained from blood (RR, 4.5), and serogroup C (RR, 1.6) were associated with increased case fatality . Among serogroup B isolates, the most commonly expressed serosubtype was P1.15; 68% of isolates expressed 1 of the 6 most common serosubtypes . Compared with cases occurring in previous years, recent cases are more likely to be caused by serogroup Y and to occur among older age groups . Ongoing surveillance is necessary to determine the stability of serogroup and serosubtype distribution.

Infect Immun, 1999 Dec, 67(12), 6526 - 32
Human opsonins induced during meningococcal disease recognize transferrin binding protein complexes; Lehmann AK et al.; Patient serum opsonins against transferrin binding protein A+B (TbpA+B) complexes from two Neisseria meningitidis strains (K454 and B16B6, with 85- and 68-kDa TbpB, respectively) were quantified by a functional phagocytosis and oxidative burst assay . TbpA+B complexes adsorbed to fluorescent beads were opsonized with individual acute and convalescent sera from 40 patients infected by a variety of meningococcal strains . Flow cytometric quantitation of leukocyte phagocytosis products (PP) demonstrated that disease-induced serum opsonins recognized TbpA+B, and the highest anti-TbpA+B serum opsonic activities were found between admission to hospital and 6 weeks later . The PP values obtained with TbpA+B from strain B16B6 (PP(B16B6)) were higher than those obtained with TbpA+B from strain K454 (PP(K454)), with both acute and convalescent sera (P < 0.0001), and correlated positively with higher immunoglobulin G enzyme-linked immunosorbent assay titers against TbpA+B from strain B16B6 than from strain K454 (P < 0.001) . In spite of considerable variations between individuals, significant correlations were found between the PP(B16B6) and PP(K454) values, and the PP values did not depend on the variability of the TbpB proteins of the disease-causing strains . Simultaneously measured oxidative burst activity correlated closely with the PP values . We conclude that highly cross-reactive anti-TbpA+B serum opsonins are produced during meningococcal disease . The anti-TbpA+B opsonic activities were not affected by the variability of the TbpB proteins of the disease-causing strains, which further adds to the evidence for the vaccine potential of meningococcal TbpA+B complexes.

J Clin Microbiol, 1999 Dec, 37(12), 3883 - 7
Multilocus sequence typing and antigen gene sequencing in the investigation of a meningococcal disease outbreak; Feavers IM et al.; Multilocus sequence typing and antigen gene sequencing were used to investigate an outbreak of meningococcal disease in a university in the United Kingdom . The data obtained showed that five distinct Neisseria meningitidis strains belonging to the ET-37 complex were present in the student population during the outbreak . Three of these strains were not associated with invasive disease, and two distinct strains caused invasive disease, including several fatalities . The initial case of the disease cluster was caused by a strain distinct from that responsible for at least two subsequent cases and two cases remote from the university, which were epidemiologically linked to the outbreak . These observations were consistent with pulsed-field gel electrophoresis data, but the sequence data alone were sufficient to resolve the strains involved in the disease cluster . Interpretation of the nucleotide sequence data was more straightforward than interpretation of the fingerprint patterns, and the sequence data provided information on the genetic differences among the isolates.

Int J Clin Pract, 1999 Jun, 53(4), 306 - 7
Staphylococcus aureus endocarditis presenting as meningitis and mimicking meningococcal sepsis; Kelly J et al.; A case of Staphylococcus aureus meningitis (SAM) secondary to endocarditis is presented . The presence of a petechial rash affecting the lower limbs led to an initial presumptive diagnosis of meningococcal meningitis . There were no stigmata of endocarditis at presentation, though these subsequently developed . Underlying endocarditis should be diligently sought in any patient presenting with spontaneous SAM, even if typical stigmata are initially absent . In view of the association with skin lesions and neurological complications, S . aureus endocarditis may mimic the classical presentation of meningococcal sepsis.

Biochim Biophys Acta, 1999 Sep 21, 1421(1), 77 - 90
Incorporation of bacterial membrane proteins into liposomes: factors influencing protein reconstitution; Parmar MM et al.; Meningococcal and gonococcal outer membrane proteins were reconstituted into liposomes using detergent-mediated dialysis . The detergents octyl glucopyranoside (OGP), sodium cholate and Empigen BB were compared with respect to efficiency of detergent removal and protein incorporation . The rate of OGP removal was greater than for cholate during dialysis . Isopycnic density gradient centrifugation studies showed that liposomes were not formed and hence no protein incorporation occurred during dialysis from an Empigen BB containing reconstitution mixture . Cholate-mediated reconstitution yielded proteoliposomes with only 75% of the protein associated with the vesicles whereas all of the protein was reconstituted into the lipid bilayer during OGP-mediated reconstitution . Essentially complete protein incorporation was achieved with an initial protein-to-lipid ratio of 0.01:1 (w/w) in the reconstitution mixture; however, at higher initial protein-to-lipid ratios (0.02:1) only 75% protein incorporation was achieved . Reconstituted proteoliposomes were observed as large (>300 nm), multilamellar structures using cryo-electron microscopy . Size reduction of these proteoliposomes by extrusion did not result in significant loss of protein or lipid . Extruded proteoliposomes were unilamellar vesicles with mean diameter of about 100 nm.

Mol Biol Evol, 1999 Nov, 16(11), 1496 - 502
The relative contributions of recombination and mutation to the divergence of clones of Neisseria meningitidis; Feil EJ et al.; Multilocus sequence typing (MLST) is a recently developed nucleotide sequence-based method for the definitive assignment of isolates within bacterial populations to specific clones . MLST uses the same principles as multilocus enzyme electrophoresis and provides data that can be used to investigate aspects of the population genetics and evolution of bacterial species . We used an MLST data set consisting of the sequences of approximately 450-bp fragments from seven housekeeping loci from a large strain collection of Neisseria meningitidis to estimate the relative impact of recombination compared with point mutation in the diversification of N . meningitidis clonal complexes . 126 meningococcal isolates were assigned to 10 clonal complexes, 9 of which contained minor clonal variants . The allelic variation within each complex was classified as a recombinational exchange or a putative point mutation through a comparison of the sequences of each variant allele with that of the allele typically found in the clonal complex . The nine clonal complexes contained a total of 23 allelic variants, and analysis of the sequences of these variant alleles revealed that a single nucleotide site in a meningococcal housekeeping gene is at least 80-fold more likely to change as a result of recombination than as a result of mutation . This value is estimated to be 10-50-fold for Escherichia coli and approximately 50-fold for Streptococcus pneumoniae.

Clin Exp Immunol, 1999 Nov, 118(2), 278 - 84
Properdin deficiency in a large Swiss family: identification of a stop codon in the properdin gene, and association of meningococcal disease with lack of the IgG2 allotype marker G2m(n); Spath PJ et al.; Properdin deficiency was demonstrated in three generations of a large Swiss family . The concentration of circulating properdin in affected males was < 0.1 mg/l, indicating properdin deficiency type I . Two of the nine properdin-deficient males in the family had survived meningitis caused by Neisseria meningitidis serogroup B without sequel . Two point mutations were identified when the properdin gene in one of the properdin-deficient individuals was investigated by direct solid-phase sequencing of overlapping polymerase chain reaction (PCR) products . The critical mutation was found at base 2061 in exon 4, where the change of cytosine to thymine had generated the stop codon TGA . The other mutation was positioned at base 827 in intron 3 . The stop codon in exon 4 was also demonstrated by standard dideoxy sequencing in three additional family members . The question was asked if genetic factors such as partial C4 deficiency and IgG allotypes could have influenced susceptibility to meningococcal disease in the family . No relationship was found between C4 phenotypes and infection . Interestingly, the two properdin-deficient males with meningitis differed from the other properdin-deficient persons in that they lacked the G2m(n) allotype, a marker known to be associated with poor antibody responses to T-independent antigens . This implies that the consequences of properdin deficiency might partly be determined by independent factors influencing the immune response.

Clin Diagn Lab Immunol, 1999 Nov, 6(6), 838 - 43
Comparative analysis of two meningococcal immunotyping monoclonal antibodies by resonant mirror biosensor and antibody gene sequencing; Charalambous BM et al.; Lipooligosaccharide (LOS) is a major surface component of the cell walls of Neisseria meningitidis, which is important for its roles in pathogenesis and antigenic variation, as a target for immunological typing, and as a possible vaccine component . Although the structures of many antigenic variants have been determined, routine immunological typing of these molecules remains problematic . Resonant mirror analysis was combined with gene sequencing to characterize two monoclonal antibodies (MAbs) used in typing panels that were raised against the same LOS immunotype, L3,7,9 . The two MAbs (MAb 4A8-B2 and MAb 9-2-L379) were of the same immunoglobulin subtype, but while MAb 9-2-L379 was more than a 1,000-fold more sensitive in immunotyping assays of both whole meningococcal cells and purified LOS, MAb 4A8-B2 was more specific for immunotype L3,7,9 . The differences in sensitivity were a consequence of MAb 9-2-L379 having a 44-fold-faster association constant than MAb 4A8-B2 . Comparison of the amino acid sequences of the variable chains of the MAbs revealed that they had very similar heavy chains (81% amino acid sequence identity) but diverse light chains (54% sequence identity) . The differential binding kinetics and specificities observed with these MAbs were probably due to differences in the epitopes recognized, and these were probably a consequence of the different immunization protocols used in their production.

Crit Care Med, 1999 Oct, 27(10), 2257 - 61
Admission cortisol and adrenocorticotrophic hormone levels in children with meningococcal disease: evidence of adrenal insufficiency?
Riordan FA, Thomson AP, Ratcliffe JM, Sills JA, Diver MJ, Hart CA.
OBJECTIVE: To measure admission cortisol and adrenocorticotrophic hormone (ACTH) levels in children with meningococcal disease to try and determine the prevalence of adrenal insufficiency . DESIGN: Prospective observational study . SETTING: Pediatric departments of four hospitals in Merseyside, United Kingdom . PATIENTS: Ninety-six children with meningococcal disease; 29 with hypotension, ten of whom died . MEASUREMENTS AND MAIN RESULTS: Admission cortisol, ACTH, and proinflammatory cytokine levels were measured . Serial cortisol levels also were measured during the first 48 hrs . Significantly lower cortisol levels were found in those who died compared with survivors . Significantly higher ACTH levels also were found in those who died . However, no child had a cortisol level <5 microg/dL (<138 nmol/L) implying definite adrenal insufficiency . Three of 29 children with hypotension had plasma cortisol levels implying possible adrenal insufficiency (<18 microg/dL {<497 nmol/L}), but high ACTH levels were only found in one of those three . Cortisol levels decreased significantly after antibiotic treatment, unless steroid therapy was administered . ACTH levels did not correlate with cortisol or proinflammatory cytokine levels . CONCLUSIONS: Children with meningococcal disease have a wide range of initial plasma cortisol levels, with lower levels found in those who die . Many factors may affect cortisol levels, but adrenal insufficiency is probably uncommon.

Vaccine, 1999 Nov 12, 18(7-8), 641 - 6
Safety and immunogenicity of a new Neisseria meningitidis serogroup C-tetanus toxoid conjugate vaccine in healthy adults; Richmond P et al.; We evaluated the safety and immunogenicity of a single dose of a new serogroup C O-deacetylated meningococcal polysaccharide-tetanus toxoid conjugate vaccine in 30 healthy adult volunteers . The vaccine was well tolerated with no serious adverse events and minimal local reactions and systemic symptoms . All subjects developed a fourfold or greater increase in serum bactericidal antibody (SBA) to serogroup C meningococcus . SBA geometric mean titre increased from 11 to 3649 (p<0.001) . Serogroup C-specific IgG levels increased postvaccination from 0.65 to 17.02 microg/ml (p<0.001) . Bactericidal titres pre- and postimmunisation showed significant correlation with serogroup C-specific IgG (r(2)=0.693) . Antibody levels fell by 6 months postvaccination, however, meningococcal C IgG avidity increased indicating the successful induction of a T-cell-dependent antibody response . Conclusion: meningococcal C-tetanus toxoid conjugate vaccine is immunogenic and well tolerated in healthy adults.

Arch Intern Med, 1999 Oct 25, 159(19), 2329 - 40
Meningococcal disease in a large urban population (Barcelona, 1987-1992): predictors of dismal prognosis . Barcelona Meningococcal Disease Surveillance Group; Barquet N et al.; CONTEXT: Studies on meningococcal disease in large urban communities have rarely been performed and are usually based on passive epidemiologic surveillance . Active surveillance may provide new insights . OBJECTIVES: To determine epidemiologic, clinical, and bacteriological characteristics and predictors of dismal prognosis (death and sequelae) in meningococcal disease . DESIGN: Prospective, population-based study . SETTING: All the acute care hospitals (n = 24) in Barcelona, Spain . PATIENT: The 643 patients whose conditions were diagnosed from 1987 through 1992 were detected by 2 active surveillance methods . OUTCOME MEASURES: Incidence and notification to Public Health Service . Clinical and bacteriological features were determined . Dismal prognosis predictors were determined by logistic regression . RESULTS: Average annual incidence was 6.41 per 100,000 inhabitants, with no clear trend of change (P = .08) . Sensitivity of the Public Health Service surveillance system was 69.1% . Children younger than 10 years from the inner city were at higher risk than those from the highest income district (relative risk, 3.00; 95% confidence interval {CI}, 1.84-5.06) . Increasing annual incidence of serogroup C (0.82-1.29/100,000; P = .008) and decreasing incidence of serogroup B (5.11-2.82/100,000; P = .004) was noted . Average annual mortality was 0.40 per 100,000 inhabitants, while the annual average potential years of life lost was 18 per 100,000 inhabitants . Overall case-fatality rate was 6.4% . Independent predictors of death were hemorrhagic diathesis (odds ratio {OR}, 63; 95% CI, 21-194), focal neurologic signs (OR, 10; 95% CI, 3-30), and age 60 years or older (OR, 6; 95% CI, 2-17), whereas preadmission antibiotic therapy was associated with favorable outcome (OR, 0.07; 95% CI, 0.02-0.3) . Four percent of survivors presented with sequelae . Independent predictors of sequelae were hemorrhagic diathesis (OR, 21; 95% CI, 3-131), focal neurologic signs (OR, 16; 95% CI, 5-53), age 60 years or older (OR, 7; 95% CI, 2-26), and age between 15 and 59 years (OR, 5; 95% CI, 2-14), whereas preadmission antibiotic therapy had a protective effect (OR, 0.2; 95% CI, 0.04-0.5) . CONCLUSIONS: Active epidemiologic surveillance significantly improved detection of cases and allowed us to observe that meningococcal disease still causes much morbidity and mortality, especially among children living in the inner city . Hemorrhagic diathesis, focal neurologic signs, and age were independent predictors of dismal prognosis, whereas preadmission antibiotic therapy had a protective effect.

Gesundheitswesen, 1999 Aug-Sep, 61(8-9), 393 - 7
{Epidemiologic and serologic studies of pneumococcal infections with reference to the new STIKO recommendations}; Hulsse C et al.; Pneumococcal diseases play an important role especially for babies and toddlers (otitis media) and for older persons (pneumonia) . 28% of the 481 reported cases of bacterial meningitides (without meningococcus) in Mecklenburg-Vorpommern were caused by pneumoniae streptococcus . A pneumococcus antibody study by the land register confirms the high contamination in older people . Therefore STIKO recommends since March 1998 to effect pneumococcal vaccination with every person from the age of 60 and dove as well as for children, adolescents and adults with higher risk due to a primary disease.

Infect Immun, 1999 Nov, 67(11), 5664 - 75
Differences in surface expression of NspA among Neisseria meningitidis group B strains; Moe GR et al.; NspA is a highly conserved membrane protein that is reported to elicit protective antibody responses against Neisseria meningitidis serogroups A, B and C in mice (D . Martin, N . Cadieux, J . Hanel, and B . R . Brodeur, J . Exp . Med . 185:1173-1183, 1997) . To investigate the vaccine potential of NspA, we produced mouse anti-recombinant NspA (rNspA) antisera, which were used to evaluate the accessibility of NspA epitopes on the surface of different serogroup B strains by an immunofluorescence flow cytometric assay and by susceptibility to antibody-dependent, complement-mediated bacteriolysis . Among 17 genetically diverse strains tested, 11 (65%) were positive for NspA cell surface epitopes and 6 (35%) were negative . All six negative strains also were resistant to bactericidal activity induced by the anti-rNspA antiserum . In contrast, of the 11 NspA surface-positive strains, 8 (73%; P < 0.05) were killed by the antiserum and complement . In infant rats challenged with one of these eight strains, the anti-rNspA antiserum conferred protection against bacteremia, whereas the antiserum failed to protect rats challenged by one of the six NspA cell surface-negative strains . Neither NspA expression nor protein sequence accounted for differences in NspA surface accessibility, since all six negative strains expressed NspA in outer membrane preparations and since their predicted NspA amino acid sequences were 99 to 100% identical to those of three representative positive strains . However, the six NspA cell surface-negative strains produced, on average, larger amounts of group B polysaccharide than did the 11 positive strains (reciprocal geometric mean titers, 676 and 224, respectively; P < 0.05), which suggests that the capsule may limit the accessibility of NspA surface epitopes . Given these strain differences in NspA surface accessibility, an rNspA-based meningococcal B vaccine may have to be supplemented by additional antigens.

Infect Immun, 1999 Nov, 67(11), 5626 - 33
Endothelial adhesion molecule expression and its inhibition by recombinant bactericidal/permeability-increasing protein are influenced by the capsulation and lipooligosaccharide structure of Neisseria meningitidis; Dixon GL et al.; Vascular endothelial injury is responsible for many of the clinical manifestations of severe meningococcal disease . Binding and migration of activated host inflammatory cells is a central process in vascular damage . The expression and function of adhesion molecules regulate interactions between leukocytes and endothelial cells . Little is known about how meningococci directly influence these receptors . In this study we have explored the effect of Neisseria meningitidis on endothelial adhesion molecule expression and found this organism to be a potent inducer of the adhesion molecules CD62E, ICAM-1, and VCAM-1 . Exposure of endothelium to a serogroup B strain of Neisseria meningitidis, B1940, and a range of isogenic mutants revealed that lipooligosaccharide (LOS) structure and capsulation influence the expression of adhesion molecules . Following only a brief exposure (15 min) to the bacteria, there were large differences in the capacity of the different mutants to induce vascular cell adhesion molecules, with the unencapsulated and truncated LOS strains being most potent (P < 0.05) . Furthermore, the pattern of cell adhesion molecule expression was different with purified endotoxin from that with intact bacteria . Meningococci were more potent stimuli of CD62E expression than was endotoxin, whereas endotoxin was at least as effective as meningococci in inducing ICAM-1 and VCAM-1 . The effect of bactericidal/permeability increasing protein (rBPI(21)), an antibacterial molecule with antiendotoxin properties, was also dependent on LOS structure . The strains which possessed a truncated or nonsialylated LOS, whether capsulated or not, were more sensitive to the inhibitory effects of rBPI(21) . These findings could have important implications for the use of antiendotoxin therapy in meningococcal disease.

Pediatr Infect Dis J, 1999 Oct, 18(10), 893 - 6
Effect of the Factor V Leiden mutation on the severity of meningococcal disease; Kondaveeti S et al.; BACKGROUND: One of the most serious complications of meningococcal disease is the syndrome of purpura fulminans, which is characterized by intravascular thrombosis and hemorrhagic infarction of skin, limbs and digits . The reasons why some patients with meningococcal disease develop purpura fulminans while others have minimal thrombotic and skin involvement despite having profound septic shock are not yet understood . The Factor V Leiden mutation (FV(L)) is associated with thrombotic events, and we hypothesized that children carrying FV(L) who develop meningococcal disease may be at increased risk of purpura fulminans . METHODS: We determined the FV(L) genotype by PCR and restriction enzyme digestion (Mnl1) in 259 children with meningococcal disease and 80 healthy controls . In addition 79 parents of children with fatal meningococcal disease were studied . RESULTS: There was no significant increase in the frequency of FV(L) in patients with meningococcal disease (10%) as compared with healthy controls (9%) or with the parents of children who died of meningococcal disease (12%) . Although the mortality was not increased in patients heterozygous for FV(L), they had increased complications of purpura fulminans, as assessed by requirement for skin grafting, referral to plastic surgeon and/or amputation . Among survivors 5 of 24 (21%) of those heterozygous for FV(L) had complications, compared with 14 of 233 (7%) who were wild type {P < 0.03; relative risk, 3.1 (95% confidence intervals, 1.2 to 7.9)} . CONCLUSIONS: FV(L) exacerbates purpura fulminans in meningococcal disease but does not have a significant effect on mortality.

FEMS Microbiol Lett, 1999 Oct 15, 179(2), 247 - 53
Comparison of conventional ribotyping and PCR-RFLP ribotyping for the analysis of endemic strains of Neisseria meningitidis isolated in a local community over 7 years; Verdu ME et al.; Conventional ribotyping was compared with the PCR amplification of the intergenic spacer region between 16S and 23S rRNA genes (PCR-RFLP ribotyping) when applied to the subtyping of sporadic Neisseria meningitidis strains . Thirty isolates out of a total of 36 meningococcal disease cases, reported as having occurred in a particular community over a 7-year endemic period, were analyzed by each of the methods . Only ribotyping with three restriction enzymes (EcoRI, ClaI and XhoI) gave acceptable discriminatory power for short-term epidemiological purposes . We conclude that conventional ribotyping is a suitable method for typing sporadic meningococcal strains and that it cannot be replaced by the more straightforward PCR-RFLP ribotyping method.

FEMS Immunol Med Microbiol, 1999 Oct, 26(1), 75 - 82
A mouse model utilising human transferrin to study protection against Neisseria meningitidis serogroup B induced by outer membrane vesicle vaccination; Oftung F et al.; We have previously developed a mouse model based on transient bacteraemia in normal B10.M mice to evaluate the protective efficacy of outer membrane vesicle vaccines against serogroup B meningococci . To obtain a course of infection similar to that observed in man, we have in this work modified the mouse model by administration of human holo-transferrin upon bacterial challenge . Co-challenge with holo-transferrin induced increasing bacteraemia and subsequent death in normal non-immune mice, but not in vaccinated animals . The model system is dependent on challenge with meningococci expressing the transferrin receptor which is obtained by culturing the bacteria under iron restriction . The modified model system for protection against meningococcal infection presented here makes it possible to measure outer membrane vesicle vaccine induced protection by using bacteraemia as well as survival as parameters.

Neurol Clin, 1999 Nov, 17(4), 801 - 12
Central nervous system involvement in Rickettsial diseases; Bleck TP; The Rickettsia are obligate intracellular parasites that are usually spread to humans by insects and typically produce vasculitides . The prototypic rickettsial disorder in the United States is Rocky Mountain spotted fever (RMSF) . The differential diagnosis of RMSF and related disorders includes other conditions that produce vasculitis, most importantly meningococcemia . The rickettsial disorders are usually treated effectively with tetracycline derivatives.

J Mol Biol, 1999 Oct 15, 293(1), 81 - 91
Crystal structure of an Fab fragment in complex with a meningococcal serosubtype antigen and a protein G domain; Derrick JP et al.; Many pathogens present highly variable surface proteins to their host as a means of evading immune responses . The structure of a peptide antigen corresponding to the subtype P1.7 variant of the porin PorA from the human pathogen Neisseria meningitidis was determined by solution of the X-ray crystal structure of the ternary complex of the peptide (ANGGASGQVK) in complex with a Fab fragment and a domain from streptococcal protein G to 1.95 A resolution . The peptide adopted a beta-hairpin structure with a type I beta-turn between residues Gly4P and Gly7P, the conformation of the peptide being further stabilised by a pair of hydrogen bonds from the side-chain of Asn2P to main-chain atoms in Val9P . The antigen binding site within the Fab formed a distinct crevice lined by a high proportion of apolar amino acids . Recognition was supplemented by hydrogen bonds from heavy chain residues Thr50H, Asp95H, Leu97H and Tyr100H to main-chain and side-chain atoms in the peptide . Complementarity-determining region (CDR) 3 of the heavy chain was responsible for approximately 50 % of the buried surface area formed by peptide-Fab binding, with the remainder made up from CDRs 1 and 3 of the light chain and CDRs 1 and 2 of the heavy chain . Knowledge of the structures of variable surface antigens such as PorA is an essential prerequisite to a molecular understanding of antigenic variation and its implications for vaccine design .

