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 patie