J Med Microbiol, 1999 Oct, 48(10), 943 - 6
Upper respiratory tract infection, heterologous immunisation and meningococcal disease; Scholten RJ et al.; To test the hypothesis that an episode of upper respiratory tract infection or heterologous immunisation is a predisposing factor for the occurrence of meningococcal disease, data from 377 cases of meningococcal disease and their household contacts (n = 1124) were analysed by conditional logistic regression analysis with stratification for household . The odds ratio for a recent upper respiratory tract infection for patients versus household contacts, adjusted for age and the presence of an underlying predisposing disease, was 2.8 and that for recent heterologous immunisation 1.0 . These results support previous observations regarding the association between a preceding upper respiratory tract infection and the occurrence of meningococcal disease; however, no association was found between preceding heterologous immunisation and meningococcal disease . Therefore, increased alertness after heterologous immunisation does not seem warranted.

Wien Klin Wochenschr, 1999 Sep 3, 111(16), 650 - 4
Thrombolytic therapy in adult meningococcal purpura fulminans with acute renal failure and severe perfusion deficits to the extremities; Pechlaner C et al.; OBJECTIVE: To investigate whether systemic administration of recombinant tissue plasminogen activator would improve organ perfusion in an adult patient with fulminant meningococcal disease . DESIGN: Descriptive case report . PATIENT: A 45-year-old female with meningococcal septic shock, purpura fulminans and multiple organ failure who was treated in an eight-bed medical intensive care unit of a University hospital . INTERVENTION: In addition to standard aggressive treatment, on each of three consecutive days the patient received recombinant tissue plasminogen activator infusions at a dose of 20 mg over 4 hrs . RESULTS: Urine output was recorded before, during, and after the recombinant tissue plasminogen activator infusions . In addition, the patient's peripheral perfusion status was documented by clinical assessment . The patient showed a dramatic improvement in urine output, as well as a perceived increase in skin perfusion after recombinant tissue plasminogen activator therapy . The amount of exogenous vasopressor and inotropic support required to maintain the patient's hemodynamic status also rapidly decreased . CONCLUSIONS: In this adult patient, recombinant tissue plasminogen activator therapy resulted in improved organ perfusion similar to that reported for paediatric patients . The findings indicate a need for controlled studies concerning the use of thrombolytics in severe meningococcal disease.

Lancet, 1999 Sep 25, 354(9184), 1094 - 5
Association of familial deficiency of mannose-binding lectin and meningococcal disease; Bax WA et al.; We report the case of an 18-year-old man with meningococcal meningitis and low serum concentrations of mannose-binding lectin (MBL) . His mother and grandfather, who had also had meningitis in early adulthood, also had low concentrations of MBL in their serum.

Microb Pathog, 1999 Oct, 27(4), 207 - 14
Assessment of immune response to meningococcal disease: comparison of a whole-blood assay and the serum bactericidal assay; Ison CA et al.; A whole-blood assay (WBA), which assesses the complete bactericidal activity of blood, was compared with the serum bactericidal assay (SBA), which measures antibody and complement mediated cell lysis . Twenty children infected with serogroup B strains and 25 infected with serogroup C strains were studied 8-12 weeks after disease, and 29 healthy children were used as controls . The infecting strain (convalescent children only) and two reference strains, MC58 (B:15:P1.7, 16) and NCTC 8554 (C:NT:P1.5) were used . In children previously infected with a serogroup B strain, bactericidal activity was detected in 95% and 85% to their infecting strain by the WBA (>50% killing) and the SBA (s), respectively . Bactericidal activity to the reference serogroup B and C strain was detected by WBA in 70 and 75% of children, respectively, and the SBA in 45% and 20% . In contrast bactericidal activity was detected to both serogroup C strains in >80% of children previously infected with a serogroup C strain using either assay and in 48% (WBA) and 20% (SBA) to the reference serogroup B strain . Levels of bactericidal activity were detectable in fewer control children . Children convalescing from meningococcal disease develop an immune response to their infecting strain, detectable by both the WBA and SBA, which is independent of age . However, the WBA appears to be a more sensitive measure of bactericidal activity to heterologous strains than the SBA .

Vaccine, 1999 Aug 20, 18(1-2), 160 - 72
Safety and immunogenicity testing of an intranasal group B meningococcal native outer membrane vesicle vaccine in healthy volunteers; Drabick JJ et al.; An intranasal vaccine composed of native outer membrane vesicles (NOMV) not exposed to detergent or denaturing agents was prepared from the group B meningococcal strain 9162 SynX(-)(-:15:P1.3:P5.10,11:L3,7,9) and tested in 32 healthy adult volunteers . Four groups of 8 volunteers were vaccinated intranasally with three doses of vaccine . The vaccine was very well tolerated in all dosing groups, despite the presence of lipo-oligosaccharide in the vaccine at a level of 25% relative to protein . The antibody response as measured by ELISA in serum, saliva and nasal wash fluids was relatively low in all 4 groups, but the induced serum antibodies had strong bactericidal activity . Persistent bactericidal antibodies (> or =4-fold increase) were produced in 75% of the recipients . Some of the bactericidal antibodies were cross reactive against divergent group B strains . Most of the bactericidal antibodies appeared to be specific for PorA and L3,7,9 LOS . The vaccine also produced a local antibody response which was detected in the nasal wash fluids of volunteers . These data suggest that nasal immunization with NOMV is a safe and effective approach to induce systemic and local immunity against the group B meningococcus and deserves further study.

Vaccine, 1999 Aug 20, 18(1-2), 131 - 9
Effect of adjuvant composition on immune response to a multiple antigen peptide (MAP) containing a protective epitope from Neisseria meningitidis class 1 porin; Christodoulides M et al.; A variety of adjuvants with the potential for use with experimental human vaccines were used for immunisation of mice, in an attempt to augment the humoral immune response to a multiple antigen peptide (MAP) containing a protective epitope from the sero-subtype specific class 1 porin protein of Neisseria meningitidis, in tandem with a Th-cell epitope . Surface plasmon resonance showed that combinations of the immunomodulators pluronic block co-polymer, muramyl dipeptide and monophosphoryl lipid A (MPL), increased the magnitude and avidity of the immune response in comparison with both Al(OH)3 and Freund-type adjuvants . In addition, the incorporation of MPL was essential for the induction of a broad distribution of antibody isotypes . The antibodies induced recognised the native protein in meningococcal outer membranes in a subtype-specific manner . The formulations containing these multiple immunomodulators which have already been used in human phase I/II trials with experimental vaccines, are candidates for inclusion in future human vaccines based on synthetic peptides containing defined, protective epitopes.

FEMS Immunol Med Microbiol, 1999 Sep, 25(4), 385 - 9
Nitric oxide participates in the immune response against Neisseria meningitidis serogroup B; Padron J et al.; The present report explores the role of nitric oxide into the immune response against Neisseria meningitidis serogroup B . Here we show that NO mediates the alphaTNF increase induced by N . meningitidis derived lipopolysaccharides (LPS), at the same time that participates in the bactericidal activity of resting or gammaIFN activated macrophages and plays a role in the specific DTH and IgG response induced by a commercial anti-meningococcal vaccine . Our findings suggest a positive role for NO at the final effector mechanisms and in the early events driving the immunity against N . meningitidis, suggesting also an insight into its role in endotoxic shock.

FEMS Immunol Med Microbiol, 1999 Sep, 25(4), 349 - 54
Analysis of the human Ig isotype response to lactoferrin binding protein A from Neisseria meningitidis; Johnson AS et al.; An effective vaccine for serogroup B meningococci has yet to be developed and attention has turned to subcapsular antigens of the meningococcus as possible vaccine candidates . Iron binding proteins are being studied, with most interest focused on the transferrin binding proteins (TbpA and TbpB) and the ferric binding protein (FbpA) . This study describes the purification of lactoferrin binding protein A (LbpA) from two meningococcal strains and assesses the human isotype-specific serum antibody response to these proteins in patients with proven meningococcal disease due to a range of phenotypes . Overall, fewer than 50% of sera contained IgG that recognised LbpA isolated from either strain and this antibody response was not uniform between the two proteins . There was some evidence that the antibody response varied between meningococcal phenotypes . This study demonstrates that LbpA does not induce a highly cross-reactive antibody response, indicating that it is unlikely to be an effective vaccine antigen.

Infect Immun, 1999 Oct, 67(10), 4988 - 93
Immunogenicity of outer membrane proteins in a lipopolysaccharide-deficient mutant of Neisseria meningitidis: influence of adjuvants on the immune response; Steeghs L et al.; The immunogenicity of outer membrane complexes (OMCs) or heat-inactivated bacteria of a lipopolysaccharide (LPS)-deficient mutant derived from meningococcal strain H44/76 was studied . The immune response in BALB/c mice to the major outer membrane proteins was poor compared to the immune response elicited by wild-type immunogens . However, addition of external H44/76 LPS to mutant OMCs entirely restored the immune response . By using an LPS-deficient mutant, it may be possible to substitute a less toxic compound as adjuvant in meningococcal outer membrane vaccines . Therefore, a broad panel of adjuvants were tested for their potential to enhance the immunogenicity of LPS-deficient OMCs . AlPO(4), Rhodobacter sphaeroides LPS, monophosphoryl lipid A and alkali-hydrolyzed meningococcal LPS showed significantly lower adjuvant activity than did H44/76 LPS . Adjuvant activity similar to H44/76 LPS was found for Escherichia coli LPS, meningococcal icsB and rfaC LPS, QuilA, subfractions of QuilA, and MF59 . Good adjuvant activity was also found with meningococcal htrB1 LPS, containing penta-acylated lipid A . Antisera elicited with the less active adjuvants showed relatively high immunoglobulin G1 (IgG1) titers, whereas strong adjuvants also induced high IgG2a and IgG2b responses in addition to IgG1 . Antisera with the IgG2a and IgG2b isotypes showed high bactericidal activity, indicating that adjuvants promoting the IgG2a and IgG2b response contribute most to the protective mechanism . Thus, this study demonstrates that the immunogenicity of meningococcal LPS-deficient OMCs can be restored by using less toxic adjuvants, which opens up new avenues for development of vaccines against meningococcal disease.

Commun Dis Public Health, 1999 Sep, 2(3), 215 - 6
Meningococcal disease in siblings caused by rifampicin sensitive and rifampicin resistant strains; Dawson SJ et al.; Two brothers presented with meningococcal infection in a five day period, the first with a rifampicin sensitive strain and the second, who had received rifampicin chemoprophylaxis, with a resistant strain . Secondary cases of meningococcal disease can occur despite chemoprophylaxis, and may be rifampicin resistant . Close contacts should be informed of the early symptoms of meningococcal disease and of the need to seek medical advice urgently if they occur.

Commun Dis Public Health, 1999 Sep, 2(3), 168 - 73
Practical guidelines for responding to an outbreak of meningococcal disease among university students based on experience in Southampton; Barker RM et al.; Six students at the University of Southampton developed meningococcal disease in October 1997, five of them with confirmed serogroup C infections, and three died . The outbreak had major organisational and financial implications for the agencies involved . Detailed planning and good working relationships with the management of higher educational institutions can prove invaluable in such situations . This paper summarises the management of the outbreak in Southampton and presents recommendations based on our experience.

Acad Emerg Med, 1999 Sep, 6(9), 906 - 10
Can sick children tell time?: emergency department presentation patterns of critically ill children; Sacchetti A et al.; OBJECTIVE: Children show a consistent pattern of ED use, with the majority of patients presenting during the late afternoon and evening hours . This study evaluated whether such a diurnal pattern also exists for critically ill children and the implications of such a presentation pattern on ED staffing . METHODS: A review was performed of the ED diagnoses and times of presentation for children less than 12 years of age at 28 nonpediatric hospitals over the six-year period from July 1990 to October 1996 . In addition to total ED pediatric visits, a subset of critically ill children (CIC) were identified as those with an ED diagnosis of: meningitis, cardiac arrest, diabetic ketoacidosis, status epilepticus, meningococcemia, or epiglottitis, or those undergoing endotracheal intubation in the ED . A second group of non-critically ill children (NCIC) was composed of children with an ED diagnosis of otitis media, tonsillitis, or pharyngitis . Data collected on each patient included age, diagnosis, site of care, and time of service . Presentation patterns for all three groups were compared for time of day, with statistical analysis through chi-square, ANOVA, and Spearman's rho correlation . RESULTS: A total of 409,820 pediatric ED visits were examined, with 688 CIC children and 28,344 NCIC identified . Presentation patterns for NCIC visits mirrored those of the total pediatric population, with the traditional increase in the late afternoon and evening hours (correlation 0.96) . CIC presented much more erratically, with a distribution spread more uniformly throughout the day compared with the total pediatric population (correlation 0.72) . Thirty-seven percent of CIC presented during the evening hours of 16:00 to 24:00, compared with 49% for NCIC and 53% for the total pediatric population, while 22% of CIC presented from 24:00 to 08:00 compared with only 13% of NCIC and 10% of total pediatric patients (p < 0.001) . CONCLUSION: Critically ill children present more uniformly throughout the day and do not have the same presentation patterns as ambulatory children . ED staffing should reflect this difference and not focus pediatric ED services simply on hours of peak pediatric visits.

Mikrobiol Z, 1999 May-Jun, 61(3), 57 - 62
{A modification to the method for determining the antilysozyme activity of meningococcal strains}; Belozerskii VI; A method of determination of antilysozyme activity in the meningococcus strains has been suggested which consisted in preparing the meningococcus strains culture suspension in liquid media with different lysozyme concentration, incubation of mixtures for some time at 37 degrees C determination of residual lysozyme contents with the use of highly sensitive gel bacterial medium.

J Bacteriol, 1999 Sep, 181(18), 5551 - 6
Population genetic and evolutionary approaches to analysis of Neisseria meningitidis isolates belonging to the ET-5 complex; Bygraves JA et al.; Periodically, new disease-associated variants of the human pathogen Neisseria meningitidis arise . These meningococci diversify during spread, and related isolates recovered from different parts of the world have different genetic and antigenic characteristics . An example is the ET-5 complex, members of which were isolated globally from the mid-1970s onwards . Isolates from a hyperendemic outbreak of meningococcal disease in Worcester, England, during the late 1980s were characterized by multilocus sequence typing and sequence determination of antigen genes . These data established that the Worcester outbreak was caused by ET-5 complex meningococci which were not closely related to the ET-5 complex bacteria responsible for a hyperendemic outbreak in the nearby town of Stroud during the years preceding the Worcester outbreak . A comparison with other ET-5 complex meningococci established that there were at least three distinct globally distributed subpopulations within the ET-5 complex, characterized by particular housekeeping and antigen gene alleles . The Worcester isolates belonged to one of these subpopulations, the Stroud isolates belonged to another, and at least one representative of the third subpopulation identified in this work was isolated elsewhere in the United Kingdom . The sequence data demonstrated that ET-5 variants have arisen by multiple complex pathways involving the recombination of antigen and housekeeping genes and de novo mutation of antigen genes . The data further suggest that either the ET-5 complex has been in existence for many years, evolving and spreading relatively slowly until its disease-causing potential was recognized, or it has evolved and spread rapidly since its first identification in the 1970s, with each of the subpopulations attaining a distribution spanning several continents.

Med Trop (Mars), 1999, 59(1), 68 - 78
{Neisseria meningitidis and meningitis}; Nicolas P et al.; Meningococcal meningitis epidemics can occur anywhere in the world . However this risk is particularly high during the dry season in the sub-Saharan zone of Africa known as the Lapeyssonnie meningitis belt . This area characterized by hyperendemicity that regularly gives rise to epidemics . Multilocus enzyme electrophoresis has made possible identification and monitoring of the progression of virulent clones of Neisseria meningitidis strains in the world . Monitoring is now possible by multilocus sequence typing and data bank on the Internet . Vaccination is a major prophylactic modality . The usefulness of plain group A plus C polysaccharide vaccines is limited because of poor effectiveness in young children who constitute the highest risk group . During epidemics, mass vaccination should be carried out as early as possible according to the state of alert defined for the area . More recent conjugate vaccines against group A and C, which are effective in young children and provide long-term protection by induction of immunologic memory, may allow routine vaccination in the future . Although clinical signs are often apparent, not all cases are diagnosed by clinical examination unless gravity is taken into account . Untreated the disease is always fatal . The only hope of survival is early institution of appropriate antimicrobial therapy (even prior to hospitalization) . Several strains resistant to chloramphenicol have been reported and the number of strains with reduced sensitivity to penicillin is rising constantly . Although treatment remains feasible, the existence of resistant forms raises the need to monitor the sensitivity of meningococci using standardized of antibiograms.

Lancet, 1999 Aug 14, 354(9178), 561 - 3
Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock; Westendorp RG et al.; BACKGROUND: Some patients infected with Neisseria meningitidis develop septic shock accompanied by fibrin deposition and microthrombus formation in various organs, whereas others develop bacteraemia or meningitis without septic shock . We investigated whether genetic differences in the fibrinolytic system influence the development of meningococcal septic shock . METHODS: We investigated 50 patients who survived meningococcal infection, and 131 controls from the same geographical region . Because we had no information on genotypes of patients who died, we also genotyped 183 first-degree relatives of a consecutive series of patients with meningococcal infection for the 4G/5G deletion/insertion polymorphism in the promoter region of the plasminogen-activator-inhibitor-1 gene (PAI-1) . The 4G allele is associated with increased gene transcription in cell lines in vitro and with increased PAI-1 concentrations in carriers in vivo . FINDINGS: The allele frequencies of 4G and 5G were similar between patients and controls . However, the 4G/4G genotype was present in only 9% of relatives of patients with meningitis compared with 36% of relatives of patients with septic shock . The 5G/5G genotype was more common among relatives of patients with meningitis (31 vs 11%, p=0.001) . Patients whose relatives were carriers of the 4G/4G genotype had a six-fold higher risk of developing septic shock than meningitis (odds ratio 5.9 {95% CI 1.9-18.0}) compared with all other genotypes . INTERPRETATION: Variation in the PAI-1 gene does not affect the probability of contracting meningococcal infection, but does influence the development of septic shock.

Lancet, 1999 Aug 14, 354(9178), 556 - 60
4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease . Meningococcal Research Group; Hermans PW et al.; BACKGROUND: Intravascular coagulation with infarction of skin, digits, and limbs is a characteristic feature of meningococcal sepsis . Children with meningococcal sepsis have higher than normal concentrations of plasminogen activator inhibitor 1 (PAI-1) in plasma . Combined with the widespread venous thrombosis, this finding suggests an impairment of fibrinolysis . A common functional insertion/deletion (4G/5G) polymorphism exists in the promoter region of the PAI-1 gene . We tested the hypothesis that children with the 4G/4G genotype produce higher concentrations of PAI-1, develop more severe coagulopathy, and are at greater risk of death during meningococcal sepsis . METHODS: The relation between meningococcal disease outcome, PAI-1 concentration, and PAI-1 genotype was investigated in 175 children with meningococcal disease (37 from Rotterdam, the Netherlands, and 138 from London, UK) and 226 controls (137 from Rotterdam, 89 from London) . PAI-1 concentrations in plasma were measured by ELISA, and the 4G/5G PAI-1 polymorphism was detected by PCR and hybridisation . FINDINGS: Concentrations of PAI-1 on admission correlated with presentation (sepsis or meningitis) and outcome . The median PAI-1 concentration in children who died was substantially higher than that in survivors (2448 {IQR 1115-3191} vs 370 {146-914} ng/mL; p<0.0001) . Patients with the 4G/4G genotype had significantly higher PAI-1 concentrations than those with the 4G/5G or 5G/5G genotype (1051 {550-2440} vs 436 {198-1225} ng/mL; p=0.03), and had an increased risk of death (relative risk 2.0 {1.0-3.8} for the two cohorts combined, and 4.8 {1.8-13} for the London cohort) . INTERPRETATION: A genetic predisposition to produce high concentrations of PAI-1 is associated with poor outcome of meningococcal sepsis . This finding suggests that impaired fibrinolysis is an important factor in the pathophysiology of meningococcal sepsis.

Infect Dis Clin North Am, 1999 Sep, 13(3), 661 - 84, viii
Early management of meningococcal disease; Cartwright KA; Meningococcal disease is increasing in incidence in many countries, and effective vaccines for serogroup B strains will not be available for at least 5 to 10 years . In the interim, it is attention to principles of good clinical practice, particularly in the early management of the disease, that have the potential to reduce by half the current case fatality rate of approximately 10% . As discussed in this article, those principles include increased awareness, understanding of the disease and its early symptoms by parents and healthcare professionals, and careful attention to the patient before admission and during the hospital stay.

J Trop Pediatr, 1999 Aug, 45(4), 248 - 51
Classification trees and logistic regression applied to prognostic studies: a comparison using meningococcal disease as an example; Werneck GL et al.; The authors used logistic regression and classification trees to develop prediction models for fatal outcomes in meningococcal disease in a cohort of 829 children hospitalized for meningococcal disease during 1989-1990 in Rio de Janeiro . The area under the receiver operator characteristic (ROC) curve was 92 per cent for logistic regression and 88 per cent for classification trees . Logistic regression may be preferred when the main objective is to obtain explicit measures for statistical inference and measures of the force of the association between each variable and the outcome . However, estimation of the probability of dying for each patient involves manipulation of the logistic regression formula, which would not easily be done in an emergency room . Classification trees provided comparable discrimination between fatal and non-fatal outcomes, and yielded a graphical display of the results that is easier to understand and is straightforward to apply in clinical settings.

J Infect, 1999 Jul, 39(1), 42 - 8
Meningococcal carriage in relation to an outbreak of invasive disease due to Neisseria meningitidis serogroup C in the Netherlands; Conyn-van Spaendonck MA et al.; BACKGROUND: a cross-sectional study on meningococcal carriage was performed in Putten, a small rural town in the Netherlands where an unusual high incidence of invasive meningococcal disease (IMD) due to Neisseria meningitidis C:2a:P1.5 occurred . The outbreak was controlled by mass vaccination of all inhabitants aged 2 to 20 years . METHODS: meningococcal carriage was studied in three groups: (1) a systematic age-specific sample of 2-20 year olds who visited the immunization clinic in Putten (January 1998: n=411); (2) children and adolescents in the same age range recruited through a kindergarten and schools in Venlo, a town where the causative strain of IMD had not been encountered (February 1998; n=374); (3) all initial carriers in Putten and a sample of non-carriers in that town (March 1998: n=145) . Oropharyngeal swabs were taken for the purpose of isolating N . menigitidis . RESULTS: the prevalence of carriage was 12.4% in Putten and 18.2%, in Venlo, but the prevalence of group C meningococci was higher in Putten (1.7%) than Venlo (0.5%) . N . meningitidis C:2a:P1.5 was isolated twice in Putten and not at all in Venlo . A second examination in Putten showed that 18 of the 22 repeatedly tested carriers were still carriers, and six new carriers were found among the 55 initial non-carriers . Of the two known carriers of C:2a:P1.5, one was still carrying the same strain, and the other did not participate in the second investigation . Carriage was associated with increasing family size, discotheque visits and visits to youth clubs and sports clubs . In contrast, visits to the swimming pool appeared to be related to a lower risk, as was recent antibiotic use . CONCLUSION: the prevalence of carriage with the invasive strain C:2a:P1.5 was low in the population that experienced a community-wide outbreak recently: the specific strain was not found in the reference population . This indicates a relatively high risk of developing the invasive disease for those who become infected with such strains.

Infect Control Hosp Epidemiol, 1999 Aug, 20(8), 564 - 5
Nosocomial meningococcemia in a physician; Gehanno JF et al.; We report the case of a pediatrician who developed meningococcal meningitis after performing endotracheal intubation without protection on a child who was suspected of having meningoencephalitis . This case emphasizes the necessity for healthcare workers who perform high-risk procedures to use personal protection devices (i.e., respirators and protective goggles) . Unprotected healthcare workers with high exposure to Neisseria meningitidis should receive chemoprophylaxis.

Clin Exp Rheumatol, 1999 Jul-Aug, 17(4), 471 - 3
Bacterial infection presenting as cutaneous vasculitis in adults; Garcia-Porrua C et al.; OBJECTIVE: To examine the frequency and clinical features of patients with bacterial infection presenting with biopsy-proven leukocytoclastic cutaneous vasculitis (CV) in a well-defined area of southern Europe (northwestern Spain) . METHODS: A retrospective study of an unselected population of adult patients (age > 20 years) with biopsy-proven leukocytoclastic CV diagnosed at the Hospital Xeral-Calde (Lugo, Spain) was carried out from January 1988 through December 1997 . Cutaneous vasculitis related to bacterial infection was considered if the vasculitis was confirmed by a skin biopsy showing leukocytoclastic vasculitis, if no drug intake was registered prior to the development of CV, and if bacteriologic evidence of infection was obtained . RESULTS: Four of 138 patients (2.9%) presenting with biopsy-proved CV were diagnosed with leukocytoclastic CV related to bacterial infection . Three patients (2 with bacterial endocarditis and 1 with meningococcemia) met the ACR criteria for the classification of hypersensitivity vasculitis . Another patient with bacterial endocarditis met the criteria for mixed cryoglobulinemia . All of them presented with palpable purpura, high or low grade fever, an elevated erythrocyte sedimentation rate and leukocytosis . CONCLUSION: Cutaneous vasculitis may be the presenting manifestation of bacterial infection . In this respect, rheumatologists should be aware of possible infectious causes of vasculitis, even though they are not common.

Vaccine, 1999 Aug 6, 17(23-24), 3086 - 93
Immune response to revaccination with meningococcal A and C polysaccharides in Gambian children following repeated immunisation during early childhood; MacLennan J et al.; Forty-two Gambian children randomised to receive two doses of meningococcal A/C polysaccharide vaccine (MPS) in infancy and either MPS (n = 15), meningococcal A/C conjugate (n = 13) or inactivated polio vaccine (IPV n = 14) at 2 years, were revaccinated with MPS at 5 years of age along with 39 matched control children . Meningococcal A and C polysaccharide antibodies were analysed by ELISA and bactericidal assay (SBA) in sera taken before and 10 days after revaccination . The geometric mean group SBA titre in the MPS group following revaccination was about half that of the unvaccinated controls (0.51 95%CI: 0.28, 0.90) for group A and less than half that of the controls for group C (0.41, 95%CI: 0.16, 1.03 P = 0.06) . The group C SBA response in the conjugate group was 14-fold higher than in the MPS group (P < 0.001) . Multiple doses of meningococcal polysaccharide in childhood may therefore attenuate the SBA response to both group A and group C polysaccharides . In contrast, vaccination with meningococcal A/C conjugate after MPS in infancy gives immunological memory to N . meningitidis group C.

Vaccine, 1999 Aug 6, 17(23-24), 2951 - 8
Neisseria meningitidis serogroup C polysaccharide and serogroup B outer membrane vesicle conjugate as a bivalent meningococcus vaccine candidate; Fukasawa LO et al.; Neisseria meningitidis serogroup C polysaccharide (PS C) was conjugated to serogroup B outer membrane vesicles (OMV) in order to test the possibility of obtaining a bivalent group B and C meningococcus vaccine . The conjugate and controls were injected intraperitoneally into groups of ten mice with boosters on days 14 and 28 after the primary immunization . The following groups were used as control: (i) PS C; (ii) PS C plus OMV; (iii) OMV; and (iv) saline . The serum collected on days 0, 14, 28 and 42 were tested by enzyme-linked immunosorbent assay (ELISA) for PS C and OMV, and by complement mediated bactericidal assay against serogroups B and C . ELISA for PS C as well as bactericidal titres against serogroup C meningococci of the conjugated vaccine increased eight-fold (ELISA) and 32 fold (bactericidal) after 42 days in comparison with the PS C control group . ELISA for OMV and bactericidal titre against serogroup B meningococci of the conjugate showed no significant difference in comparison with the OMV containing controls . Furthermore, Western Blot assay of the conjugate immune serum did not bind OMV class four protein which is related to the complement dependent antibody suppressor . The results indicate that the PS C-OMV conjugate could be a candidate for a bivalent vaccine toward serogroups B and C meningococci.

Epidemiol Infect, 1999 Jun, 122(3), 351 - 7
Invasive meningococcal disease among university undergraduates: association with universities providing relatively large amounts of catered hall accommodation; Neal KR et al.; The incidence of invasive meningococcal disease (IMD) among UK university students and non-students of similar age was investigated . In addition, we sought to identify structural risk factors associated with high rates of IMD in individual universities . Cases were ascertained via Consultants in Communicable Disease Control (or equivalent officers) between September 1994 and March 1997 . Data on individual universities were obtained from university accommodation officers . University students had an increased annual rate of invasive meningococcal disease (13.2/10(5), 95% CI 11.2-15.2) compared with non-students of similar age in the same health districts (5.5/10(5), CI 4.7-6.4) and in those health districts without universities (3.7/10(5), CI 2.9-4.4) . This trend was highly significant . Regression analysis demonstrated catered hall accommodation to be the main structural risk factor . Higher rates of disease were observed at universities providing catered hall places for > 10% of their student population (15.3/10(5), CI 11.8-18;8) compared with those providing places for < 10% of students (5.9/10(5), CI 4.1-7.7) . The majority of IMD amongst students was caused by serogroup B organisms . University students in the UK are at increased risk of IMD compared with non-students of a similar age . The incidence of IMD tends to be greatest at universities with a high provision of catered hall accommodation.

MMWR Morb Mortal Wkly Rep, 1999 Jul 30, 48(29), 629 - 33
Meningococcal disease--New England, 1993-1998; Bactericidal and cross-protective activities of a monoclonal antibody directed against Neisseria meningitidis NspA outer membrane protein; Unite de Recherche en Vaccinologie, Centre Hospitalier Universitaire de Quebec et Universite Laval, Ste-Foy, Quebec, Canada G1V 4G2The cross-bactericidal and cross-protective activities of a monoclonal antibody (MAb) named Me-7, which is directed against an antigenically highly conserved epitope on the meningococcal NspA protein, were studied . This MAb efficiently killed in vitro, in the presence of rabbit or human serum, 13 of 14 meningococcal strains tested, including 9 of 9, 2 of 3, and 2 of 2 strains of serotypes B, A, and C, respectively . MAb Me-7 also significantly reduced by more than 75% the levels of bacteremia recorded for mice challenged with 10 of 11 meningococcal strains tested . Analysis of the predicted amino acid sequence of the NspA protein from the meningococcal strain MCH88 (A:4:P1.10), which was not killed by MAb Me-7, indicated the presence of an additional glutamine residue at position 73, compared to the three other NspA sequences . The data presented in this study suggest that antibodies directed against this highly conserved outer membrane protein could protect against meningococcal infections.

Med Clin North Am, 1999 Jul, 83(4), 903 - 22, vi
Travel immunizations; Jong EC; An updated approach to selecting and prioritizing immunizations for the international traveler is presented . This article addresses vaccines against yellow fever, typhoid fever, cholera, meningococcal meningitis, rabies, tetanus, diphtheria, measles, mumps, rubella, polio, varicella, and influenza . Vaccine preparations, dosing regimens, efficacy, adverse effects, indications, and contraindications are discussed in the context of pre-travel preparation.

Shock, 1999 Aug, 12(2), 145 - 54
Cardiovascular aspects of experimental meningococcal sepsis in young and older awake piglets: age-related differences; Hazelzet JA et al.; Severe meningococcal disease is characterized by: a high load of specific endotoxin, capillary leakage and coagulation disorders . We studied the possible age-related differences in global hemodynamic and regional blood flow responses to different dosages (1 and 10 microg/kg body weight) of rough meningococcal endotoxin in young (8 kg) and older piglets (40 kg) . Animals were chronically instrumented and studied in the awake state . The response to plasma infusion (30 mL/kg in 30 min) was evaluated after placebo and endotoxin infusion . The clinical picture was similar in all groups . The mortality was 0/8, 3/8,1/8, 4/9 in young-low, young-high, old-low, and old-high dose respectively . Most important findings were that cardiac index (CI) decreased in the young animals after endotoxin infusion, while it was well preserved in the older animals; in the older animals the systemic vascular resistance dropped 20%, while in the younger ones there was no change in resistance . Conductance to the kidneys, intestines, and spleen decreased significantly more in the young animals, while the increase in conductance and flow to the liver was higher in the old animals; subsequent volume loading resulted only partly in a recovery of the hemodynamic parameters, but failed to improve oxygen delivery.

Mem Inst Oswaldo Cruz, 1999 Jul-Aug, 94(4), 433 - 40
The epidemiological impact of antimeningococcal B vaccination in Cuba; Rodriguez AP et al.; The incidence of invasive meningococcal disease (IMD) before (1984-1988) and after (1989-1994), a nationwide intervention with VA-MENGOC-BC vaccination started in 1989, was compared . The prevaccination period incidence density (ID> 8.8/10(5) year-person) was higher than the postvaccination ID (ID< 6.5/10(5) year-person) . The percentage proportional differences from the start to the end of each period of ID in the vaccinal period was higher (87%) than the prevaccinal (37%) with significant differences among vaccinated groups (< 25 years old) . A break-point (Chow test) was confirmed by the decrease in the ID between 1989 and 1990 in children under 1 year old, 5-9, 10-14, 15-19 and 50-54 years . Comparison of ID using maps showed a decrease in IMD in all municipalities during the postvaccination period . These findings support the epidemiological impact of VA-MENGOC-BC vaccination in the reduction of IMD morbidity.

Curr Opin Pediatr, 1999 Aug, 11(4), 367 - 73
Neonatal jaundice, animal-based injuries, and immunizations; Davis IJ et al.; The authors describe current investigation in three areas of pediatrics commonly faced by the office practitioner . Despite the fact that changes in medical practice and in patient demographics have resulted in the reemergence of severe hyperbilirubinemia and bilirubin encephalopathy, clinical assessment and evaluation of discharge bilirubin levels may help predict those infants at greatest risk . Progress in the use of inhibitors of bilirubin production may eventually decrease the need for phototherapy . Although dog-associated injuries continue to affect children disproportionately, additional attention to anticipatory guidance may prove beneficial . The practice of routine immunization has reshaped our view of pediatric illness . The development of pneumococcal, meningococcal, and rotaviral vaccines will alter significantly the prevalence of common pediatric infectious disease . However, with the advent of additional vaccines, attention to pain control will take on increasing urgency.

J Infect Dis, 1999 Sep, 180(3), 755 - 61
The role of B/T costimulatory signals in the immunopotentiating activity of neisserial porin; Mackinnon FG et al.; A T cell-dependent immune response to group C meningococcal capsular polysaccharide (CPS) can be elicited when CPS is conjugated to the class 3 neisserial porin (CPS-porin) . Treatment of CPS-porin-immunized mice with B7-2 blocking monoclonal antibody (MAb) caused a dramatic reduction in the CPS-specific IgG response, treatment with anti-B7-1 MAb had no effect, and concurrent blockade of B7-1 and B7-2 resulted in a synergistic abrogation of the CPS-specific IgG response while the CPS IgM response was unaffected . Anti-CD40L MAb treatment caused a significant reduction of both CPS-specific IgG and IgM levels . In contrast, blockade of CTLA4 interactions resulted in increases in both CPS IgG and IgM responses in CPS-porin-immunized mice . These data support the hypothesis that the ability of neisserial porins to improve the immune response to poorly immunogenic antigens (e.g., polysaccharides) is related to porin-induced increases in B7-2 expression on antigen-presenting cells and enhanced B/T cell interactions.

J Infect Dis, 1999 Sep, 180(3), 747 - 54
Immunization with meningococcal outer-membrane protein vesicles containing lipooligosaccharide protects mice against lethal experimental group B Neisseria meningitidis infection and septic shock; Quakyi EK et al.; Detergent-treated group B Neisseria meningitidis outer membrane vesicles (D-OMVs) from wild-type M986 and from nonencapsulated mutant M986-non-capsule variant (NCV) were compared as immunogens . Eight weeks after 3 consecutive immunizations with the immunogens, mice were challenged with a lethal dose of purified endotoxin or heat-killed or living N . meningitidis, plus d-galactosamine (400 mg/kg) . D-OMVs from M986 induced bactericidal antibodies to both M986 (B : 2a : P1.5,2 : L3,7) and 6275 (B : 2a : P1.2,5 : L3) and protected the animals against both strains, whereas D-OMVs from M986-NCV did not protect the animals against infection with 6275 even when high serum bactericidal activity was induced . Tumor necrosis factor-alpha detected after bacterial infection was high in both protected and unprotected mice; interleukin (IL)-6 was high in mice that died but low in animals that survived . Exogenous administration of recombinant mouse IL-6 reversed the immunogens' protective effects . Protection against infection in mice does not necessarily correlate with the measured levels of serum bactericidal antibody alone, opsonic antibody alone, or cytokine profile alone . A comprehensive assessment of the preclinical efficacy of group B outer-membrane protein vaccines should include monitoring humoral antibodies, cytokine response, and protective effects against lethal infection.

Brain, 1999 Aug, 122 ( Pt 8), 1579 - 87
Differential expression of matrix metalloproteinases in bacterial meningitis; Kieseier BC et al.; Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of various inflammatory diseases of the central nervous system . Evidence is accumulating that gelatinase B (MMP-9) might be involved in the pathogenesis of meningitis, but the spectrum of different MMPs involved in the inflammatory reaction of this disease has not been determined . We investigated the temporal and spatial mRNA expression pattern of gelatinase B in experimental meningococcal meningitis in rats . In contrast to controls, increased mRNA levels with peak values 6 h after injection with menigococci were found in brain specimens of the animals . Elevated MMP-9 mRNA expression was accompanied by enhanced proteolytic activity, as demonstrated by gelatin zymography, and positive immunoreactivity . The mRNA expression pattern of six other MMPs was investigated . Collagenase-3 and stromelysin-1 mRNAs were also found to be upregulated . In contrast, mRNA levels for gelatinase A, matrilysin, stromelysin-2 and stromelysin-3 remained unchanged . As evidenced by significantly increased intracranial pressure and by leakage of intravenously injected Evans blue through the blood vessel walls into the brain parenchyma, the animals injected with meningococci revealed signs of blood-brain barrier disruption . Augmented proteolytic activity of MMP-9 could also be demonstrated in CSF samples obtained from patients with bacterial meningitis, underlining the clinical relevance of our experimental findings . Our data indicate that gelatinase B, collagenase-3 and stromelysin-1 are selectively upregulated in bacterial meningitis and thus may contribute to the pathogenesis of this infectious disease of the central nervous system.

Cas Lek Cesk, 1999 May 10, 138(10), 298 - 300
{Post-vaccination immunity after allogenic and autologous bone marrow transplantation}; Skovrankova J; In the submitted review the author describes time correlation's of reconstitution of immunity during the post-transplantation period in patients after autologous and allogeneic bone marrow transplantations . The authors presents values of different immunological parameters incl . functional examinations of immunity by the method of blastic lymphocyte transformation after stimulation with mitogens and vaccination antigens during the post-transplantation period . She also evaluates mechanisms involved in this process . An illustrative idea on the character and degree of affection of immunity mechanisms after bone marrow transplantation is provided by the state of postvaccination immunity after immunization made before the disease and bone marrow transplantation . The titres of postvaccination antibodies after a 1-4-year interval following bone marrow transplantation gradually drop to low or zero values . The author emphasises therefore the necessity of revaccination of patients with killed vaccines against tetanus, diphtheria, poliovirus and pneumococcal, meningococcal and haemophil infection during the post-transplantation period . Recommended vaccination patterns are also presented.

Vaccine, 1999 Jun 4, 17(20-21), 2702 - 12
Immunogenicity of various presentation forms of PorA outer membrane protein of Neisseria meningitidis in mice; Peeters CC et al.; In this study we compare different vaccine formulations containing meningococcal PorA outer membrane protein; purified PorA, outer membrane vesicles (OMV) and immune-stimulating complexes (iscom) . Bactericidal antibodies could be generated by the OMV and iscom formulation but not with purified PorA using either A1PO4 or Quil-A as adjuvant . OMV and iscom formulations revealed similar immunogenicity when tested in a dose response manner, with respect to bactericidal as well as OMV-binding antibodies . The anti-OMV IgG subclass response induced by PorA in OMV formulation was found in all subclasses IgG1, IgG2a, IgG2b, IgG3 . OMP-iscoms induced very high IgG1 anti-OMV antibodies but almost no IgG3 response . Also, OMP-iscoms appeared to be a potent inducer of antibodies directed against linear peptides corresponding to surface exposed loops of PorA . In addition, iscoms as well as purified PorA with Quil-A as adjuvant (but not with A1PO4) induced high levels of antibodies against purified PorA . In summary, in addition to the OMV formulation, only iscoms containing PorA are able to generate an anamnestic and bactericidal antibody response.

Vaccine, 1999 Jun 4, 17(20-21), 2677 - 89
The infant rat model adapted to evaluate human sera for protective immunity to group B meningococci; Toropainen M et al.; The infant rat infection model previously developed to evaluate protective ability of passively administered murine antibodies to group B meningococcal (MenB) surface antigens was adapted for human sera . Several challenge doses were tested, aiming at sensitive detection of protection with little interassay variability . Doses of 10(5) and 10(6) colony forming units of strain IH5341 (MenB:15:P1.7,16) injected intraperitoneally gave consistently high levels of bacteremia and meningitis developed in 6 h in 50-100% of the pups . A monoclonal antibody mAb735 to the MenB capsule, injected 1-2 h before bacterial challenge, gave full protection at a dose of 2 microg/pup . Sera from adult volunteers immunized with a MenB outer membrane vesicle vaccine reproducibly reduced bacterial counts in the blood and cerebrospinal fluid, whereas a normal human serum, lacking bactericidal and opsonophagocidal activity, was unprotective.

Vaccine, 1999 Jun 4, 17(20-21), 2612 - 9
Immunogenicity and reactogenicity in UK infants of a novel meningococcal vesicle vaccine containing multiple class 1 (PorA) outer membrane proteins; Cartwright K et al.; The development of effective vaccines against serogroup B meningococci is of great public health importance . We assessed a novel genetically engineered vaccine containing six meningococcal class 1 (PorA) outer membrane proteins representing 80% of prevalent strains in the UK . 103 infants were given the meningococcal vaccine at ages 2, 3 and 4 months with routine infant immunisations, with a fourth dose at 12-18 months . The vaccine was well tolerated . Three doses evoked good immune responses to two of six meningococcal strains expressing PorA proteins contained in the vaccine . Following a fourth dose, larger bactericidal responses to all six strains were observed, suggesting that the initial course had primed memory lymphocytes and revaccination stimulated a booster response . This hexavalent PorA meningococcal vaccine was safe and evoked encouraging immune responses in infants . Vaccines of this type warrant further development and evaluation.

Trop Doct, 1999 Apr, 29(2), 108 - 9
Neisseria meningitidis nasopharynx colonization of diseased patients on presentation and on discharge; Barroso D; Fifty-one meningococcal disease patients were randomly selected and a paired throat swab was taken before and after specific therapy . Neisseria meningitidis nasopharyngeal carriage after intravenous antibiotic therapy were found in only two cases (4%; 95% confidence interval (CI) 0.5-13) . All close contacts of the cases received chemoprophylaxis and throat swabs taken 10 days later were negative.

Infect Immun, 1999 Aug, 67(8), 3842 - 6
Antigenic variation of the class I outer membrane protein in hyperendemic Neisseria meningitidis strains in the netherlands; Bart A et al.; Since 1980, the number of cases of meningococcal disease caused by serogroup B isolates with the P1.4 serosubtype has greatly increased in The Netherlands . Screening for this serosubtype in the strain collection of The Netherlands Reference Laboratory for Bacterial Meningitis revealed that a low number of P1.4 strains had been present in the Dutch meningococcal population since 1965 . Genotyping of P1.4 strains showed that one cluster of strains, the hyperendemic lineage III (D . A . Caugant et al., J . Infect . Dis . 162:867-874, 1990), is responsible for the increase since 1980 . The diversity of the porA genes, which encode the P1 protein on which serosubtyping is based, was studied for genotypically different P1.4 strains and for lineage III strains expressing antigenically different P1 proteins . Sequence analysis showed that porA genes of genotypically distinct strains that express antigenically indistinguishable P1 proteins are identical only in the epitope-encoding region, suggesting that this region has spread through the meningococcal population via horizontal gene transfer . Analysis of porA genes of lineage III strains showed that both horizontal gene transfer and partial deletion of the epitope-encoding region may contribute to the different antigenic properties for P1 of these strains . Phase variation of expression of the porA gene seems to account for most nonreacting strains . These results show that serosubtyping may underestimate the rise of a hyperendemic clone.

Mol Microbiol, 1999 Jul, 33(1), 119 - 27
Intracistronic transcription termination in polysialyltransferase gene (siaD ) affects phase variation in Neisseria meningitidis; Lavitola A et al.; Expression of serogroup B meningococcal capsular polysaccharide is subject to frequent phase variation . A reversible +1/-1 frameshift mutation within a poly(dC) repeat altering the reading frame of the polysialyltransferase gene (siaD ), thereby causing premature arrest of translation, is responsible for loss of capsule expression . After analysis of transcription of the siaD gene from an encapsulated strain and from two unencapsulated derivatives, we have found that the siaD mRNA in the unencapsulated strains is reduced in size as a result of premature transcription termination at a cryptic Rho-dependent site within the proximal region of the siaD cistron . Termination is sensitive to bicyclomycin, a natural inhibitor of Rho activity . Bicyclomycin decreased the rates of capsule re-expression (off-on) without affecting the rates of loss of capsule expression (on-off) . This finding suggested the existence of a novel mechanism linking transcription elongation termination and mutation frequency . A genetic system was therefore developed to measure phase variation of siaD-ermC' gene fusions in wild type and Rho-defective Escherichia coli strains . These studies demonstrated that in the Rho-defective E . coli strain readthrough transcription of the mutated siaD gene caused a fourfold lower off-on phase variation rate than in the congenic Rho+ strain . Analysis of phase variation of siaD-ermC' gene fusions in a DNA mismatch-defective E . coli strain suggests that the effect of transcription on mutation rates required a functional mismatch repair system.

Klin Padiatr, 1999 Mar-Apr, 211(2), 65 - 9
Diagnosis and stage-related treatment of disseminated intravascular coagulation in meningococcal infections; Mertens R et al.; Disseminated intravascular coagulation (DIC) is a frequent complication of meningococcal sepsis in children . Despite the availability of potent antibiotics, mortality in meningococcal disease remains high (about 10%), rising to 40% in patients presenting in severe shock and consecutive DIC . As the clinical course and the severity of manifestations of systemic meningococcal infections varies there is a need for early diagnosis of the infection and of the stage of coagulopathy in order to reduce the high mortality rate . Few and rapidly available parameters are needed to classify the wide spectrum of clinical and laboratory findings in patients with DIC . The parameters include partial thromboplastin time, prothrombin time, plasma levels of fibrinogen, antithrombin III (AT III), fibrin monomers and D-dimer concentration, fibrin degradation products and the thrombocyte count . Monitoring the course of hemostasis findings in 28 pediatric patients (age between 3 months and 8 years, mean 3.1 years) with systemic meningococcal infections we observed a change of coagulation parameters already in the first stages of the infection: A prolongation of partial thromboplastin time mean 69.1 sec (range 22-150 sec, normal 30-45 sec), a decrease of prothrombin time to 45.7% (range 13-71%, normal 70-100%) and of AT III to an average level of 70% (normal 85-125%) was found 1 to 4 (-6) hours after admission . The following deterioration of prothrombin time and partial thromboplastin time turned out to be statistically significant (p < 0.05, signed rank test) . The monitoring of hemostasis parameters mentioned above made it to possible define the stage of coagulopathy and thus to start a stage related therapy . Treatment consisted of shock control by liquid substitution, compensation of metabolic acidosis, correction of clotting disorders (AT III and heparin in case of pre-DIC; AT III and fresh frozen plasma in case of advanced DIC), antibiotic treatment (beta-lactam antibiotics e.g . cefotaxime or ceftriaxone), and--when necessary--catecholamine infusions . An early assessment of the coagulation disorders in meningococcal disease can be based on few coagulation parameters . Thus an appropriate treatment can be arranged in order to prevent a fatal outcome of meningococcal sepsis and to protect against the development of a Water-house-Friderichsen-syndrome.

J Clin Microbiol, 1999 Aug, 37(8), 2402 - 7
Cleavase fragment length polymorphism analysis of Neisseria meningitidis basic metabolic genes; Tondella ML et al.; Cleavase fragment length polymorphism (CFLP) is a subtyping system based on the property of the enzyme cleavase to recognize junctions between single- and double-stranded regions of DNA formed after denaturation and cooling . To assess the capacity of CFLP for discriminating Neisseria meningitidis serogroup B strains belonging to the electrophoretic type (ET) 5 (ET-5) complex from other serogroup B strains, 30 serogroup B N . meningitidis isolates were subtyped by CFLP with internal fragments of five housekeeping genes, adk, aspC, carA, dhp, and glnA . Two genes (glnA and carA) which demonstrated a high degree of diversity for the serogroup B isolates were then used to further evaluate the suitability of CFLP for screening 50 serogroup C N . meningitidis outbreak-associated and sporadic-case isolates with a single metabolic gene . The results were compared to those from multilocus enzyme electrophoresis (MEE), the current standard subtyping method . CFLP was able to distinguish the ET-5 complex isolates from other serogroup B isolates as efficiently as MEE . Furthermore, CFLP analysis of a single gene was sufficient to identify and cluster the serogroup C isolates belonging to the ET-37 complex from other, unrelated serogroup C isolates but was not capable of differentiating between the isolates of the major individual ETs of this complex (ET-17 and ET-24) causing most serogroup C meningococcal disease outbreaks in the United States . CFLP based on a single gene with a high degree of diversity but not under selective pressure can be applied to the rapid screening of a large number of isolates related to the recognized epidemic complex ET-5 or ET-37 . Additionally, CFLP can be used as an initial screening tool to survey the amount of diversity in genes that might be used to develop a DNA sequence-based subtyping system.

J Bacteriol, 1999 Jul, 181(14), 4417 - 9
Structural characterization of the lactoferrin receptor from Neisseria meningitidis; Prinz T et al.; The meningococcal lactoferrin receptor is composed of the integral outer membrane protein LbpA and the peripheral lipoprotein LbpB . Homooligomeric complexes of LbpA and heterooligomers consisting of LbpA and LbpB were identified . Furthermore, five cell surface-exposed loops of LbpA were identified, which partially confirms a previously proposed topology model.

Crit Care Med, 1999 Jun, 27(6), 1187 - 90
Nitric oxide production in meningococcal disease is directly related to disease severity; Baines PB et al.; OBJECTIVES: Meningococcal disease is a homogeneous and well-characterized form of sepsis . Cardiovascular collapse is prominent in severe meningococcal disease . Nitric oxide overproduction may be a mediator of cardiovascular collapse . We relate the level of nitric oxide metabolites, nitrates and nitrites, to disease severity in meningococcal disease . DESIGN: Prospective, nonrandomized study . SETTING: Tertiary referral pediatric intensive care unit . PATIENTS: Children admitted with a clinical diagnosis of meningococcal disease . INTERVENTIONS: Blood was sampled from children with meningococcal disease . Disease severity was scored using the Glasgow meningococcal septicemia prognostic score and pediatric risk of mortality score . Plasma nitrates and nitrites were measured in stored plasma using the Greiss reaction after conversion of all the nitrate to nitrite . MEASUREMENTS AND MAIN RESULTS: Twenty-two children were studied . In 19, the final diagnosis was meningococcal disease . Of the 19 children with meningococcal disease, 7 had a Glasgow meningococcal septicemia prognostic score of <8 (mild) and 12 had a Glasgow meningococcal septicemia prognostic score > or = 8 (severe) . Three children died, all of these being in the severely affected group . Higher levels of nitrates and nitrites were seen in the more severely affected children (median admission nitrates and nitrites, 27.5 vs . 59.7 nmol/mL; p = 0.063; median peak nitrates and nitrites, 49.9 vs . 114 nmol/mL; p = .01) or those with an increased predicted mortality using pediatric risk of mortality (Spearman's p 0.742; p = .0003) . CONCLUSIONS: Higher levels of nitrates and nitrites are seen in sicker children with meningococcal disease.

Vestn Ross Akad Med Nauk, 1999, (5), 40 - 5
{Human resistance to generalized bacterial infections (exemplified by meningococcal infection)}; Platonov AE; The hierarchical organization of human host defense systems against systemic bacterial infections is considered by using meningococcal disease as a model . The bactericidal action of the complement system is the most potent defense mechanism against meningococci . The antibody-independent alternative pathway of complement activation is more important in infancy . When the specific antibody level increases by natural immunization or vaccination, the antibody-dependent classical pathway of complement activation provides an additional protection . The bactericidal effect of human phagocytes, primarily neutrophils, is mediated partly by the receptors of complement components and immunoglobulins and serves as an additional mechanism of resistance . The relative risk of meningococcal disease may be approximately estimated as 1,000 for the individuals without blood complement bacteriolytic activity, as 80 for those without specific bactericidal antibodies, and as 3 for individuals with ineffective phagocytosis as compared to those with the normal complement system, high levels of bactericidal antibodies, and effective phagocytosis by neutrophils.

Vaccine, 1999 May 14, 17(19), 2377 - 83
Neisseria meningitidis serogroup B outer membrane vesicle vaccine in adults with occupational risk for meningococcal disease; Fischer M et al.; Vaccination provides a safe and effective means of reducing the risk of laboratory-acquired infection due to some Neisseria meningitidis serogroups . However, there is currently no serogroup B meningococcal vaccine licensed for use in the US . We used an investigational N . meningitidis serogroup B outer membrane vesicle (B:15:P1.7,16) vaccine produced by the National Institute of Public Health (NIPH) in Norway to immunize 20 researchers with occupational risk for disease . Three doses of vaccine were administered via intramuscular injection at 8-week intervals . The vaccine produced moderate or severe pain with 19 (33%) of the 58 doses administered . Reactions were similar following first, second and third doses . The number and severity of reactions peaked at 24 h postvaccination and then gradually waned . Of 16 vaccinees with results available from all blood draws, 12 (75%) showed a fourfold or greater rise in serum bactericidal activity (SBA) against the vaccine type-strain following two doses of vaccine, and 15 (94%) responded after three doses . Geometric mean titers increased by more than sixfold following two doses of vaccine when compared with prevaccination levels, and by more than 11-fold following a third dose . There was no significant difference between SBA measured using the vaccinee's own complement versus a donor complement source . The NIPH vaccine elicited an excellent bactericidal response against the vaccine type-strain in researchers with an occupational risk for disease . It may be useful for other laboratory personnel who routinely work with meningococcal strains containing similar outer membrane antigens . These findings reconfirm that the NIPH vaccine is immunogenic in adults and support the validity of using properly screened human donor complement in serum bactericidal assays against serogroup B meningococci.

Vaccine, 1999 May 14, 17(19), 2336 - 45
Outer membrane vesicles from group B meningococci are strongly immunogenic when given intranasally to mice; Dalseg R et al.; Outer membrane vesicles (OMVs) from group B meningococci induced both serum and mucosal antibodies when given as a nasal and rectal vaccine to mice . Cholera toxin (CT) enhanced the antibody responses in serum both after nasal and rectal immunizations, and the mucosal responses after rectal immunizations only . Nasal immunizations, however, were most effective, with mucosal responses which were not dependent on the use of CT . The serum bactericidal activity was similarly not enhanced by CT, indicating that the positive effect of CT on the serum IgG level was not including bactericidal activity . A small nasal booster dose induced antibody responses in serum as far as eight months after intranasal and subcutaneous immunizations, and in saliva after intranasal immunizations . Nasal vaccines may thus be favorably combined with parenteral vaccines.

Clin Diagn Lab Immunol, 1999 Jul, 6(4), 639 - 42
Redesignation of a purported P1.15 subtype-specific meningococcal monoclonal antibody as a P1.19-specific reagent; Wedege E et al.; Two reference monoclonal antibodies against the meningococcal P1.15 subtype PorA, MN3C5C and 2-1-P1.15, showed only partial concordant recognition of meningococcal isolates . Cyanogen bromide cleavage of P1.19,15 PorA, peptide mapping, and sequencing of porA regions demonstrated that 2-1-P1.15 was specific for subtype P1.19, and henceforth it is to be redesignated as 2-1-P1.19.

Mol Microbiol, 1999 Jun, 32(6), 1316 - 32
Type IV pili of pathogenic Neisseriae elicit cortical plaque formation in epithelial cells; Merz AJ et al.; The pathogenic Neisseriae Neisseria meningitidis and Neisseria gonorrhoeae, initiate colonization by attaching to host cells using type IV pili . Subsequent adhesive interactions are mediated through the binding of other bacterial adhesins, in particular the Opa family of outer membrane proteins . Here, we have shown that pilus-mediated adhesion to host cells by either meningococci or gonococci triggers the rapid, localized formation of dramatic cortical plaques in host epithelial cells . Cortical plaques are enriched in both components of the cortical cytoskeleton and a subset of integral membrane proteins . These include: CD44v3, a heparan sulphate proteoglycan that may serve as an Opa receptor; EGFR, a receptor tyrosine kinase; CD44 and ICAM-1, adhesion molecules known to mediate inflammatory responses; f-actin; and ezrin, a component that tethers membrane components to the actin cytoskeleton . Genetic analyses reveal that cortical plaque formation is highly adhesin specific . Both pilE and pilC null mutants fail to induce cortical plaques, indicating that neisserial type IV pili are required for cortical plaque induction . Mutations in pilT, a gene required for pilus-mediated twitching motility, confer a partial defect in cortical plaque formation . In contrast to type IV pili, many other neisserial surface structures are not involved in cortical plaque induction, including Opa, Opc, glycolipid GgO4-binding adhesins, polysialic acid capsule or a particular lipooligosaccharide variant . Furthermore, it is shown that type IV pili allow gonococci to overcome the inhibitory effect of heparin, a soluble receptor analogue, on gonococcal invasion of Chang and A431 epithelial cells . These and other observations strongly suggest that type IV pili play an active role in initiating neisserial infection of the mucosal surface in vivo . The functions of type IV pili and other neisserial adhesins are discussed in the specific context of the mucosal microenvironment, and a multistep model for neisserial colonization of mucosal epithelia is proposed.

Mol Microbiol, 1999 Jun, 32(6), 1133 - 9
Mechanisms of neisserial serum resistance; Vogel U et al.; Pathogenic Neisseria use a variety of mechanisms to survive the bactericidal action of the complement system . Serum resistance is a crucial virulence factor for the development of severe meningococcal disease, meningococcal meningitis and disseminated gonococcal infection . Furthermore, local inflammation at the site of gonococcal infection exposes the bacteria to moderate concentrations of complement factors . We review current concepts of neisserial serum resistance with emphasis on porins and polysaccharides exposed on the neisserial surface and their interaction with components of normal human serum.

Klin Med (Mosk), 1999, 77(2), 32 - 7
{The interconnection between the severity of meningococcal infection and the endotoxicity levels and patient's blood complement}; Platonov AE et al.; Seventy-eight patients with severe systemic meningococcal disease admitted to the Intensive Care Unit of the Second Moscow Hospital for Infectious Diseases were divided into four groups by complications of their disease: patients with refractory septic shock (RSS)--group 1; patients with early septic shock (ESS)--group 2; patients without shock but with severe mental disorders--group 3; patients without any of these complications--group 4 . The LPS concentration in plasma was assessed by chromogenic method . Initial LPS levels in plasma of group 3 or group 4 patients (170 ng/l, median value and 360 ng/l, respectively) were greater than those of healthy donors (LPS < 15 ng/l) . LPS concentration was significantly greater in group 2 (920 ng/l) or group 1 (12,400 ng/l) . LPS levels declined exponentially in all the patients . The half-life was calculated to be 1.4 (+) -0.3 h . In group 2 and 1, respectively, the classical pathway complement activity in patients' serum was 50 and 10% of normal control values . To estimate significant prognostic factors for fatality in our patients, specificity and factor fatality difference of various clinical and laboratory factors were calculated . The cut-off LPS value for development of ESS was 600 ng/l and that for development of RSS and death was 8000 ng/l . For the prediction of fatality using the former cut-off value of LPS, sensitivity was 84% and specificity 100% . Using plasma complement activity (cut-off--15% of normal value) for prediction, sensitivity was 75% and specificity was 100% . Other factors (platelet and WBC count, blood pH, BP, etc.) had lower predictive power . Thus to date plasma endotoxin level and complement activity are the best prognostic factors in meningococcal disease.

Mol Immunol, 1999 Feb, 36(2), 113 - 24
Molecular analysis of the heavy chain of antibodies that recognize the capsular polysaccharide of Neisseria meningitidis in hu-PBMC reconstituted SCID mice and in the immunized human donor; Smithson SL et al.; The severe combined immunodeficient (SCID) mouse model, engrafted with human peripheral blood mononuclear cells (hu-PBMC) has proven to be useful in studying the human immune response . A major limitation of the hu-PBMC-SCID model has been the failure to consistently demonstrate a primary human immune response . Previously we developed a hu-PBMC-SCID mouse model in which we addressed both issues of adequate human lymphocyte engraftment and impaired differentiation . We demonstrated that a primary human immune response to the T-independent (TI-2) meningococcal group C capsular polysaccharide (MCPS) can be obtained in hu-PBMC-SCID mice by the administration of human cytokines . In this study we compared the V(H) sequence of the MCPS response generated by B cells derived from a volunteer in the SCID mouse model to those generated by the donors' B cells in vivo . Human peripheral blood mononuclear cells were recovered from MCPS immunized hu-PBMC-SCID mice and immunized donor . B cells with specificity for MCPS were isolated from these cell preparations using an anti-idiotypic monoclonal antibody which mimics MCPS . Immunoglobulin mRNA was isolated from single cells, amplified by the polymerase chain reaction, cloned and sequenced . We analysed a total of 15 V(H) regions from B cells obtained from SCID mice and a total of 13 V(H) regions from B cells obtained from the immunized donor . The response differed between SCID and in vivo cells, when studied at the genetric level . V, D and J gene usage was markedly different, however canonical structures of the hypervariable loops were conserved . The complementary determining region 3 (CDR3) varied, such that SCID-derived sequences encoded longer CDR3 s than those of the donor . However all CDR3 s were rich in hydrophobic amino acids, most notably tyrosine and tryptophan, a characteristic common to many carbohydrate binding antibodies.

Infect Immun, 1999 Jul, 67(7), 3533 - 41
Identification and characterization of TspA, a major CD4(+) T-cell- and B-cell-stimulating Neisseria-specific antigen; Kizil G et al.; In search for novel T-cell immunogens involved in protection against invasive meningococcal disease, we screened fractionated proteins of Neisseria meningitidis (strain SD, B:15:P1.16) by using peripheral blood mononuclear cells (PBMCs) and specific T-cell lines obtained from normal individuals and patients convalescing from N . meningitidis infection . Proteins of iron-depleted meningococci produced higher PBMC proliferation indices than proteins of iron-replete organisms, indicating that iron-regulated proteins are T-cell immunogens . Insoluble proteins of the iron-depleted cells, which produced better T-cell stimulation than soluble ones, were fractionated by using sodium dodecyl sulfate-polyacrylamide gels and recovered as five fractions (F1 to F5) corresponding to decreasing molecular weight ranges . The proteins were purified (by elution and precipitation) or electroblotted onto nitrocellulose membranes (dissolved and precipitated) before use in further T-cell proliferation assays . One of the fractions (F1), containing high-molecular-mass proteins (>130 kDa), consistently showed the strongest T-cell proliferation responses in all of the T-cell lines examined . F1 proteins were subdivided into four smaller fractions (F1A to F1D) which were reexamined in T-cell proliferation assays, and F1C induced the strongest responses in patients' T-cell lines . Rabbit polyclonal antibodies to F1C components were used to screen a genomic expression library of N . meningitidis . Two major clones (C1 and C24) of recombinant meningococcal DNA were identified and fully sequenced . Sequence analysis showed that C24 (1,874 bp) consisted of a single open reading frame (ORF), which was included in clone C1 (2, 778 bp) . The strong CD4(+) T-cell-stimulating effect of the polypeptide product of this ORF (named TspA) was confirmed, using a patient T-cell line . Immunogenicity for B cells was confirmed by showing that convalescent patients' serum antibodies recognized TspA on Western blots . Additional genetic sequence downstream of C24 was obtained from the meningococcal genomic sequence database (Sanger Centre), enabling the whole gene of 2,761 bp to be reconstructed . The DNA and deduced amino acid sequence data for tspA failed to show significant homology to any known gene, except for a corresponding (uncharacterized) gene in Neisseria gonorrhoeae genome sequences, suggesting that tspA is unique to the genus Neisseria . The DNA and deduced amino acid sequence of the second ORF of clone C1 showed significant homology to gloA, encoding glyoxalase I enzyme, of Salmonella typhimurium and Escherichia coli . Thus, we have identified a novel neisserial protein (TspA) which proved to be a strong CD4(+) T-cell- and B-cell-stimulating immunogen with potential as a possible vaccine candidate.

Res Microbiol, 1999 May, 150(4), 273 - 80
Microevolution through DNA exchange among strains of Neisseria meningitidis isolated during an outbreak in the Czech Republic; Kriz P et al.; Neisseria meningitidis is a highly variable bacterium . Indeed, N . meningitidis is naturally competent for transformation, and horizontal DNA exchange between strains may lead to mosaic genetic loci in N . meningitidis . We studied such an exchange in nature during an epidemic provoked by N . meningitidis . This epidemic started in the Czech Republic in 1993 and the original epidemic clone was shown to have the antigenic formula (serogroup:serotype:serosubtype) C:2a:P1.2,5 . We analysed 145 meningococcal strains isolated in the Czech Republic between 1993 and 1997 using serological and genetic typing methods (multilocus enzyme electrophoresis and polymorphism of pilA and pilD genes) . This analysis showed that genetic exchange between epidemic and endemic strains had occurred . Exchanges involved mostly surface-exposed structures such as the capsule, giving rise to new meningococcal variants . The expansion of these variants should be kept under close surveillance.

J Theor Biol, 1999 Jun 21, 198(4), 497 - 505
A dynamic model of the meningococcal transferrin receptor; Boulton IC et al.; Iron is an essential nutrient for all organisms and consequently, the ability to bind transferrin and sequester iron from his source constitutes a distinct advantage to a blood-borne bacterial pathogen . Levels of free iron are strictly limited in human serum, largely through the action of the iron-binding protein transferrin . The acquisition of trasferrin-iron is coincident with pathogenicity among Neisseria species and a limited number of other pathogens of human and veterinary significance . In Neisseria meningitidis, transferrin binding relies on two co-expressed, outer membrane proteins distinct in aspects of both structure and function . These proteins are independently and simultaneously capable of binding human transferrin and both are required for the optimal uptake of iron from this source . It has been established that transferrin-binding proteins (designated TbpA and TbpB) form a discrete, specific complex which may be composed of a transmembrane species (composed of the TbpA dimer) associated with a single surface-exposed lipoprotein (TbpB) . This more exposed protein is capable of selectively binding iron-saturated transferrin and the receptor complex has ligand-binding properties which are distinct from either of its components . Previous in vivo analyses of N . gonorrhoeae, which utilizes a closely related transferrin-iron uptake system, indicated that this receptor exists in several conformations influenced in part by the presence (or absence) of transferrin.Here we propose a dynamic model of the meningococcal transferrin receptor which is fully consistent with the current data concerning this subject . We suggest that TbpB serves as the initial binding site for iron-saturated transferrin and brings this ligand close to the associated transmembrane dimer, enabling additional binding events and orientating transferrin over the dual TbpA pores . The antagonistic association of these receptor proteins with a single ligand molecule may also induce conformational change in transferrin, thereby favouring the release of iron . As, in vivo, transferrin may have iron in one or both lobes, this dynamic molecular arrangement would enable iron uptake from either iron-binding site . In addition, the predicted molecular dimensions of the putative TbpA dimer and hTf are fully consistent with these proposals . Given the diverse data used in the formulation of this model and the consistent characteristics of transferrin binding among several significant Gram-negative pathogens, we speculate that such receptor-ligand interactions may be, at least in part, conserved between species . Consequently, this model may be applicable to bacteria other than N . meningitidis .

Mol Biol Evol, 1999 Jun, 16(6), 741 - 9
The influence of recombination on the population structure and evolution of the human pathogen Neisseria meningitidis; Holmes EC et al.; The extent to which recombination disrupts the bifurcating treelike phylogeny and clonal structure imposed by binary fission on bacterial populations remains contentious . Here, we address this question with a study of nucleotide sequence data from 107 isolates of the human pathogen Neisseria meningitidis . Gene fragments from 12 house-keeping loci distributed around the meningococcal chromosome were analyzed, showing that (1) identical alleles are disseminated among genetically diverse isolates, with no evidence for linkage disequilibrium; (2) different loci give distinct and incongruent phylogenetic trees; and (3) allele sequences are incompatible with a bifurcating treelike phylogeny at all loci . These observations are consistent with the hypothesis that meningococcal populations comprise organisms assembled from a common gene pool, with alleles and allele fragments spreading independently, together with the occasional importation of genetic material from other species . Further, they support the view that recombination is an important genetic mechanism in the generation new meningococcal clones and alleles . Consequently, for anything other than the short-term evolution of this species, a bifurcating treelike phylogeny is not an appropriate model.

Ned Tijdschr Geneeskd, 1999 May 22, 143(21), 1073 - 7
{Multiple amputations due to sepsis: however, functional rehabilitation is possible}; Hacking HG et al.; Three patients had several major amputations because of disseminated intravascular coagulation accompanying purpura fulminans . A 31-year-old woman underwent a transfemoral amputation after a septic shock caused by haemolytic streptococcus A, which led to gangrene . A 57-year-old woman had a bilateral transtibial amputation after pneumococcaemia, and the third patient, a 37-year-old woman, underwent a quadruple amputation following a meningococcal septic shock . The amputations were accompanied by contractures and skin damage due to ischaemic tissue changes . Additionally, cerebral and peripheral nerve dysfunction occurred . An intensive rehabilitation programme led to completely independent functioning with the use of orthotics and prosthetics . By starting a multidisciplinary approach as early as possible impairments can be treated properly and future disabilities minimized.

Mol Microbiol, 1999 Jun, 32(5), 977 - 89
Phase variation of HpuAB and HmbR, two distinct haemoglobin receptors of Neisseria meningitidis DNM2; Lewis LA et al.; We have previously described HpuAB, a two-component receptor that mediates binding to haemoglobin (Hb), haemoglobin-haptoglobin (Hb-Hp) and apo-haptoglobin (Hp) . In this communication, we constructed non-polar mutations in the hpuA and hpuB loci to examine the individual roles of HpuA and HpuB . Our results indicate that both HpuA and HpuB are required for the acquisition of Fe from Hb and Hb-Hp . We isolated Hb utilization-positive (Hb+) variants of our Hb utilization-negative (Hb-) hpu mutants at a frequency of 10(-3) and demonstrated that the Hb+ phenotype resulted from the expression of a second Hb receptor, HmbR . Expression of HmbR in DNM2 was found to be controlled by translational frameshifting involving a polyguanine (G) tract located within the hmbR locus . The hpuA locus also contains a poly(G) tract, which suggested that meningococci could phase vary each Hb receptor independently by slip-strand mispairing in the poly(G) tracts found in hpuA and hmbR . Thus, we isolated a naturally occurring Hb- variant of DNM2, designated DNM2 Hb-, which did not express either HpuAB or HmbR . Hb+ variants of DNM2Hb- were selected and examined for HpuAB and HmbR expression . In each instance, acquisition of HpuAB or HmbR expression was correlated with phase variation in the poly(G) tract of each Hb receptor.

Mol Microbiol, 1999 Jun, 32(5), 942 - 52
Multiple lysophosphatidic acid acyltransferases in Neisseria meningitidis; Shih GC et al.; Lysophosphatidic acid (LPA) and phosphatidic acid (PA) are critical phospholipid intermediates in the biosynthesis of cell membranes . In Escherichia coli, LPA acyltransferase (1-acyl-sn-glycerol-3-phosphate acyltransferase; EC 2.3.1.51) catalyses the transfer of an acyl chain from either acyl-coenzyme A or acyl-acyl carrier protein onto LPA to produce PA . While E . coli possesses one essential LPA acyltransferase (PlsC), Neisseria meningitidis possesses at least two LPA acyltransferases . This study describes the identification and characterization of nlaB (neisserial LPA acyltransferase B), the second LPA acyltransferase identified in N . meningitidis . The gene was located downstream of the Tn916 insertion in N . meningitidis mutant 469 and differed in nucleotide and predicted amino acid sequence from the previously characterized neisserial LPA acyltransferase homologue nlaA . NlaB has specific LPA acyltransferase activity, as demonstrated by complementation of an E . coli plsC(Ts) mutant in trans, by decreased levels of LPA acyltransferase activity in nlaB mutants and by lack of complementation of E . coli plsB26,X50, a mutant defective in the first acyltransferase step in phospholipid biosynthesis . Meningococcal nlaA mutants accumulated LPA and demonstrated alterations in membrane phospholipid composition, yet retained LPA acyltransferase activity . In contrast, meningococcal nlaB mutants exhibited decreased LPA acyltransferase activity, but did not accumulate LPA or display any other observable membrane changes . We propose that N . meningitidis possesses at least two LPA acyltransferases to provide for the production of a greater diversity of membrane phospholipids.

Klin Med (Mosk), 1999, 77(4), 32 - 8
{Prognosis in meningococcal disease: methodology and practice}; Platonov AE et al.; 78 patients with systemic meningococcal disease admitted to the Intensive Care Unit of the 2nd Moscow Hospital for Infectious Diseases were studied and the composite prognostic score was developed to estimate the risk of lethal outcome . The stepwise variable selection procedure for the multiple logistic regression was applied to 30 potential clinical and laboratory risk factors and markers . Five factors were selected for the score, namely the platelet count (< 150 x 10(6)/ml), the presence of hemorrhages into the eye or mucosal tissue, the interval from the last urination before admission (> 4 h), the respiration rate (> 170% of age-adjusted normal value) and age (< 2 or > 65 years) with regression coefficients 0.3, 0.2, 0.2 and 0.1, respectively . Both for the source clinical group and for the additional test group (64 patients), the scale was able to classify correctly 95% of cases using the data collected at admission . Ten prognostic scores proposed previously by foreign investigators were tested in the same patients and the best four scores were selected (GMSPS, Gedde-Dahl, Niklasson, Kahn); the scores classified correctly 85-90% of cases . This study is an example of methodological approaches to prognostic score construction in medicine.

J Accid Emerg Med, 1999 May, 16(3), 227 - 9
Abdominal pain as an atypical presentation of meningococcaemia; Winrow AP; An atypical presentation of meningococcaemia without purpura poses diagnostic problems . The importance of the identification of shock manifest as delayed capillary refill in two children with meningococcal septicaemia presenting with fever and abdominal pain is discussed . Abdominal pain is an unusual presentation of meningococcal disease.

JAMA, 1999 May 26, 281(20), 1906 - 10
Risk of meningococcal infection in college students; Harrison LH et al.; CONTEXT: The number of meningococcal outbreaks on college campuses have been increasing in the past few years . However, no published studies have documented the incidence of invasive meningococcal infection in college students or whether the incidence is higher than in the general population of the same age . OBJECTIVE: To compare the incidence of invasive meningococcal infection in Maryland college students with that of the general population of the same age . DESIGN: Retrospective cohort study . SETTING AND PATIENTS: Maryland residents with meningococcal infection from 1992-1997 identified from active, laboratory-based, statewide surveillance for invasive meningococcal disease . MAIN OUTCOME MEASURES: Incidence of invasive meningococcal infection . RESULTS: Of 228 patients with invasive meningococcal infection, 67 were aged 16 to 30 years; 11 and 3 of these attended Maryland 4- and 2-year colleges, respectively . Of these, 12 (86%) had infection caused by Neisseria meningitidis serogroups included in the current meningococcal vaccine . The average annual incidence was 1.74 per 100000 among students in 4-year schools vs 1.44 per 100000 for the general population of the same age (P=.60) . Among students in 4-year schools, the incidence was 3.24 per 100000 in on-campus residents vs 0.96 per 100000 in off-campus residents (relative risk, 3.4; 95% confidence interval, 1.0-11.6; P=.05) . CONCLUSIONS: The incidence of meningococcal infection in college students is similar to the incidence in the general population of the same age, but college students residing on campus appear to be at higher risk than those residing off campus.

S Afr Med J, 1999 Apr, 89(4), 411 - 5
An outbreak of meningococcal meningitis in Gauteng, Spring 1996; Balfour TM et al.; OBJECTIVE: To describe a Neisseria meningitidis outbreak in Gauteng during the period 1 July to 31 December 1996 . DESIGN: A descriptive study . SETTING: Patients with meningococcal meningitis in Gauteng who had been diagnosed by laboratory means, or notified during the period 1 July to 31 December 1996 . MAIN OUTCOME MEASURES: Data including age, sex, date of admission to hospital, N . meningitidis serogroup and outcome were collected from Gauteng notification lists, South African Institute of Medical Research (SAIMR) records, a linelist compiled by the Gauteng Health Department, and hospital records . RESULTS: A total of 201 patients was studied; of this number 87 (43%) had been notified . Seventy per cent of cases were below 30 years of age and 78% were male . More than half (54%) of the cases were from the West Rand . The case fatality rate for 70 cases of known outcome was 14% . Serotyping of 85 isolates showed that a majority (76%) were serogroup A, with 57% being serogroup A clone I-1 . Serogroup A clone III-1 accounted for 14% of the typed isolates . All isolates were sensitive to penicillin with minimum inhibitory concentrations of < 0.05 microgram/ml . CONCLUSION: In 1996 Gauteng experienced an epidemic of serogroup A meningococcal meningitis . The serotype that caused the majority of cases had been recorded in South Africa before, but serogroup A clone III-1, responsible for epidemics spreading across two continents, was recorded in South Africa for the first time . Notification of cases by health workers was inadequate in this epidemic.

Emerg Infect Dis, 1999 May-Jun, 5(3), 464 - 7
Fulminant meningococcal supraglottitis: An emerging infectious syndrome?
Schwam E, Cox J.
We report a case of fulminant supraglottitis with dramatic external cervical swelling due to associated cellulitis . Blood cultures were positive for Neisseria meningitidis . The patient recovered completely after emergency fiberoptic intubation and appropriate antibiotic therapy . We summarize five other cases of meningococcal supraglottitis, all reported since 1995, and discuss possible pathophysiologic mechanisms.

FEMS Immunol Med Microbiol, 1999 May, 24(1), 73 - 8
Detection of IgG and IgM to meningococcal outer membrane proteins in relation to carriage of Neisseria meningitidis or Neisseria lactamica; Kremastinou J et al.; Carriage of non-serogroupable Neisseria meningitidis or Neisseria lactamica induces antibodies protective against meningococcal disease . Antibodies directed against outer membrane proteins are bactericidal and the serotype and subtype outer membrane protein antigens are being examined for their value as vaccine candidates for serogroup B disease . The aim of this study was to examine the effect of carriage of these two Neisseria species among children and young adults on induction of antibodies to outer membrane components from strains causing disease in Greece . Among 53 patients with meningococcal disease, IgG or IgM antibodies were detected by ELISA in 9 of 13 (69%) from whom the bacteria were isolated and 27 of 40 (67%) who were culture-negative . For military recruits (n = 604), the proportion of carriers of meningococci with IgM or IgG to outer membrane proteins was higher than non-carriers, P < 0.05 and P = 0.000000, respectively . Among school children (n = 319), the proportion with IgM or IgG to outer membrane proteins for carriers of meningococci was higher compared with non-carriers, P = 0.000000 and P = 0000043, respectively . Carriage of N . lactamica was not associated with the presence of either IgM or IgG to the outer membrane proteins in the children . The higher proportion of children (50%) with IgM to outer membrane proteins compared with recruits (10%) might reflect more recent exposure and primary immune responses to the bacteria . The lack of association between antibodies to outer membrane proteins and carriage of N . lactamica could reflect observations that the majority of N . lactamica isolates from Greece and other countries do not react with monoclonal typing reagents . Bactericidal antibodies to meningococci associated with high levels of IgG to N . lactamica were found in a previous study; these are thought to be directed to antigens other than outer membrane proteins or capsules and imply antigens such as lipo-oligosaccharide are involved in induction of antibodies cross-reactive with meningococci.

N Z Med J, 1999 Apr 23, 112(1086), 134 - 6
Meningococcal disease and meningitis: a review of deaths proceeding to coroner directed autopsy in Auckland; John SM et al.; AIMS: To assist the early diagnosis of meningitis, by finding trends and patient profiles, where delay or other factors may have lead to a fatal outcome . METHODS: All deaths from meningitis and meningococcal disease, confirmed at autopsy were reviewed . The study involved the Auckland area, in the period January 1988 November 1997 . RESULTS: Cases were divided into those caused by N meningitidis and other meningitides . Death due to N meningitidis is often within 12-24 hours of the first symptomatology . Symptoms are often vague and may be indistinguishable from any other infection, often leading to fatal patient or doctor delay . A diagnosis of meningococcal disease cannot be excluded on: no rash (44%), no "meningitis" symptoms as sepsis without meningitis occurs (44%), age (50% were over 15 years old) or the presence of other abnormalities, eg bronchopneumonia or hydrocephalus . Non-N meningitidis menigitis is a disease of the very young or old, its time course is also swift with 30% suffering similar vague symptoms for less than 24 hours before death . CONCLUSIONS: For both categories, treat immediately and treat on suspicion, otherwise conformation of the diagnosis might be postmortem.

Infect Immun, 1999 Jun, 67(6), 3082 - 6
Coinfection with influenza B virus does not affect association of Neisseria meningitidis with human nasopharyngeal mucosa in organ culture; Read RC et al.; There is an epidemiological association between influenza virus infection and meningococcal disease . Proposed mechanisms are the destruction of the normal epithelial barrier function of the upper respiratory tract by influenza virus or the expression of human or viral surface-exposed proteins that enhance bacterial adherence and/or invasion . To test these hypotheses, human nasopharyngeal mucosa specimens from a total of 19 individual donors were successfully infected with influenza B virus and then inoculated with serogroup B Neisseria meningitidis . Subsequent bacterial association with the epithelial surface was measured in three separate series of experiments by using transmission electron microscopy (n = 6), scanning electron microscopy (n = 6), and counting of viable bacteria within homogenates of explants (n = 7) . Penetration of the mucosa was estimated by measuring the count of viable bacteria recovered from explants after exposure to sodium taurocholate . Bacterial association with the surface of explants was time dependent over 24 h of superinfection . Influenza virus did not positively or negatively influence bacterial attachment to or penetration of explant mucosa compared to those of uninfected controls, even when the period of preincubation with virus was extended to 7 days . When proteins were purified from mucosal epithelium and immobilized on nitrocellulose membranes, N . meningitidis attached predominantly to bands corresponding to proteins of 210 and 130 kDa . In the presence of influenza virus infection, these proteins were gradually lost over the course of 72 h . In conclusion, influenza B virus did not increase association of serogroup B N . meningitidis with human nasopharyngeal mucosa.

Infect Immun, 1999 Jun, 67(6), 2928 - 34
Deletion of porA by recombination between clusters of repetitive extragenic palindromic sequences in Neisseria meningitidis; van der Ende A et al.; PorA is an important component in a vaccine against infection with Neisseria meningitidis . However, porA-negative meningococci were isolated from patients, thereby potentially limiting the role of PorA-mediated immunity . To analyze the mechanism by which the porA deletion occurred, the regions upstream and downstream of porA from three meningococcal strains (H44/76, H355, and 860183) were sequenced . The porA upstream region in strain 860183 contains a cluster of 22 repetitive palindromic RS3 core sequences (ATTCCC-N8-GGGAAT) and 10 RS3 core sequences (ATTCCC) in direct orientation . The cluster is flanked by neisserial repeats, so-called Correia elements, and can be subdivided into three repeats of 518 bp followed by a truncated repeat . The porA upstream region of the other two strains showed deletions, probably caused by a recombination between RS3 core sequences . The porA downstream region of H44/76 and H355 contains the IS1106 element followed by a cluster of 10 palindromic RS3 core sequences, 4 RS3 core sequences, and 1 other RS3 core sequence (GGGAAT) and is followed by a Correia element . This cluster can be subdivided into four direct repeats of 370 bp . Strain 860183 had two such repeats instead of four . Sequence analysis of the porA-negative variants indicated that the deletion of porA occurred via a recombination between two copies of the 116-bp region, containing two palindromic RS3 core sequences and a single RS3 core sequence . This region is homologous in the upstream and downstream clusters.

Infect Immun, 1999 Jun, 67(6), 2855 - 61
Antigenic and molecular conservation of the gonococcal NspA protein; Plante M et al.; A low-molecular-weight protein named NspA (neisserial surface protein A) was recently identified in the outer membrane of all Neisseria meningitidis strains tested . Antibodies directed against this protein were shown to protect mice against an experimental meningococcal infection . Hybridization experiments clearly demonstrated that the nspA gene was also present in the genomes of the 15 Neisseria gonorrhoeae strains tested . Cloning and sequencing of the nspA gene of N . gonorrhoeae B2 revealed an open reading frame of 525 nucleotides coding for a polypeptide of 174 amino acid residues, with a calculated molecular weight of 18,316 and a pI of 10.21 . Comparison of the predicted amino acid sequence of the NspA polypeptides from the gonococcal strains B2 and FA1090, together with that of the meningococcal strain 608B, revealed an identity of 93%, suggesting that the NspA protein is highly conserved among pathogenic Neisseria strains . The level of identity rose to 98% when only the two gonococcal predicted NspA polypeptides were compared . To evaluate the level of antigenic conservation of the gonococcal NspA protein, monoclonal antibodies (MAbs) were generated . Four of the seven NspA-specific MAbs described in this report recognized their corresponding epitope in 100% of the 51 N . gonorrhoeae strains tested . Radioimmunobinding assays clearly indicated that the gonococcal NspA protein is exposed at the surface of intact cells.

Hum Exp Toxicol, 1999 Apr, 18(4), 202 - 5
Passive smoking, sudden infant death syndrome (SIDS) and childhood infections; Dybing E et al.; 1 . A number of cohort and case-control studies have shown clear, dose-related associations between maternal smoking and infant death . The strongest relationships were found when the mother smoked during pregnancy as well as postnatally . Maternal smoking during pregnancy increases the risk for SIDS in most studies, whereas it appears that maternal smoking only postnatally also leads to an increase in risk . In addition, smoking only by the father appears to increase the risk for SIDS, but this is not seen in all studies . 2 . Exposure of children to environmental tobacco smoke (ETS) increases the risk of having night cough and respiratory infections (bronchitis, bronchiolitis, pneumonia), especially during the first 2 years of life . An increased risk is also seen in studies not distinguishing between upper and lower respiratory diagnoses . Long-term breastfeeding may have a protective effect on ETS-increased risk of lower respiratory tract illness . One study of older children reports that ETS combined with allergy increased the risk of acute respiratory tract infections above that due to ETS alone . 3 . The number of new episodes and duration of otitis media with effusion in young children is positively correlated with ETS exposure . Especially infants with lower birth weights had a high risk of recurrent otitis media during the first year of life when the mother was a heavy smoker . 4 . Passive smoking has been reported as a risk factor in meningococcal disease and tuberculosis in young children.

Arch Dis Child, 1999 Mar, 80(3), 290 - 6
Emergency management of meningococcal disease; Pollard AJ et al.; Meningococcal disease remains a major cause of mortality in children in the UK . Aggressive early volume resuscitation, meticulous attention to the normalisation of all physiological and laboratory parameters, and prompt referral to specialist paediatric intensive care may lead to a sharp reduction in mortality . Application of the management algorithm described in this article may be helpful to those involved in the early part of management of critically ill patients with meningococcal disease.

N Z Med J, 1999 Apr 9, 112(1085), 115 - 7
Meningococcal disease in Auckland, July 1992 - June 1994; Jefferies C et al.; AIMS: To assess two years of meningococcal disease in the Auckland area, the outcomes and management issues, and the specific socio-geographic groups that are affected . METHODS: Using the nationally agreed case definition, a retrospective chart review was undertaken . Case finding was through the National surveillance system at ESR, backed by hospital laboratory and coroner case findings . RESULTS: There were 106 cases of meningococcal disease, both adult and paediatric, from July 1992 to June 1994 . Group B (n=61), was predominant throughout this period especially in the winter months . There were two main age groups most affected . The first, and most striking, was in Maori and New Zealand Pacific Island children younger than five years, with rates of 52.6 and 54.2/100,000 respectively . The second peak was in European, and to a lesser extent Maori, 15-24 year-olds, (rates 11.7 and 8.5/100,000, respectively) . The annual incidence was 5.6/100,000 with an overall case fatality rate of 6.6%, (n=7) . South Auckland had the greatest proportion of cases with 42/106 . Two-thirds of the cases were referred for hospital admission by a general practitioner . From both general practitioner and self-referred groups, two-thirds had a petechial/purpuric rash on arrival at hospital . For general practitioner referred cases, 24 received parenteral antibiotics on referral, and from these cases there was one death, (1/24) . Those not treated with antibiotics (general practitioner or self-referred) had a mortality of 2/41 . There were 31 cases of paediatric meningococcal meningitis . Nineteen cases had dexamethasone in appropriate dose and timing; no hearing loss occurred in the 17 cases that survived (0/17), compared to 2/12 not treated with dexamethasone . This compares to a published rate of 5-7% . CONCLUSIONS: Meningococcal disease, predominantly serogroup B, is of high incidence in Auckland . The highest rates of disease are occurring in the under five-year-olds, where an effective group B vaccine is awaited . The benefit of dexamethasone is suggestive . There was no clear benefit in outcome by pre-treatment with parenteral antibiotics for paediatric meningococcal disease though no suggestive detrimental effect either.

Arch Dis Child, 1999 Jan, 80(1), 74 - 6
Endothelial cell adhesion molecules in meningococcal disease; Baines PB et al.; BACKGROUND: Endothelial damage is important in meningococcal disease . Cell adhesion molecules, including P selectin, E selectin, and intercellular cell adhesion molecule 1 (ICAM-1), are expressed by activated endothelium and then subsequently shed . METHODS: ICAM-1, P selectin, and E selectin were measured on admission to hospital in children with meningococcal infections . RESULTS: Concentrations of shed cell adhesion molecules are reported for 78 children . Eleven did not have meningococcal disease . Of the 67 with meningococcal disease, 40 had mild disease (Glasgow meningococcal septicaemia prognostic score (GMSPS) < 8) and 27 had severe disease (GMSPS > or = 8) . E selectin and ICAM-1 values were higher in those with meningococcal disease . The E selectin values in those with severe disease were higher than in those with mild disease . P selectin concentrations were not altered in meningococcal disease, but those who died had lower concentrations . CONCLUSIONS: Endothelial activation in meningococcal disease is reflected by shed ICAM-1 and E selectin concentrations.

J Clin Microbiol, 1999 Jun, 37(6), 1797 - 801
Ultrasound-enhanced latex immunoagglutination and PCR as complementary methods for non-culture-based confirmation of meningococcal disease; Gray SJ et al.; Preadmission administration of antibiotics to patients with suspected meningococcal infection has decreased the likelihood of obtaining an isolate and has stimulated development of rapid and reliable non-culture-based diagnostic methods . The sensitivity of the conventional test card latex agglutination test (TCLAT) for detection of capsular polysaccharide has been reported to be suboptimal . In the United Kingdom meningococcal DNA detection by PCR has become readily available and is now used as a first-line investigation . Recently, the performance of latex antigen detection has been markedly improved by ultrasound enhancement . Three tests for laboratory confirmation of meningococcal infection, (i) PCR assays, (ii) TCLAT, and (iii) ultrasound-enhanced latex agglutination test (USELAT), were compared in a retrospective study of 125 specimens (serum, plasma, and cerebrospinal fluid specimens) from 90 patients in whom meningococcal disease was suspected on clinical grounds . Samples were from patients with (i) culture-confirmed meningococcal disease, (ii) culture-negative but PCR-confirmed meningococcal disease, and (iii) clinically suspected but non-laboratory-confirmed meningococcal disease . USELAT was found to be nearly five times more sensitive than TCLAT . Serogroup characterization was obtained by both PCR and USELAT for 44 samples; all results were concordant and agreed with the serogroups determined for the isolates when the serogroups were available . For 12 samples negative by USELAT, the serogroup was determined by PCR; however, for 12 other specimens for which PCR had failed to indicate the serogroup, USELAT gave a result . USELAT is a rapid, low-cost method which can confirm a diagnosis, identify serogroups, and guide appropriate management of meningococcal disease contacts . A complementary non-culture-based confirmation strategy of USELAT for local use supported by a centralized PCR assay service for detection of meningococci would give the benefits of timely information and improved epidemiological data.

J Public Health Med, 1999 Mar, 21(1), 8 - 13
Should we be doing more to prevent Group C meningococcal infection in school age children? How can we decide?
Round A, Palmer S.
Meningococcal Group C infections are potentially preventable by vaccination in most cases . Population immunization has not been adopted because the disease is rare and the vaccine effective for only about three years . However, the recent rise in cases in school age children has prompted an assessment of the cost-effectiveness of alternative strategies for management of a case of Group C infection . Chemoprophylaxis and vaccination of close contacts is the most cost-effective strategy but will prevent relatively few cases . Population vaccination prevents considerably more cases, but at a much higher total and marginal cost . An intermediate strategy of giving antibiotics to and vaccinating the school population following a single case, in addition to contact tracing, has intermediate cost-effectiveness . Policy decisions will take into account other important factors but the approach we have taken makes explicit key assumptions so that wider debate including profession and public can be developed.

FEMS Microbiol Lett, 1999 May 1, 174(1), 191 - 9
Characterisation of the lpdA gene from Neisseria meningitidis by polymerase chain reaction, restriction fragment length polymorphism and sequencing; Silva R et al.; P64k protein from Neisseria meningitidis is well recognised in sera from individuals convalescent from meningococcal disease or vaccinated with the Cuban antimeningococcal vaccine VA-MENGOC-BC . The presence of the protein in more than 80 meningococcal strains has also been verified . It is immunogenic in animal models and the antibodies elicited show bactericidal activity against meningococci . To further investigate at the molecular level whether lpdA, the gene coding for P64k protein, is conserved among different N . meningitidis strains, a total of 20 strains isolated from different geographic areas were differentiated on the basis of restriction fragment length polymorphism (RFLP) patterns after polymerase chain reaction (PCR) amplification of the lpdA gene and restriction endonuclease digestion with HpaII . Although a total of five different PCR-RFLP patterns were present, nucleotide sequence determination showed that identity levels were as high as 93-99% among the N . meningitidis strains analysed.

J Paediatr Child Health, 1999 Feb, 35(1), 42 - 8
Invasive meningococcal infection in Western Australia; Olesch CA et al.; OBJECTIVES: To review signs and symptoms in children diagnosed with meningococcal infection; to assess age, sex and race distribution of meningococcal infection; and to assess associations of the presenting features with morbidity and mortality . DESIGN: Retrospective case notes review for a 5-year period . SUBJECTS: 105 patients aged between 19 days and 13 years . MAIN DATA REVIEWED: Temperature, blood pressure, heart rate, respiratory rate, type of rash, age, sex, race and outcome . RESULTS: Of the 105 patients, 67.6% were Caucasian, 27.6% Aboriginal and 4.8% of other origin . There were 14.3% patients under 3 months of age (2.9% neonates), 48.6% between 3 months and 2 years, 21% between 2 and 4 years and 16.2% older than 4 years . The male:female ratio was 1.4 . Features at presentation in decreasing order of frequency were: fever (89.5%), tachypnoea (73.3%), rash (59% {maculopapular 17.1%, petechial 27.6% and purpuric 14.3%}), vomiting (52.4%), irritability (44.8%), tachycardia (37.5%), lethargy (36.2%), neck stiffness (32.4%) and non-specific immediately preceding illness (15.2%) . Purpura and a reduced systolic blood pressure were significantly associated with an increased risk of mortality, purpura and reduced diastolic blood pressure with an increased risk of morbidity . Initial misdiagnosis occurred in 17.1% of cases, with the majority of those misdiagnosed (83.3%) aged less than 2 years . Predominant serotyping was Group B followed by Group C . Major findings were a marked male preponderance in patients under 3 months of age . The incidence of meningococcal infection in the Aboriginal population was approximately six times that in the non-Aboriginal population . The yearly incidence of meningococcal disease during the study period ranged from 5.2 to 10.5 per 100,000 . Long-term morbidity occurred in 8.6% of cases and mortality was 8.6% . Higher morbidity and mortality figures were found in those with septicaemia alone . Children referred from peripheral hospitals had a higher mortality but a comparable morbidity.

Clin Exp Dermatol, 1999 Mar, 24(2), 97 - 8
Erythema nodosum secondary to meningococcal septicaemia; Whitton T et al.; We report a case of erythema nodosum (EN) secondary to Neisseria meningitidis infection in a 77-year-old woman . Histology of two biopsy specimens from two different lesions showed characteristic features of EN . Blood culture showed Neisseria meningitidis group C.

Gene, 1999 Apr 29, 231(1-2), 105 - 10
Sequence variability of the meningococcal lactoferrin-binding protein LbpB; Pettersson A et al.; The lactoferrin receptor of Neisseria meningitidis consists of two proteins, LbpA and LbpB . LbpB is considered a promising vaccine candidate, and therefore its sequence variability was studied . LbpB from five different strains exhibited 70-80% mutual identity at the amino acid level . Most sequence variability was found in two stretches with a high content of negatively charged amino acids . These stretches were sequenced from six additional strains . One of the stretches is of variable length and is missing in some of the strains . The other stretch is present in all strains, but varies considerably in its exact amino acid sequence . The high degree of variability is disadvantageous for vaccine development, but may be useful for epidemiological studies.

Mol Cell, 1999 Apr, 3(4), 435 - 45
Hypermutation in pathogenic bacteria: frequent phase variation in meningococci is a phenotypic trait of a specialized mutator biotype; Bucci C et al.; Expression of serogroup B meningococcal capsular polysaccharide undergoes frequent phase variation involving reversible frameshift mutations within a homopolymeric repeat in the siaD gene . A high rate of phase variation is the consequence of a biochemical defect in methyl-directed mismatch repair . The mutator phenotype is associated to the absence of DNA adenine methyltransferase (Dam) activity in all pathogenic isolates and in 50% of commensal strains . Analysis of the meningococcal dam gene region revealed that in all Dam- strains a gene encoding a putative restriction endonuclease (drg) that cleaves only the methylated DNA sequence 5'-GmeATC-3' replaced the dam gene . Insertional inactivation of the dam and/or drg genes indicated that high rates of phase variation and hypermutator phenotype are caused by absence of a functional dam gene.

Dtsch Med Wochenschr, 1999 Apr 9, 124(14), 424 - 8
{Meningococcal sepsis in 3 young men}; Diet F et al.; HISTORY AND CLINICAL FINDINGS: Three young men became ill one after the other with fever, headaches, vomiting, arthralgias and muscle pain . One day after beginning of symptoms all three patients developed a haemorrhagic rash with petechial and ecchymotic lesions most intense on distal extremities . 24 hours later patient no . 1 and 3 were in septic shock . INVESTIGATIONS: Laboratory tests showed signs of systemic infection, disseminated intravascular coagulation and renal failure . On the day of admission to the hospital blood cultures showed Neisseria meningitidis in patient no . 1 and 3 . In patient no . 2 blood cultures were negative . TREATMENT AND COURSE: Intravenous antibiotic therapy was started immediately after admission . In patient no . 1 and 3 purpura fulminans with multiple organ failure demanded intensive care treatment . Patient no . 1 recovered . Necrotic toes made amputations necessary . Patient no . 2 was never critically ill . Patient no . 3, whose course was complicated by a long lasting disseminated intravascular coagulation, died from massive cerebral bleeding 6 days after admission . Patient no . 2, who was treated with ciprofloxacin after symptoms began was never critically ill . CONCLUSION: Neisseria meningitidis sepsis has a high mortality rate . Rapid admission to the hospital and beginning of an antibiotic therapy with penicillin G or a third-generation cephalosporin is a priority when meningococcal disease is suspected . Chemoprophylaxis should be offered to close contacts of patients.

J Infect Dis, 1999 Jun, 179(6), 1569 - 72
Meningococcal serogroup C conjugate vaccine is immunogenic in infancy and primes for memory; Richmond P et al.; The safety, immunogenicity, and immunologic priming of 2 dosages (2 microgram or 10 microgram) of a meningococcal C oligosaccharide-CRM197 conjugate vaccine was evaluated in 114 infants vaccinated at ages 2, 3, and 4 months . Antibody persistence and response to boosting with 10 microgram of meningococcal C polysaccharide were assessed . The meningococcal conjugate vaccine produced fewer local reactions than concurrent routine immunizations . Total serogroup C-specific immunoglobulin geometric mean concentration (GMC) increased from 0.3 microgram/mL before vaccination to 13.1 microgram/mL at age 5 months . Serum bactericidal antibody (SBA) geometric mean titers (GMTs) rose from <1:4 to 1:1057 at 5 months and fell by 14 months to 1:19 . Following boosting, anti-C-specific immunoglobulin GMC rose to 15.9 microgram/mL and SBA GMT to 1:495 . Antibody responses in the 10-microgram dose cohort were significantly higher at 5 months (P<.01) than in the 2-microgram dose cohort but were lower after polysaccharide boosting (P=.02) . This meningococcal conjugate vaccine was well tolerated and immunogenic and induced immunologic memory in infants.

Acta Paediatr, 1999 Mar, 88(3), 265 - 9
Nasopharyngeal carriage of meningococcus and meningococcal meningitis in Sokoto, Nigeria; Emele FE et al.; In an attempt to determine the epidemiology of meningococcal diseases in Sokoto, Nigeria, nasopharyngeal carriage of meningococcus was studied among the groups at the greatest risk of the disease, i.e . children and young adults . Of 726 subjects sampled, 45 (6.2%) carried meningococcus . Sixteen (35.6%) of the 45 isolates belonged to serogroup B . Others were as follows: group A, 8 (17.8%), C, 5 (11.1%), D, 1 (2.2%) and non-groupable 11 (24.4%) . Clinical cases encountered during the period were caused by serogroups A (5, 62.5%) and C (3, 37.5%) . A male:female carriage ratio of 1.2:1 was recorded for the potential epidemic serogroups, A and C (chi2 = 1.0091; p>0.05), while the clinical case ratio for the genders was 1.8:1 (chi = 16.1619; p<0.001) . The 5-9-y-old age group carried meningococci more frequently (8.5%) than other age brackets, and also registered the highest incidence (46.5%) of the cases . Closeness of contact with a clinical case increased the carriage of the strain of the case (chi2 = 33.3940; p<0.001) . Rural dwellers carried meningococcus more frequently than urban dwellers (chi2 = 9.5591; p<0.05) . The season had no consistent influence on carriage rates, even though it significantly influenced the outbreaks of the disease . Mass vaccination with polysaccharide vaccine and improved living conditions appear to be the most practical ways to control meningococcal diseases in Africa.

Curr Opin Pulm Med, 1999 May, 5(3), 157 - 63
Upper respiratory tract infections; Moore DA et al.; In reviewing recent advances in upper respiratory tract infections, we focus on five key topics . First, the use of ribavirin in the treatment of respiratory syncytial virus infection has been limited to the immunosuppressed . Prophylaxis in high-risk patients with specific immunoglobulin is effective and a new monoclonal antibody shows promise . Second, the efficacy of neuraminidase inhibitors in the treatment of influenza has become established . There are unresolved concerns about early implementation of therapy without a firm diagnosis; resource implications are enormous . Third, an outbreak of influenza due to avian influenza virus (H5N1) raised the possibility of a new pandemic . However, there was minimal person-to-person spread although much was learned about pathogenesis of infection . Fourth, evidence favoring the use of ciprofloxacin rather than rifampicin for meningococcal chemoprophylaxis is reviewed . Efficacy in eradicating nasopharyngeal carriage is excellent . Finally, the management of sore throat has been considered . This remains controversial but evidence supporting antibiotic therapy in adults is lacking . If treatment is indicated in childhood, shorter courses of antibiotics may be effective.

JAMA, 1999 Apr 28, 281(16), 1520 - 7
Immunogenicity of 2 serogroup B outer-membrane protein meningococcal vaccines: a randomized controlled trial in Chile; Tappero JW et al.; CONTEXT: Meningococcal disease occurs worldwide, and serogroup B disease accounts for a large proportion of cases . Although persons younger than 4 years are at greatest risk for serogroup B meningococcal disease, vaccine efficacy has not been demonstrated in this age group . OBJECTIVE: To evaluate serum bactericidal activity (SBA) against homologous vaccine type strains and a heterologous Chilean epidemic strain of Neisseria meningitidis as a potential correlate for vaccine efficacy . DESIGN: Double-blind, randomized controlled trial conducted between March 14 and July 20, 1994 . All blood samples were taken by December 1994 . SETTING: Santiago, Chile, where a clonal serogroup B meningococcal disease epidemic began in 1993 . PARTICIPANTS: Infants younger than 1 year (n = 187), children aged 2 to 4 years (n = 183), and adults aged 17 to 30 years (n = 173) . INTERVENTION: Participants received 3 doses of outer-membrane protein (OMP) meningococcal vaccine developed in either Cuba or Norway or a control vaccine, with each dose given 2 months apart . Blood samples were obtained at baseline, prior to dose 3, and at 4 to 6 weeks after dose 3 . MAIN OUTCOME MEASURE: Immune response, defined as a 4-fold or greater rise in SBA titer 4 to 6 weeks after dose 3 compared with prevaccination titer . RESULTS: Children and adult recipients of either meningococcal vaccine were more likely than controls to develop an immune response to the heterologous epidemic strain . After 3 doses of vaccine, 31% to 35% of children responded to the vaccine vs 5% to placebo; 37% to 60% of adults responded to vaccine vs 4% to placebo (P<.05 vs control for all) . Infants, however, did not respond . In contrast, against homologous vaccine type strains, the response rate was 67% or higher among children and adults and 90% or higher among infants (P<.001 vs control for all) . Subsequent SBA against 7 isogenic homologous target strains identified class 1 OMP as the immunodominant antigen . CONCLUSIONS: These data suggest that neither serogroup B OMP meningococcal vaccine would confer protection during a heterologous epidemic . However, epidemic strain-specific vaccines homologous for class 1 OMP are promising candidates for the control of epidemic serogroup B meningococcal disease.

JAMA, 1999 Apr 28, 281(16), 1493 - 7
Epidemic serogroup B meningococcal disease in Oregon: the evolving epidemiology of the ET-5 strain; Diermayer M et al.; CONTEXT: In 1993, Oregon's incidence of serogroup B meningococcal disease began to rise because of a highly clonal group of strains designated enzyme type 5 (ET-5), the first such increase observed in the United States . OBJECTIVE: To evaluate the impact that the ET-5 strain has had on the epidemiology of meningococcal disease in Oregon . DESIGN AND SETTING: Epidemiologic analysis of surveillance data on Oregon meningococcal disease cases from 1987 through 1996 and multilocus enzyme electrophoresis typing of serogroup B isolates from June 1993 through April 1995 and from April through June 1996 . PATIENTS: A total of 836 persons with invasive meningococcal disease . MAIN OUTCOME MEASURES: Disease frequency and clonality of strains . RESULTS: Serogroup B disease incidence rates more than doubled from the preepidemic period in 1987-1992 (1.0 case per 100000 population) to the recent epidemic period in 1995-1996 (2.2 cases per 100000) . The age-specific incidence rate of serogroup B disease among those 15 through 19 years old increased 13-fold between the preepidemic period (0.5 case per 100000) and 1995-1996 (6.4 cases per 100000) . However, the proportion of cases with meningococcemia and the case-fatality rate did not change . Of 99 Neisseria meningitidis isolates obtained from 1993-1995, 88 (89%) belonged to the ET-5 complex . Of these, 69 (78%) were a single clone, designated 301 . Of 20 serogroup B isolates from 1996, 18 (90%) belonged to the ET-5 complex; 17 (94%) were the 301 clone . CONCLUSION: Serogroup B meningococcal disease incidence continues at high levels in Oregon with increasing predominance of the ET-5 clonal strains.

Infect Immun, 1999 May, 67(5), 2552 - 60
Human opsonins induced during meningococcal disease recognize outer membrane proteins PorA and PorB; Lehmann AK et al.; Human opsonins directed against specific meningococcal outer membrane structures in sera obtained during meningococcal disease were quantified with a recently developed antigen-specific, opsonin-dependent phagocytosis and oxidative burst assay . Outer membrane vesicles (OMVs) and PorA (class 1) and PorB (class 3) proteins purified from mutants of the same strain (44/76; B:15:P1.7 . 16) were adsorbed to fluorescent beads, opsonized with acute- and convalescent-phase sera from 40 patients with meningococcal disease, and exposed to human leukocytes . Flow cytometric quantitation of the resulting leukocyte phagocytosis products (PPs) demonstrated that disease-induced serum opsonins recognized meningococcal OMV components and both porins . The PPPorA and PPPorB values induced by convalescent-phase sera correlated positively with the PPOMV values . However, the PPPorB values were higher than the PPPorA values in convalescent-phase sera (medians {ranges} of 754 {17 to 1,057} and 107 {4 to 458}, respectively) (P < 0.0001) and correlated positively with higher levels of immunoglobulin G against PorB than against PorA as evaluated by enzyme-linked immunosorbent assay . Extensive individual variations in the anti-OMV and antiporin serum opsonic activities between patients infected by serotypes and serosubtypes homologous and heterologous to the target antigens were observed . Simultaneously measured oxidative burst activity correlated with the opsonophagocytosis, an indication that both of these important steps in the in vitro phagocytic elimination of meningococci are initiated by opsonins directed against OMV components, including PorA and PorB . In conclusion, human patient opsonins against meningococcal OMV components and in particular PorB epitopes were identified by this new method, which might facilitate selection of opsonin-inducing meningococcal antigens for inclusion in future vaccines.

Infect Immun, 1999 May, 67(5), 2452 - 63
Cellular immune responses to Neisseria meningitidis in children; Pollard AJ et al.; There is an urgent need for effective vaccines against serogroup B Neisseria meningitidis . Current experimental vaccines based on the outer membrane proteins (OMPs) of this organism provide a measure of protection in older children but have been ineffective in infants . We postulated that the inability of OMP vaccines to protect infants might be due to age-dependent defects in cellular immunity . We measured proliferation and in vitro production of gamma interferon (IFN-gamma), tumor necrosis factor alpha, and interleukin-10 (IL-10) in response to meningococcal antigens by peripheral blood mononuclear cells (PBMCs) from children convalescing from meningococcal disease and from controls . After meningococcal infection, the balance of cytokine production by PBMCs from the youngest children was skewed towards a TH1 response (low IL-10/IFN-gamma ratio), while older children produced more TH2 cytokine (higher IL-10/IFN-gamma ratio) . There was a trend to higher proliferative responses by PBMCs from older children . These responses were not influenced by the presence or subtype of class 1 (PorA) OMP or by the presence of class 2/3 (PorB) or class 4 OMP . Even young infants might be expected to develop adequate cellular immune responses to serogroup B N . meningitidis vaccines if a vaccine preparation can be formulated to mimic the immune stimulus of invasive disease, which may include stimulation of TH2 cytokine production.

Infect Immun, 1999 May, 67(5), 2441 - 51
Humoral immune responses to Neisseria meningitidis in children; Pollard AJ et al.; An understanding of the nature of immunity to serogroup B meningococci in childhood is necessary in order to establish the reasons for poor responses to candidate vaccines in infancy . We sought to examine the nature of humoral immune responses following infection in relation to age . Serum bactericidal activity was poor in children under 12 months of age despite recent infection with Neisseria meningitidis . The highest levels of bactericidal activity were seen in children over 10 years of age . However, infants produced levels of total immunoglobulin G (IgG) and IgG subclass antibodies similar to those in older children in a meningococcal enzyme-linked immunosorbent assay . Most antibody was of the IgG1 and IgG3 subclasses . This striking age dependency of bactericidal antibody response following infection is not apparently due to failure of class switching in infants but might be due to qualitative differences in antibody specificity or affinity.

Prehosp Emerg Care, 1999 Apr-Jun, 3(2), 102 - 6
Use of EMS for seriously ill children in the office: a survey of primary care physicians; Davis CO et al.; OBJECTIVES: To describe how primary care physicians (PCPs) transport seriously ill children from their offices to emergency departments (EDs) . METHODS: The authors conducted a mail survey of PCPs in upstate New York . RESULTS: The response rate was 60% (119/199) . Sixty-six percent (79/119) of the physicians had transferred at least one child from their office to an ED via EMS . Forty-five percent (53/119) had encountered a case of suspected epiglottitis in the office . EMS was used to send 45% (24/53) of suspected epiglottitis cases to the ED, while 40% (21/53) transferred children with possible epiglottitis via family auto . Similarly, the family's auto was used to transport 26% (6/23) of the patients with suspected foreign body aspiration, 46% (32/70) with severe asthma, 59% (30/51) with severe dehydration, and 37% (14/38) with suspected meningococcemia . In contrast, the family's auto was never used for patients with active seizures . The physicians denied that they would call EMS more often if transport time were shorter (58%) or if costs were less (64%) . Sixty percent of the PCPs were not sure whether EMS personnel are skilled in pediatric emergencies . CONCLUSION: The PCPs often failed to call EMS for seriously ill children seen in the office and, instead, used the family's auto for emergency transportation . In this survey, transport time and cost were not barriers to use of EMS . The physicians expressed a lack of confidence in EMS providers' pediatric skills . Targeting educational programs to PCPs that highlight 1) the availability, training, and skill of EMS personnel and 2) the medicolegal risks of family transportation may result in more appropriate use of EMS for children.

Scand J Infect Dis, 1998, 30(6), 636 - 8
Adverse events after polysaccharide meningococcal A&C vaccine; Diez-Domingo J et al.; The incidence of adverse events due to meningococcal polysaccharide A&C vaccine was studied in 312 subjects 18 months to 20 y of age who were part of a mass vaccination program . Fever > 38 degrees C occurred in 5.1% (95% CI: 3.1-8.4%) . Injection site pain was reported in 78.8% (95% CI: 74.3-83.4%), was severe in 7.4% (95% CI: 4.7-10.9%) and was most frequent in the oldest age group.

Scand J Infect Dis, 1998, 30(6), 629 - 30
Acute abdomen as an atypical presentation of meningococcal septicaemia; Schmid ML; The clinical manifestations and course of meningococcal disease have been well described, but atypical presentations may, if unrecognized, lead to a delay in treatment . We describe here an unusual case of this disease in a 21-y-old woman who presented with an acute rigid abdomen, clinical and laboratory features of sepsis, shock and early DIC with no indication of meningococcal infection . She developed a rapidly spreading purpuric rash, conjunctival haemorrhages, hypotension and tachycardia and a low urine output . Laboratory investigations showed a low platelet count, low haemoglobin and normal WBC . A presumptive diagnosis of meningococcal septicaemia was made and recovery followed treatment with cefotaxime, fluids and inotropes . A fully sensitive Neisseria meningitis Group C, type 2a, subtype NT was isolated from blood cultures, but not from CSF obtained after antibiotic treatment.

APMIS, 1999 Feb, 107(2), 217 - 24
Survival and function of phagocytes in blood culture media; Fischer TK et al.; The survival and function of human phagocytes in sterile aerobic and anaerobic blood culture media were investigated using neutrophil morphology, white blood cell count in a haemoanalyser, flow cytometry, oxidative burst response, and bactericidal effect in Colorbact and Septi-Chek blood culture media and Bact/Alert . When comparing agitation to stationary incubation no difference in phagocytic activity was found . The methods showed the same trends demonstrating that the phagocytes' viability and activity were prolonged by oxygen and shortened by anaerobic conditions and sodium polyethanol sulfonate (SPS) . Best preserved activity and viability were found in the aerobic media containing less than 0.5 g/l SPS, in which significant phagocyte oxidative burst and bactericidal activity were found up to 4 days after inoculation . Considering that the majority of bacteremias are due to aerobic or facultatively anaerobic bacteria, the present data suggest that most bacteria may be recovered by the use of one aerobic bottle with SPS concentration below 0.5 g/l to protect meningococci and other SPS-sensitive bacteria and one above 0.5 g/l to stop phagocytic activity, plus one anaerobic bottle with SPS below 0.5 g/l.

FEMS Immunol Med Microbiol, 1999 Apr, 23(4), 331 - 41
Binding of bacteria to HEp-2 cells infected with influenza A virus; El Ahmer OR et al.; Epidemiological studies indicate influenza virus infection increases susceptibility to bacterial respiratory pathogens and to meningococcal disease . Because density of colonisation is an important factor in the development of bacterial disease, the objectives of the study were to use flow cytometry methods for assessment of bacterial binding and detection of cell surface antigens to determine: (1) if HEp-2 cells infected with human influenza A virus bind greater numbers of bacteria than uninfected cells; (2) if influenza infection alters expression of cell surface antigens which act as receptors for bacterial binding; (3) if neuraminidase affects binding of bacteria to HEp-2 cells . There was significantly increased binding of all isolates tested regardless of surface antigen characteristics . There were no significant differences between virus-infected and -uninfected Hep-2 cells in binding of monoclonal antibodies to Lewisb, Lewisx or H type 2 . There were significant increases in binding of monoclonal antibodies to CD14 (P < 0.05) and CD18 (P < 0.01) . Treatment of cells with monoclonal antibodies significantly reduced binding of Neisseria meningitidis strain C:2b:P1.2, CD14 (P < 0.001) and CD18 (P < 0.001) . No reduction in binding of a strain of Streptococcus pneumoniae (12F) was observed in these experiments . Neuraminidase treatment of HEp-2 cells increased binding of monoclonal antibodies to CD14 (P < 0.01) and CD18 (P < 0.01) . In three experiments, the increase in binding of meningococcal strain C:2b:P1.2 to neuraminidase-treated cells was not significant, but binding of Staphylococcus aureus strain NCTC 10655 was significant (P < 0.05).

Am J Public Health, 1999 May, 89(5), 712 - 7
Maternal cigarette smoking and invasive meningococcal disease: a cohort study among young children in metropolitan Atlanta, 1989-1996; Yusuf HR et al.; OBJECTIVES: This study assessed the association between maternal cigarette smoking during pregnancy and the risk of invasive meningococcal disease during early childhood . METHODS: Using a retrospective cohort study design, cases from an active surveillance project monitoring all invasive meningococcal disease in the metropolitan Atlanta area from 1989 to 1995 were merged with linked birth and death certificate data files . Children who had not died or acquired meningococcal disease were assumed to be alive and free of the illness . The Cox proportional hazards analysis was used to assess the independent association between maternal smoking and meningococcal disease . RESULTS: The crude rate of meningococcal disease was 5 times higher for children whose mothers smoked during pregnancy than for children whose mothers did not smoke (0.05% vs 0.01%) . Multivariate analysis revealed that maternal smoking (risk ratio {RR} = 2.9; 95% confidence interval {CI} = 1.5, 5.7) and a mother's having fewer than 12 years of education (RR = 2.1; 95% CI = 1.0, 4.2) were independently associated with invasive meningococcal disease . CONCLUSIONS: Maternal smoking, a likely surrogate for tobacco smoke exposure following delivery, appears to be a modifiable risk factor for sporadic meningococcal disease in young children.

Soc Sci Med, 1999 May, 48(9), 1205 - 20
A cost-effectiveness analysis of vaccination strategies against N . meningitidis meningitis in sub-Saharan African countries; Bovier PA et al.; This analysis evaluates the cost-effectiveness (C/E) of routine vaccination against Neisseria meningitidis . Three different preventive strategies are analyzed: mass vaccination during epidemics (the current standard of care), routine preventive vaccination and a combination strategy of routine vaccination with mass vaccination during epidemics . A Markov model is used to simulate the epidemics of meningitis in a cohort of 5-year old children and compare these different strategies . The results show that mass vaccination strategy is dominated by the two other strategies . The incremental C/E ratios are US$50/QALY for the routine vaccination, and US$199/QALY for the combination strategy . The costs per fatal case averted are US$1161 for the routine vaccination, and US$2397 for the combination strategy . The C/E ratios are sensitive to: the incidence of meningococcal meningitis, the costs of treating cases, the costs of routine vaccination and the costs and effectiveness of mass immunization campaign . However the rank ordering of the strategies is almost never altered . In conclusion, the results of this analysis suggest that mass vaccination in sub-Saharan Africa in case of epidemics should be reconsidered . Routine vaccination against meningococcal meningitis at an early age, with or without mass vaccination during epidemics is more effective, with a C/E ratio within the range of other vaccination strategies currently in place in Africa.

Gac Sanit, 1999 Jan-Feb, 13(1), 62 - 9
{Meningococcal C disease epidemic in Galicia 1996: the decision making process}; Aboal Vinas JL et al.; In this article we describe the decision making process used to choose the best alternative for bringing under control an epidemic of meningococcal C disease, which occurred in Galicia in 1996 . In the decision making process, we used a methodology which consisted on the identification and definition of a problem, in order to identify alternative solutions and to select one, and finally implement and evaluate it . The health problem was detected studying the data obtained from a survey conducted following an outbreak of meningococcal C disease in february 1995 and from the active epidemiological surveillance system created thereafter . Because this was a new, complex and severe problem, with far-reaching social consequences, critical for our organization, and with long-term implications, and because it was considered important to take the decision as objectively as possible and to clearly explain it, the methodology chosen to solve the problem was a non-programmed, multicriteria making decision process, carried out by a working group using a criterion weighting approach . This working group was created within the General Directorate of Public Health, composed of specialist and of people responsible for the different areas involved . The working group put into practice the different steps of the methodology . The assessment criteria and their respective weights were: effect (efficacy measured by the number of cases we could have prevented if the alternatives were applied in the previous season) 40%; cost (in millions of pesetas) 15%; acceptability (acceptance of and response to each strategy from different groups: general population, health care professionals, other Administrations with competency in Public Health) 30%; and coherence (adherence to the currently accepted strategies for disease control in other countries)15% . When these criteria were applied to the ten alternatives considered, a score was obtained for each one of them . The highest scoring alternative corresponded to the massive vaccination of the total population of Galicia between 18 months and 19 years of age.

Vaccine, 1999 Apr 9, 17(15-16), 1970 - 7
Differences in the avidity of antibodies evoked by four different pneumococcal conjugate vaccines in early childhood; Anttila M et al.; Avidity of antibodies to Streptococcus pneumoniae type 6B, 14, 19F and 23F polysaccharides (PS) evoked by four different pneumococcal conjugate vaccines was compared . Infants were primed with pneumococcal PS conjugated to the variant diphtheria toxin CRM197 (PncCRM), diphtheria toxoid (PncD), tetanus toxoid (PncT) or meningococcal protein complex (PncOMPC) and boosted with the homologous conjugate or PS vaccine . No booster was given to children in the PncOMPC group . Relative antibody avidity was measured by thiocyanate EIA . No vaccine specific differences were found in avidity of anti-14 or -19F antibodies . By contrast, antibody avidity to 6B and 23F differed significantly between the vaccine groups, PncCRM and PncT inducing antibodies of highest avidity.

Lippincotts Prim Care Pract, 1999 Jan-Feb, 3(1), 108 - 25
Infectious disease emergencies in primary care; Kwitkowski VE et al.; Infectious disease emergencies can be described as infectious processes that, if not recognized and treated immediately, can lead to significant morbidity or mortality . These emergencies can present as common or benign infections, fooling the primary care provider into using more conservative treatment strategies than are required . This review discusses the pathophysiology, history and physical findings, diagnostic criteria, and treatment strategies for the following infectious disease emergencies: acute bacterial meningitis, ehrlichiosis, Rocky Mountain spotted fever, meningococcemia, necrotizing soft tissue infections, toxic shock syndrome, food-borne illnesses, and infective endocarditis . Because most of the discussed infectious disease emergencies require hospital care, the primary care clinician must be able to judge when a referral to a specialist or a higher-level care facility is indicated.

Eur J Neurol, 1998 Jan, 5(1), 75 - 81
Cerebral blood flow velocity and perfusion in purulent meningitis: a comparative TCD and 99M-TC-HMPAO-SPECT study; Haring H et al.; In 15 patients (median age 33 years; range 17-74 years) suffering from acute pneumococcal (10 cases) and meningococcal (five cases) meningitis, cerebral blood flow velocity (CBFV) was measured in the M1 - segment of the middle cerebral artery (MCA) by transcranial Doppler sonography, and cerebral perfusion changes were evaluated by 99m-Tc-hexamethylpropylene amine oxime single photon emission computed tomography (HMPAO SPECT) . The objective of the study was to test whether increased CBFV during the acute phase of purulent meningitis reflects hyperemia, and to evaluate focal perfusion abnormalities and their correlation to CBFV changes . In eight patients with marked side-differences in CBFVs during the acute phase of the disease SPECT scans were normal in five . In three patients unilateral perfusion defects correlated with the side of higher CBFV . In seven patients presenting with symmetrically elevated CBFV, SPECT scans were normal in four and revealed focal abnormalities in the remaining three . Follow up SPECT scans were normal in 14/15 patients . The results of our study suggest that elevated CBFV in acute bacterial meningitis does not reflect cerebral hyperemia . Focal cerebral perfusion defects occur independently from functional alterations in the cerebral macrovasculature . A causative pathophysiologic relationship of high CBFV and focal perfusion defects cannot be drawn from these data.

Lancet, 1999 Mar 27, 353(9158), 1049 - 53
Association of variants of the gene for mannose-binding lectin with susceptibility to meningococcal disease . Meningococcal Research Group; Hibberd ML et al.; BACKGROUND: The reasons why meningococcal disease develops in only a small proportion of individuals carrying the causative bacteria are unknown . Differences in host responses to bacterial colonisation are thought to be involved, since people with deficiencies in the terminal components of the complement pathway, or of properdin, are susceptible to meningococcal disease . We postulate that genetic variants of mannose-binding lectin (MBL), a plasma opsonin that initiates another pathway of complement activation, might similarly cause susceptibility to meningococcal disease . METHODS: The frequency of variants of the MBL gene was ascertained in children with meningococcal disease and controls from two independent studies; one hospital-based (194 patients and 272 controls {patients with non-infectious disorders}), and one community-based (72 patients and 110 controls {healthy individuals}), by means of PCR and restriction-enzyme digestion, with confirmation by DNA sequencing . FINDINGS: The proportion of people homozygous for MBL-variant alleles was higher in patients with meningococcal disease than in controls in the hospital study (15 {7.7%} vs four {1.5%}; odds ratio 6.5 {95% CI 2.0-27.2}) and in the community study (six {8.3%} vs three {2.7%}; 4.5 {0.9-29.1}) . The population attributable fraction of cases attributable to MBL variants (homozygous and heterozygous) was 32% . INTERPRETATION: The MBL pathway is a critical determinant of meningococcal-disease susceptibility, and genetic variants of MBL might account for a third of all disease cases.

Am J Kidney Dis, 1999 Apr, 33(4), 790 - 5
Meropenem pharmacokinetics in a patient with multiorgan failure from Meningococcemia undergoing continuous venovenous hemodiafiltration; Meyer MM et al.; Meropenem is a carbapenem antibiotic with a broad antibacterial spectrum of activity . Its main route of elimination is through the kidneys, with 63% of the drug excreted unchanged in the urine . Meropenem clearance is diminished in renal impairment; therefore, doses need to be adjusted in patients with varying degrees of renal function . An appropriate dose of meropenem for patients undergoing continuous venovenous hemodiafiltration (CVVHDF) is unknown . We evaluated the pharmacokinetics of meropenem in a patient with fulminant meningococcemia undergoing CVVHDF . Meropenem concentrations in serial venous, arterial, and ultrafiltrate samples after a 1 g intravenous dose were measured using high-performance liquid chromatography (HPLC) . Meropenem clearance was found to be 129.36 mL/min and 141.29 mL/min for every 8- and 12-hour dosing, respectively . Trough levels were above the MIC90 for Neisseria meningitidis and most anaerobic pathogens . We recommend that meropenem 1 g intravenously every 12 hours be used as the initial dose in patients undergoing CVVHDF . Differences between meropenem clearance during CVVHDF and other forms of renal replacement therapy are discussed.

Enferm Infecc Microbiol Clin, 1999 Feb, 17(2), 74 - 7
{Usefulness of polymerase chain reaction (PCR) in the diagnosis of meningococcal meningitis}; Pardo F et al.; BACKGROUND: The aim of this work was to evaluate the applicability of polymerase chain reaction (PCR) in the microbiological diagnostic of meningococcal meningitis as compared with the conventional methods (Gram stain and culture) . METHODS: One hundred and fifteen cerebrospinalis fluid samples from 115 patients with suspicious symptoms of meningitis were studied . 47 of them belonged to patients suspicious for meningococcal disease; 28 to patients with bacterial meningitis of other infectious etiologies; 10 to patients with meningitis showing lymphocytic pleocytosis and 30 to patients with an unconfirmed meningitis . The cerebrospinalis fluid samples were processed for culture by standard procedures and by PCR according to the method described by Newcombe et al for peripheral blood samples . RESULTS: Thirty five out of 39 patients suspicious of meningococcal meningitis were microbiologically confirmed, being 22 culture and PCR positive, 3 microscopically and PCR positive, 1 only microscopically positive, and 9 positive only by PCR . By using PCR methodology, the number of confirmed diagnostics of meningococcal meningitis increased in a 23% as compared to those obtained by microscopic observation and culture . Sensitivity, specificity, predictive positive value and predictive negative value were 87.1, 98.7, 97.1 and 94.1 respectively for the PCR method . CONCLUSIONS: Our results indicate that PCR can be used on routine basis as a complementary technique to the standard laboratory procedures for diagnosis of meningococcal meningitis.

J Infect Dis, 1999 May, 179(5), 1288 - 92
Neutrophil response to Neisseria meningitidis: inhibition of adhesion molecule expression and phagocytosis by recombinant bactericidal/permeability-increasing protein (rBPI21); Heyderman RS et al.; Polymorphonuclear neutrophil (PMNL) activation enhances microbial clearance but also contributes to the vascular damage and multiorgan failure associated with severe meningococcal sepsis . By use of a whole blood model of meningococcal bacteremia, loss of PMNL L-selectin and up-regulation of CD11b was observed in response to Neisseria meningitidis serogroups B and C, which is followed by opsonophagocytosis . PMNL priming with either Escherichia coli lipopolysaccharide (LPS) or FMLP prior to meningococcal challenge resulted in enhancement of both PMNL L-selectin shedding (1.5- to 4-fold) and phagocytosis (2- to 3-fold) . Blockade of meningococcal LPS lipid A with recombinant bactericidal/permeability-increasing protein (rBPI21) resulted in partial inhibition of the PMNL activation and phagocytosis response to N . meningitidis . The effect of rBPI21 was reversed by excess E . coli LPS or FMLP . It is proposed that PMNL priming by N . meningitidis results in an exaggerated activation and phagocytosis response to the organism.

Epidemiol Infect, 1999 Feb, 122(1), 51 - 7
Factors associated with pharyngeal carriage of Neisseria meningitidis among Israel Defense Force personnel at the end of their compulsory service; Block C et al.; In this 1 year cross-sectional study of personnel being discharged from compulsory military service, an available database of health-related information was used to examine the association of meningococcal carriage with socio-demographic factors . A representative, systematic sample of 1632 personnel was interviewed and had throat cultures taken . The overall meningococcal carriage rate was 16% . Serogroups B and Y accounted for 76% and 13% of the isolates respectively . In univariate analysis, carriage was associated with male gender (P < 0.0001), < 12 years school education (P = 0.002), smoking (P = 0.014), and service at a 'closed' base, reflecting greater interpersonal contact (P < 0.0001) . In multivariate analysis, only service on a closed base and male gender retained significance . School education of < 12 years remained significant for females only . Variables not associated with carriage included number of siblings, intensity of smoking, and use of the contraceptive pill . In this setting, meningococcal carriage was associated with the type of base on which soldiers served; and smoking was not an independent risk factor for carriage.

Epidemiol Infect, 1999 Feb, 122(1), 41 - 9
Is group C meningococcal disease increasing in Europe? A report of surveillance of meningococcal infection in Europe 1993-6 . European Meningitis Surveillance Group; Connolly M et al.; A surveillance system to assess the impact and changing epidemiology of invasive meningococcal disease in Europe was set up in 1987 . Since about 1991, contributors from national reference laboratories, national communicable disease surveillance centres and institutes of public health in 35 European countries provided information on all reported cases of meningococcal disease in their country . We describe some trends observed over the period 1993-6 . The main findings were: the overall incidence of meningococcal disease was 1.1 per 100000 population but there was some evidence of a slow increase over time and with northern European countries tending to have a higher incidence (Kendall correlation 0.5772, P < 0.001), an increasing predominance of serogroup C, and a shift in the age distribution towards teenagers and away from younger children (chi2 test for trend 44.56, P < 0.0001), although about half of the cases were under 5 years of age . The overall case fatality rate was 8.3% and the most common serosubtypes were B:15:P1.7,16 and C:2a:P1.2,5.

Proc Natl Acad Sci U S A, 1999 Mar 30, 96(7), 4017 - 22
The meningococcal PilT protein is required for induction of intimate attachment to epithelial cells following pilus-mediated adhesion; Pujol C et al.; The ability of Neisseria meningitidis (MC) to interact with cellular barriers is essential to its pathogenesis . With epithelial cells, this process has been modeled in two steps . The initial stage of localized adherence is mediated by bacterial pili . After this phase, MC disperse and lose piliation, thus leading to a diffuse adherence . At this stage, microvilli have disappeared, and MC interact intimately with cells and are, in places, located on pedestals of actin, thus realizing attaching and effacing (AE) lesions . The bacterial attributes responsible for these latter phenotypes remain unidentified . Considering that bacteria are nonpiliated at this stage, pili cannot be directly responsible for this effect . However, the initial phase of pilus-mediated localized adherence is required for the occurrence of diffuse adherence, loss of microvilli, and intimate attachment, because nonpiliated bacteria are not capable of such a cellular interaction . In this work, we engineered a mutation in the cytoplasmic nucleotide-binding protein PilT and showed that this mutation increased piliation and abolished the dispersal phase of bacterial clumps as well as the loss of piliation . Furthermore, no intimate attachment nor AE lesions were observed . On the other hand, PilT- MC remained adherent as piliated clumps at all times . Taken together these data demonstrate that the induction of diffuse adherence, intimate attachment, and AE lesions after pilus-mediated adhesion requires the cytoplasmic PilT protein.

Rev Mal Respir, 1999 Feb, 16(1), 95 - 7
{Weber-Rendu-Osler disease: pulmonary arterio-venous malformation with shunt disclosed after 5 occurrences of purulent meningococcal encephalitis}; Hazouard E et al.; Hereditary hemorrhagic telangectasis or Weber-Rendu-Osler disease is associated with the presence of capillary malformations with pulmonary visceral shunts . These shunts are the cause of recurrent infections of the nervous system by loss of the anti-infectious lung filter . Hereditary hemorrhagic telangiectasis was diagnosed in a 68-year-old woman with a history of epistaxis, cutaneous telangectasis, purulent and pyogenic brain abscesses and meningitis . Outcome was favorable with antibiotic therapy . Ventilation as well as chest x-ray, brain scan and liver ultrasongraphy were normal . Blood gases showed a PO2 at 63 mmHg in ambient air and 62 mmHg with FiO2 = 1 . There was no dyspnea or cyanosis nor any apparent polycythemia . Pulmonary angiography showed and arteriovenous malformation in the lower right lobe . Endovascular embolization was achieved with coils and N-butyl-cyano-acrylate glue which enabled angiographic occlusion and normalization of gas exchange: on ambient air the PaO2 = 71 mmHg and on FiO2 = 1, PaO2 was 359 mmHg . A true shunt was suspected on account of the association of hereditary hemorrhagic telangiectasis and recurrent meningitis . The diagnosis was suspected on blood gases alone.

Acta Crystallogr D Biol Crystallogr, 1999 Jan, 55 ( Pt 1), 314 - 6 Epub 1999 Jan 01.
Use of streptococcal protein G in obtaining crystals of an antibody Fab fragment in complex with a meningococcal antigen; Derrick JP et al.; Crystals have been obtained of an antibody Fab fragment grown in the presence of a single domain from streptococcal protein G and a ten amino-acid peptide corresponding to the P1.7 serosubtype antigen from the human pathogen Neisseria meningitidis . Crystal trials using the Fab fragment and peptide antigen alone were unsuccessful, but the inclusion of a protein G domain provided an additional variable that generated suitable crystals . Crystals are in space group P21 with unit-cell parameters a = 43.60, b = 63.42, c = 89.63 A, beta = 98.58 degrees and a data set has been collected to 2.9 A resolution using synchrotron radiation . The inclusion of protein G is likely to be of general utility for the crystallization of Fab-antigen complexes.

Biochem J, 1999 Apr 1, 339 ( Pt 1), 143 - 9
Purified meningococcal transferrin-binding protein B interacts with a secondary, strain-specific, binding site in the N-terminal lobe of human transferrin; Boulton IC et al.; Neisseria meningitidis, grown in iron-limited conditions, produces two transferrin-binding proteins (TbpA and TbpB) that independently and specifically bind human serum transferrin (hTF) but not bovine serum transferrin (bTF) . We have used surface plasmon resonance to characterize the interaction between individual TbpA and TbpB and a series of full-length human-bovine chimaeric transferrins (hbTFs) under conditions of variable saturation with iron . A comparative analysis of hTF and hbTF chimaera-binding data confirmed that the major features involved in Tbp binding are located in the C-terminal lobe of hTF and that isolated TbpA can recognize distinct sites present in, or conformationally influenced by, residues 598-679 . Binding by TbpB was maintained at a significant but decreased level after replacement of the entire hTF C-terminal lobe by the equivalent bovine sequence . The extent of this binding difference was dependent on the meningococcal strain and on the presence of hTF residues 255-350 . This indicated that TbpB from strain SD has a secondary, strain-specific, binding site located within this region, whereas TbpB from strain B16B6 does not share this recognition site . Binding of TbpA was influenced primarily by sequence substitutions in the hTF C-terminal lobe, and co-purified TbpA and TbpB (TbpA+B) was functionally distinct from either of its components . The limited divergence between hTF and bTF has been related to observed differences in binding by Tbps and has been used to delineate those regions of hTF that are important for such interactions.

An Esp Pediatr, 1999 Jan, 50(1), 17 - 20
{An analysis of prior antibiotic treatment on the impact of meningococcal disease in children of the Valencian Community . The Study Group of Invasive Diseases}; Morant Gimeno A et al.; OBJECTIVE: The objective of this study was to describe the effect of antibiotics given prior to hospitalization of children with meningococcal disease and to assess their relationship with disease outcome and microbiological isolation . PATIENTS AND METHODS: A prospective surveillance system in all hospitals of the Community of Valencia was implemented . All cases of children less than 15 years of age with clinically suspected invasive disease and: 1) N . meningitidis isolated in a normally sterile body fluid; 2) positive capsular antigens in blood or CSF and a positive Gram stain; and 3) clinical diagnosis of an invasive N . meningitidis disease . RESULTS: In a two-year period 157 cases were reported . In 143 cases, data about antibiotic prescription prior to hospitalization was known . Of these, 24.5% had received antibiotics and none had received parenteral penicillin or cephalosporins . Oral antibiotics decreased bacterial isolation (p < 0.001) and did not modify outcome (p = 0.66) . CONCLUSIONS: Oral antibiotics, not recommended for N . meningitidis diseases, did not modify prognosis, but decreased bacterial isolation, and therefore worsened clinical handling of the cases and epidemiological studies.

Biotechnol Appl Biochem, 1999 Apr, 29 ( Pt 2), 113 - 7
Preformulation study of the vaccine candidate P64k against Neisseria meningitidis; Exposito Raya N et al.; We have previously isolated, cloned and expressed in Escherichia coli the lpdA gene coding for a high-molecular-mass protein (P64k) common to many meningococcal strains . P64k is an outer membrane lipoamide dehydrogenase that is highly immunogenic in animals . Here we describe a preformulation study of the recombinant protein as a vaccine candidate against Neisseria meningitidis, in which six variants containing the candidate were tested . Three assays were used to identify the most suitable variant for further evaluation: percentage of adsorption, identification of P64k by SDS/PAGE, and immunogenicity in mice . All the preformulation variants studied showed more than 98% of adsorption of P64k on the aluminium gel . After desorption, P64k was also identified by SDS/PAGE in the six preformulation variants . Seroconversion was attained in all groups analysed . On the basis of these results, the most effective variant consisted of 20 microg/ml P64k plus 0.5 mg/ml aluminium hydroxide.

JAMA, 1999 Mar 10, 281(10), 908 - 13
Effectiveness of influenza vaccine in health care professionals: a randomized trial; Wilde JA et al.; CONTEXT: Data are limited and conflicting regarding the effectiveness of influenza vaccine in health care professionals . OBJECTIVE: To determine the effectiveness of trivalent influenza vaccine in reducing infection, illness, and absence from work in young, healthy health care professionals . DESIGN: Randomized, prospective, double-blind, controlled trial over 3 consecutive years, from 1992-1993 to 1994-1995 . SETTING: Two large teaching hospitals in Baltimore, Md . PARTICIPANTS: Two hundred sixty-four hospital-based health care professionals without chronic medical problems were recruited; 49 participated for 2 seasons; 24 participated for 3 seasons . The mean age was 28.4 years, 75% were resident physicians, and 57% were women . INTERVENTION: Participants were randomly assigned to receive either an influenza vaccine or a control (meningococcal vaccine, pneumococcal vaccine, or placebo) . Serum samples for antibody assays were collected at the time of vaccination, 1 month after vaccination, and at the end of the influenza season . Active weekly surveillance for illness was conducted during each influenza epidemic period . MAIN OUTCOME MEASURES: Serologically defined influenza infection (4-fold increase in hemagglutination-inhibiting antibodies), days of febrile respiratory illness, and days absent from work . RESULTS: We conducted 359 person-winters of serologic surveillance (99.4% follow-up) and 4746 person-weeks of illness surveillance (100% follow-up) . Twenty-four(13.4%) of 179 control subjects and 3 (1.7%) of 180 influenza vaccine recipients had serologic evidence of influenza type A or B infection during the study period . Vaccine efficacy against serologically defined infection was 88% for influenza A (95% confidence interval {CI}, 47%-97%; P=.001) and 89% for influenza B (95% CI, 14%-99%; P=.03) . Among influenza vaccinees, cumulative days of reported febrile respiratory illness were 28.7 per 100 subjects compared with 40.6 per 100 subjects in controls (P=.57) and days of absence were 9.9 per 100 subjects vs 21.1 per 100 subjects in controls (P=.41) . CONCLUSIONS: Influenza vaccine is effective in preventing infection by influenza A and B in health care professionals and may reduce reported days of work absence and febrile respiratory illness . These data support a policy of annual influenza vaccination of health care professionals.

FEMS Immunol Med Microbiol, 1999 Feb, 23(2), 115 - 24
Infection with respiratory syncytial virus enhances expression of native receptors for non-pilate Neisseria meningitidis on HEp-2 cells; Raza MW et al.; Respiratory virus infections have been suggested to be predisposing factors for meningococcal disease . Respiratory syncytial virus (RSV) affects young children in the age range at greatest risk of disease caused by Neisseria meningitidis . It has been previously shown that glycoprotein G expressed on the surface of RSV-infected HEp-2 cells (a human epithelial cell line) contributed to higher levels of binding of meningococci compared with uninfected cells . The aim of the present study was to examine the effect of RSV infection on expression of surface molecules native to HEp-2 cells and their role in bacterial binding . Flow cytometry and fluorescence microscopy were used to assess bacterial binding and expression of host cell antigens . Some molecules analysed in this study have not been reported previously on epithelial cells . RSV infection significantly enhanced the expression of CD15 (P < 0.05), CD14 (P < 0.001) and CD18 (P < 0.01), and the latter two contributed to increased binding of meningococci to cells but not the Gram-positive Streptococcus pneumoniae.

S Afr Med J, 1999 Jan, 89(1), 56 - 9
Risk factors for meningococcal disease in Cape Town; Moodley JR et al.; OBJECTIVE: To determine the risk factors associated with meningococcal disease among children living in Cape Town . DESIGN: A case-control study was conducted from October 1993 to January 1995 . SETTING: The study population consisted of all children under the age of 14 years who were resident in the Cape Town metropolitan region . Cases and controls were selected from Red Cross War Memorial Children's Hospital . RESULTS: A total of 70 cases and 210 controls were interviewed . Significant risk factors for meningococcal disease included being breast-fed for less than 3 months (adjusted odds ratio (OR) 2.4); overcrowding (adjusted OR 2.3); and age less than 4 years (adjusted OR 2.3) . Exposure to two or more household members who smoked was also a risk factor, but only in the presence of a recent upper respiratory tract infection (adjusted OR 5.0) . CONCLUSION: This is the first case-control study in South Africa examining risk factors for meningococcal disease . It provides further evidence for reduction of smoking, reduction of overcrowding and promotion of breast-feeding as important public health measures.

Vaccine, 1999 Feb 26, 17(7-8), 754 - 64
Human IgG subclass responses in relation to serum bactericidal and opsonic activities after immunization with three doses of the Norwegian serogroup B meningococcal outer membrane vesicle vaccine; Naess LM et al.; Ten adult volunteers, with low prevaccination levels of serum IgG antibodies against meningococcal antigens (< 1 microg ml(-1)), received three doses of the Norwegian group B meningococcal outer membrane vesicle (OMV) vaccine intramuscularly at weeks 0, 6 and 46 . Anti-OMV IgG subclass responses were measured and compared with serum bactericidal activity (SBA) and opsonic activity against the vaccine strain 44/76 . All vaccinees showed an IgG1 antibody response after each vaccine dose . The vaccine-induced median serum IgG1 antibody levels were 16, 17 and 18 microg ml(-1) 2-6 weeks after the first, second and third dose, respectively . Three vaccinees showed a weak IgG3 response after the first dose, whereas 8 and 9 showed a response after the second (median = 10 microg ml(-1)) and third dose (median = 10 microg ml(-1)), respectively . Low levels of anti-OMV IgG2 antibodies were found, whilst specific IgG4 antibodies were only detected for one vaccinee . The vaccine induced at least a fourfold increase in SBA titre in 8 vaccinees after the first dose, in 9 vaccinees after 2 doses and in all vaccinees after 3 doses . A positive correlation was found between IgG1 subclass antibody levels and SBA (r = 0.62, P < 0.0001) . Elevated opsonophagocytic activity, measured as respiratory burst (RB), was observed in all vaccinees after one vaccine dose and usually increased after 2 and 3 doses . A strong positive correlation was found between IgG1 antibody levels and RB (r = 0.76, P < 0.0001) . In conclusion, we have shown that systemic meningococcal OMV vaccination in adult vaccinees mainly induced IgG1 antibodies which correlated with bactericidal and opsonic activity, but also a considerable amount of IgG3 antibodies, which, in contrast to the IgG1 response, was induced only after 2 or 3 vaccine doses and declined more rapidly.

Vaccine, 1999 Feb 26, 17(7-8), 731 - 44
Human antibody responses to A and C capsular polysaccharides, IgA1 protease and transferrin-binding protein complex stimulated by infection with Neisseria meningitidis of subgroup IV-1 or ET-37 complex; Brieske N et al.; The protein sequences of the IgA1 protease, TbpA and TbpB proteins differ between meningococci representative of serogroup A, subgroup IV-1 from epidemic disease in The Gambia and serogroup C, ET-37 complex from endemic disease in Mali . The uniformity of restriction endonuclease sites was determined for the iga, tbpA and thpB genes among strains of both clonal lineages . Rare isolates had acquired a variant thpAB operon by horizontal genetic exchange but all other strains were uniform within each clonal lineage . The quantitative levels of IgG to capsular polysaccharide, IgA1 protease and TBP complex were measured in paired acute phase and convalescent phase sera from The Gambia and from Mali using antigens from the homologous clonal lineages . IgG levels to these antigens were also measured in paired sera from healthy Gambians who permanently carried meningococci in the nasopharynx or did not . The results showed that disease stimulated IgG to each antigen in Mali and to all but TBP complex in The Gambia . Similarly, higher levels of IgG were found in sera from permanent carriers than in sera from permanent non-carriers . Acute phase sera from Mali contained low levels of IgG to C capsular polysaccharide (geometric mean value of 0.3 microg ml(-1)) while such sera from The Gambia contained higher and potentially protective levels of IgG to A polysaccharide (geometric mean of 5.5 microg ml(-1)) . The concentrations of IgG to TBP complex in acute phase sera were higher and IgG to IgA1 protease was even higher, suggesting that intermediate levels of IgG to these proteins do not protect against disease.

Curr Opin Microbiol, 1999 Feb, 2(1), 71 - 7
Interaction mechanisms of encapsulated meningococci with eucaryotic cells: what does this tell us about the crossing of the blood-brain barrier by Neisseria meningitidis?
Nassif X.
An important feature of Neisseria meningitidis is its ability to invade the meninges . This requires that bacteria cross the blood-brain barrier (BBB), which is one of the tightest barriers of the body . N . meningitidis has, therefore, evolved very sophisticated means by which it circumvents the physical properties of this cellular barrier . Recent advances have allowed the identification of several steps that might occur in the interaction of N . meningitidis with the BBB and the transit of the bacteria to the meninges.

Epidemiol Infect, 1998 Dec, 121(3), 495 - 505
Acquisition and carriage of meningococci in marine commando recruits; Riordan T et al.; Meningococcal acquisition is a prerequisite for invasive disease . Three hundred and eleven male marine commando recruits were studied throughout 29 weeks of basic training to identify factors influencing meningococcal carriage and acquisition including troop number, season, smoking, respiratory infection, antibiotic usage and nasopharyngeal bacterial interference flora . A high carriage rate on entry to training (118/311, 37.9%) and subsequent sustained high rates of meningococcal acquisition were found . Of the potential factors examined, only active and passive smoking were found to be associated significantly with meningococcal carriage on entry . The association between active smoking and meningococcal carriage was dose-dependent, with odds ratios (OR) of 2.2 (95% CIs 1.0-4.8) and 7.2 (95% CIs 2.3-22.9) for light and heavy smokers respectively . Passive smoking predisposed independently to carriage (OR 1.8, 95% CIs 1.1-3.0) . Active and passive smoking combined to give an attributable risk for meningococcal carriage of 33% . In contrast, despite a high and sustained rate of meningococcal acquisition in the study population, none of the risk factors investigated, including active smoking, was associated significantly with meningococcal acquisition . No cases of meningococcal disease occurred during the 16-month study period . Therefore smoking may increase the duration of meningococcal carriage rather than the rate of acquisition, consistent with the increased risk of meningococcal disease from passive as opposed to active smoking . Public health measures that reduce the prevalence of smoking should reduce the risk of meningococcal disease.

Epidemiol Infect, 1998 Dec, 121(3), 487 - 93
Sustained reduction in the carriage of Neisseria meningitidis as a result of a community meningococcal disease control programme; Neal KR et al.; The effect of a community intervention programme of antibiotics and meningitis vaccine on pharyngeal carriage of Neisseria meningitidis was investigated . Carriage rates were determined in pupils at both secondary schools (ages 11-18 years) included in the community intervention programme and compared with two schools outside the area matched for socio-economic status . A total of 1869 pupils were studied 6 months after the programmes, and 2457 pupils after 11 months . Six months after the programme was completed there was a 72% reduction in pharyngeal carriage of Neisseria meningitidis in pupils attending the schools in the intervention area compared with pupils in the control schools . After 11 months this difference persisted in the 11-14 age group but not in the 15-18 age group . No resistance to the antibiotics used in the programme was found . A community intervention programme of antibiotics and vaccine for the control of meningococcal disease led to a long-term reduction in Neisseria meningitidis carriage in some age groups.

FEMS Immunol Med Microbiol, 1999 Jan, 23(1), 49 - 55
Recent emergence of serogroup C meningococcal disease in Greece; Kremastinou J et al.; The number of cases of meningococcal disease reported to the Meningitis Reference Laboratory in Athens rose dramatically in 1996-1997 . The aims were (1) to determine if the increase was due to introduction of new strains, (2) to assess the geographic and age distribution of the cases, (3) to compare antibiotic sensitivity patterns of the current isolates with strains from the early 1990s . In 1993-1994, 15/19 (74%) of the cases for which information on age was available were in children < or = 5 years; in 1995-1997, 80/179 (45%) of cases were in children < or = 5 years and 99 (55%) in the older age range (P < 0.02) . From 593 cases in 1993 1997, 214 (36%) isolates were available for characterisation . Serogroup B was predominant in the early 1990s, but by 1997, serogroup C accounted for 46/72 (64%) of isolates and serogroup B for 25/72 (35%) . Serogroup B was predominant in children < or = 5 years (44/78, 56%) but only 19/99 (18%) of older children and adults (P=0.0000005) . Sulfonamide resistance decreased from 10/22 (45%) in 1993-1994 to 27/192 (14%) in 1995-1997 (P<0.01) . Multilocus enzyme electrophoresis of 70 strains obtained during this period identified the epidemic ET-15 clone in 24 (34.3)% . The profiles of the Greek ET-15 isolates were identical to C:2a:P1.2(P1.5) strains responsible for the epidemic in the Czech Republic which began in 1993 . This genotype was not found in Greek strains isolated prior to 1993 . We conclude that the increase in meningococcal disease is due to introduction of the epidemic serogroup C:2a:P1.2(P1.5) strain responsible for disease in the Czech Republic and Canada.

FEMS Immunol Med Microbiol, 1999 Jan, 23(1), 13 - 20
Carriage of Neisseria meningitidis and Neisseria lactamica among ethnic Greek school children from Russian immigrant families in Athens; Kremastinou J et al.; During February and March 1995, a survey of meningococcal carriage in 625 school children was carried out in a suburb of Athens in which there was a large number of ethnic Greeks who had immigrated from Russia beginning in the early 1990s . The objectives of the study were: (1) to determine if factors associated with carriage of meningococci observed in a previous study of Greek school children were similar for the immigrant population; (2) to compare phenotypic characteristics of meningococci from the immigrant population with those isolated from children in Athens . Overall isolation rate for meningococci was 82/625 (13.1%), significantly higher than that found for school children in Athens (5.8%) during the winter of 1990 1991 (5.8%) (chi=25.98, P=0.0000003) . By univariate analysis, carriage was not associated with sex, number of individuals per household, blood group, secretor status, socioeconomic level or maternal smoking; however, it was associated with fathers' smoking . The high proportion of men who smoked compared with the low proportion of women smokers might contribute to this finding . The main serogroup of meningococci isolated from this population was A (28%) . While serogroup A appears to be more prevalent among Russian and Kurdish immigrants (14%) than among Greek school children or military recruits (4%), there has not been an increase in group A meningococcal disease in Greece . The isolation rate for N . lactamica was high 105/625 (17.3%) . A few of these strains bound some of the monoclonal antibodies used for meningococcal serotyping and subtyping, and they are being examined in greater detail.

Clin Infect Dis, 1999 Jan, 28(1), 98 - 105
Assessment of complement deficiency in patients with meningococcal disease in The Netherlands; Fijen CA et al.; The frequency of complement deficiency in 176 of 7,732 patients with meningococcal disease in the Netherlands from 1959 through 1992 was assessed . Complement deficiency was found in six patients (3%): 3 (7%) of the patients with Neisseria meningitidis serogroup C disease, 1 (2%) of the patients with N . meningitidis serogroup A disease, and 2 (33%) of the patients with infections due to uncommon serogroups and nongroupable strains of N . meningitidis . Of 91 additional patients with meningococcal infections due to uncommon serogroups, 33% also had complement deficiency . Thirty-four of the 36 complement-deficient patients with meningococcal disease who were from 33 families were 5 years of age or older . Twenty-six additional complement-deficient relatives were found . Screening individuals with meningococcal disease due to uncommon serogroups who were 5 years of age or older identified 30 of the 33 complement-deficient families . Only 27% of the complement-deficient relatives had had meningococcal disease . This risk was lower for relatives with properdin deficiency (18%) than for those deficient in the late component of complement (38%) . Therefore, pedigree studies are warranted for identifying those complement-deficient persons who require vaccination for meningococcal disease.

Infect Immun, 1999 Mar, 67(3), 1267 - 76
Functional activities and epitope specificity of human and murine antibodies against the class 4 outer membrane protein (Rmp) of Neisseria meningitidis; Rosenqvist E et al.; Antibodies against the class 4 outer membrane protein (OMP) from Neisseria meningitidis have been purified from sera from vaccinees immunized with the Norwegian meningococcal group B outer membrane vesicle vaccine . The human sera and purified antibodies reacted strongly with the class 4 OMP in immunoblots, whereas experiments with whole bacteria showed only weak reactions, indicating that the antibodies mainly reacted with parts of the class 4 molecule that were not exposed . The purified human anti-class 4 OMP antibodies and the monoclonal antibodies (MAbs) were neither bactericidal nor opsonic against live meningococci . Three new MAbs against the class 4 OMP were generated and compared with other, previously described MAbs . Three linear epitopes in different regions of the class 4 OMP were identified by the reaction of MAbs with synthetic peptides . The MAbs showed no blocking effect on bactericidal activity of MAbs against other OMPs . However, one of the eight purified human anti-class 4 OMP antibody preparations, selected from immunoblot reactions among sera from 27 vaccinees, inhibited at high concentrations the bactericidal effect of a MAb against the class 1 OMP . However, these antibodies were not vaccine induced, as they were present also before vaccination . Therefore, this study gave no evidence that vaccination with a meningococcal outer membrane vesicle vaccine containing the class 4 OMP induces blocking antibodies . Our data indicated that the structure of class 4 OMP does not correspond to standard beta-barrel structures of integral OMPs and that no substantial portion of the OmpA-like C-terminal region of this protein is located at the surface of the outer membrane.

Mayo Clin Proc, 1999 Jan, 74(1), 68 - 72
Life-threatening rashes: dermatologic signs of four infectious diseases; Drage LA; Four infectious diseases that are associated with high rates of morbidity and mortality are Rocky Mountain spotted fever, meningococcal disease, staphylococcal toxic shock syndrome, and streptococcal toxic shock syndrome . These diseases necessitate a timely diagnosis and treatment, which may be facilitated by recognition of the characteristic cutaneous findings . Herein the clinical manifestations, diagnosis, and management are presented, with emphasis on the dermatologic signs of each disease . A dermatology consultation can be valuable, but all physicians should be familiar with the cutaneous findings of these potentially life-threatening diseases.

Vaccine, 1999 Jan, 17(2), 114 - 7
For discussion: live attenuated vaccines for group B meningococcus; Tang C et al.; Current attempts at preventing infections caused by group B Neisseria meningitidis are largely directed on generating immune responses to outer membrane proteins or the lipopolysaccharide of this organism . We suggest an alternative approach: the use of a live, attenuated strain of Neisseria meningitidis which could be delivered mucosally to elicit both local and systemic immune responses.

Vaccine, 1999 Jan, 17(2), 110 - 3
Persistence of antibodies to the Salmonella typhi Vi capsular polysaccharide vaccine in South African school children ten years after immunization; Keddy KH et al.; Between 10 and 11 years after children were vaccinated with Vi capsular polysaccharide of Salmonella typhi or meningococcal A + C control vaccine in a double blind randomized trial, we traced 83 subjects, aged 16-20 years . A blood sample was taken for determination of Vi antibody titres in both groups by radioimmunoassay . TO and TH titres were also done to assess if the participants had had recent exposure to typhoid fever . Fifty-eight percent of subjects in both groups had protective levels of Vi antibody against Salmonella typhi (a titre greater than 1 microgram ml-1) . There was no significant difference in the levels of Vi antibodies in the cases versus the controls (p = 0.5) . Two of the children who had received meningococcal A + C vaccine had recently had typhoid fever . Our data show that adolescents in typhoid endemic areas have high levels of Vi antibodies regardless of previous vaccination status, suggesting that Vi antibodies are acquired in adolescence by a large percentage of the population in this area . Moreover, Vi vaccination has led to ongoing antibody production in greater than 50% of Vi vaccinated children in an endemic area for a period of 10 years . Ongoing antigenic exposure may have contributed to these antibody levels.

Ann Pharmacother, 1999 Jan, 33(1), 48 - 60
Trovafloxacin: a new fluoroquinolone; Alghasham AA et al.; OBJECTIVE: To review the pharmacology, antimicrobial activity, pharmacokinetics, clinical efficacy, and safety of trovafloxacin . DATA SOURCES: A MEDLINE search (January 1966-April 1998) was conducted for relevant literature using the terms CP-99,219, CP-116,519, trovafloxacin, and alatrofloxacin . Abstracts published by the American Society of Microbiology during 1995-1997 meetings were also reviewed . STUDY SELECTION AND DATA EXTRACTION: All in vitro, animal, and human studies were reviewed for the antimicrobial activity, pharmacokinetics, efficacy, and safety of trovafloxacin . DATA SYNTHESIS: Trovafloxacin is a new fluoroquinolone with enhanced activity against gram-positive and anaerobic microorganisms . The oral bioavailability under fasting conditions is approximately 88% . The elimination half-life of trovafloxacin is approximately 10 hours . Less than 10% of trovafloxacin is eliminated unchanged in the urine . Trovafloxacin is effective in the treatment of community-acquired pneumonia and nosocomial pneumonia with cure rates of > 90% and 77%, respectively . Trovafloxacin is comparable with ceftriaxone in the treatment of meningococcal meningitis in children; each produces a cure rate of approximately 90% . In treatment of uncomplicated urinary tract infection, both ciprofloxacin and trovafloxacin achieve an eradication rate of > or = 93% . Trovafloxacin is similar to ofloxacin in the treatment of urogenital Chlamydia trachomatis and acute exacerbations of chronic bronchitis, with clinical success in 97% of patients with each drug . The common adverse effects of trovafloxacin include dizziness, headache, and gastrointestinal intolerance . CONCLUSIONS: The advantages of once-daily dosing and enhanced activity of trovafloxacin against gram-positive and anaerobic organisms may expand its use over available fluoroquinolones . Further studies are needed to define its role in the treatment of various infectious diseases.

J Clin Pathol, 1998 Sep, 51(9), 689 - 94
The value of a thorough protocol in the investigation of sudden infant deaths; Sadler DW; AIMS: To review the diagnostic value of using a thorough necropsy protocol for the investigation of sudden infant deaths, with particular emphasis on the value of routine ancillary laboratory investigations . METHODS: The necropsy and related records of all neonatal, infant, and young childhood deaths (under three years) referred for medicolegal investigation at Dundee from 1990 to early 1998 were reviewed retrospectively . Relevant positive and negative findings were abstracted from the police reports, hospital medical records, necropsy reports, and the results of routine bacteriological, virological, toxicological, and biochemical laboratory investigations . RESULTS: Within the study period, 63 deaths presented as apparent "cot deaths," nine as suspected homicides, nine as neonatal deaths, and 14 in some other manner . An adequate cause of death was identified on the basis of necropsy and laboratory investigations in 35% of the 63 apparent cot deaths, leaving 63% to be finally categorised as sudden infant death syndrome (SIDS) . Ten (16%) of the apparent cot deaths were explained on the sole basis of unexpected positive microbiological findings, mostly pneumococcal or meningococcal meningitis and/or septicaemia . Petechial haemorrhages were identified at one or more intrathoracic site in 90% of SIDS and in 55% of explained cot deaths . CONCLUSIONS: Early and extensive laboratory investigations performed routinely in apparent cot deaths provide an unexpectedly high positive diagnostic yield . Routine early bacteriological culture of the CSF (by cisternal puncture) and blood before necropsy should be mandatory in the investigation of all sudden infant deaths.

Biophys J, 1999 Feb, 76(2), 804 - 13
Meningococcal PorA/C1, a channel that combines high conductance and high selectivity; Song J et al.; Class 1 porins (PorA/C1) from Neisseria meningitidis achieve both high selectivity and high conductance . The channel is highly selective (24:1 Na+ over Cl-), suggesting a highly negatively charged selectivity filter . The trimeric nature of PorA/C1 accounts for part of the enormous conductance in 200 mM NaCl (0.97nS) . However, the currents that can be achieved exceed the simple infinite-sink calculation for a pore 0.7 nm in radius (estimated from nonelectrolyte permeability) . The conductance is linear with salt activity from 20 mM to 2.0 M NaCl with no sign of saturation at low salt . Impermeant polymers reduce the conductance in a manner consistent with their ability to reduce bulk conductivity . Extrapolating from the known structure of homologous porins, the selectivity filter is likely to be small and localized . If small and highly negatively charged ( approximately 9 charges), the predicted conductance would be an order of magnitude higher than that observed . The rate at which ions reach the selectivity filter seems to limit overall ionic flux . PorA/C1 rectifies strongly, and this rectification can be accounted for by calculated differences in the voltage and concentration profiles in the access regions . Thus, it appears that the conductance of this channel is determined by the access resistance and the selectivity by a highly-conductive filter.

Pediatrics . 1999 Feb;103(2):E20.
Clinical and hematologic features do not reliably identify children with unsuspected meningococcal disease; Kuppermann N et al.; OBJECTIVE: To determine the frequency of unsuspected meningococcal disease (UMD) in young febrile children with meningococcal infections and evaluate whether clinical and laboratory parameters commonly used in the evaluation of fever can help identify children with UMD . METHODS: We reviewed the records of children with meningococcal disease from 1985 to 1996 at four referral centers . Children who were evaluated as outpatients and then discharged to home, from whom Neisseria meningitidis was isolated from blood or cerebrospinal fluid cultures obtained during these outpatient visits, were considered to have UMD . We compared clinical and laboratory parameters between these children and 6414 febrile outpatients 3 to 36 months old with negative blood cultures enrolled in a separate study of occult bacteremia . RESULTS: We identified 381 children with meningococcal disease, of whom 45 (12%) had UMD . Of the 45 with UMD, 37 (82%) were 3 to 36 months old . Compared with the 6414 culture-negative patients, these 37 patients with UMD were significantly younger (8.9 +/- 5.4 vs 14.2 +/- 8.1 months) and had significantly higher band counts (14.3 +/- 11.1 vs 7.3 +/- 7.5%) . There were no significant differences, however, in temperature, white blood cell counts, and absolute neutrophil counts . Multivariate analysis identified young age and the band count as independent predictors of UMD . CONCLUSIONS: Children ultimately diagnosed with meningococcal disease have commonly been evaluated as outpatients and discharged to home before diagnosis . Of the hematologic parameters frequently used in the evaluation of fever, only the band count differs significantly between young febrile children with UMD and those with negative cultures . Because UMD is uncommon in young febrile pediatric outpatients, however, the predictive value of the band count is low . Thus, the complete blood count is not routinely helpful for the diagnosis of UMD.

J Public Health Med, 1998 Dec, 20(4), 382 - 5
A primary care perspective of meningococcal disease; Wood AL et al.; BACKGROUND: It is generally agreed that pre-admission benzyl penicillin improves the outcome in infection by Neisseria meningitidis . Even so, only a minority of cases in Birmingham received such treatment . The aim of this study was, therefore, to determine the views of general practitioners (GPs) in Birmingham on the early management of meningococcal disease, including the use of parenteral antibiotics . METHODS: A standard semi-structured confidential questionnaire was posted to GPs on the list of Birmingham Family Health Services Authority . The questions covered the GPs' clinical experience of meningococcal infection and their views on the pre-hospital management of suspected cases of Neisseria meningitidis . RESULTS: Completed questionnaires were received from 372 GPs, a response rate of 70 per cent . Nearly all GPs said they carried benzyl penicillin in their on-call bag (353; 95 per cent) and would give it to a patient they suspected had meningococcal disease (361; 97 per cent) . A total of 208 GPs (56 per cent) would not give parenteral chloramphenicol to a patient they suspected had meningococcal disease and a penicillin allergy, and only 25 (7 per cent) carried it as an alternative antibiotic . The most common reason for not giving chloramphenicol was unfamiliarity with dosages (132; 63.5 per cent) . CONCLUSIONS: The vast majority of GPs in Birmingham would apparently give benzyl penicillin to a patient they suspected had meningococcal infection . No single issue emerged to explain why pre-admission administration of benzyl penicillin was so low . Further work is being carried out locally to help translate positive attitudes into a change in behaviour.

Eur J Clin Microbiol Infect Dis, 1998 Nov, 17(11), 749 - 53
Failure of mass antibiotic prophylaxis to control a prolonged outbreak of meningococcal disease in an Israeli village; Shehab S et al.; In January 1994 mass antibiotic prophylaxis was undertaken in the contiguous villages of Deir el-Asad and B'ine in northern Israel (combined population of 11600) in response to a prolonged outbreak of serogroup B meningococcal infection with an overall annual rate of 37.4 cases of infection per 100000 residents . The average case fatality rate in the villages was 23% compared with 11% in Israel during the same period . Neisseria meningitidis group B was identified in 9 of 13 (69%) cases . Seven of these were subtype P1.7,16 . The persistence of the outbreak with its accompanying public reaction prompted the establishment of an intervention programme that included antibiotic prophylaxis for the whole community with monitoring for pharyngeal carriage of meningococci in a stratified sample of the population . The objectives were to achieve a reduction of carriage of the outbreak strain and to reduce morbidity and mortality . A total of 1036 pharyngeal swabs were taken 1 day before and 6 weeks after treatment . Antibiotic prophylaxis was administered in one dose: children under 5-years-old received ceftriaxone i.m.; all others received oral ciprofloxacin . Overall, 96% of the population received treatment . The carriage rate was 8.3% prior to treatment (three serogroup B:14:P1.7,16), and 1.3% afterwards (one serogroup B:14:P1.7,16) . The intervention failed to eradicate carriage of the putative outbreak strain, or to reduce the incidence and fatality rates in the villages . The outbreak finally terminated in late 1996 . Public health professionals should bear this experience in mind when faced with prolonged, localized, nonexplosive outbreaks of meningococcal disease associated with low carriage rates of the outbreak strain.

Przegl Epidemiol, 1998, 52(3), 237 - 44
{The study of carrier of Neisseria meningitidis performed in Zielonec and characteristics of meningogocci isolated from patients at the Wołomin hospital, Warsaw district}; Grzybowska W et al.; Meningococcal carriage study, performed after N . meningitidis outbreak in Zielonka included 130 persons (111 children) . No N . meningitidis strain was isolated . Phenotype and genotype analysis of 6 meningococcal isolates obtained from blood and CSF, showed their heterogeneity with exception of 2 isolates from Zielonka's cases of meningococcal sepsis which were identical.

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