Severity Of Meningococcal Disease Research Articles

Genetic Variants in Toll-Like Receptor 2 (TLR2), TLR4, TLR9, and FCγ Receptor II Are Associated with Antibody Response to Quadrivalent Meningococcal Conjugate Vaccine in HIV-Infected Youth

This study examined the association of host genetic variants with the antibody response to the quadrivalent meningococcal conjugate vaccine (MCV4) in HIV-infected youth. Genetic variants associated with severity of meningococcal disease, including the IgG Fc receptor (FCγRII)-A484T, interleukin-10 (IL-10)-A1082G, -C819T, and -C627A, IL-4-C589T, mannose binding lectin-2 (MBL2)-A/O, -H/L, -P/Q, and -X/Y, toll-like receptor 2 (TLR2)-G2408A, TLR4-A12874G and -C13174T, and TLR9-T1237C and -T1486C were determined by real-time PCR (RT-PCR) for 271 HIV-infected subjects (median, 17 years). Response was defined as a ≥4-fold increase from entry in bactericidal antibody titers to each serogroup. Generalized estimating equation (GEE) models were used to evaluate the association of allelic variants with the immunologic response to all serogroups within each subject with and without adjusting for CD4 percentage and HIV viral load. At week 4, but not after, subjects with TLR2-2408-G/A versus -G/G genotypes and the TLR4-12874-A/A genotype were more likely to achieve a ≥4-fold increase overall in the four serogroups (unadjusted P of 0.006 and adjusted P of 0.008 and unadjusted P of 0.008 and adjusted P of 0.019, respectively). At week 28, the TLR9-1237 T allele was associated with enhanced antibody response (T allele versus C/C, unadjusted P of 0.014 and adjusted P of 0.009), which was maintained at week 72 (unadjusted and adjusted P of 0.008). At week 72, the FcγRII-131Arg allotype was associated with a ≥4-fold increase in antibody titer versus those with His/His (unadjusted P of 0.009; adjusted P of <0.001). These findings suggest that for HIV-infected youth, the initial antibody response to MCV4 is associated with variants in TLR2 and TLR4 while the long-term response is associated with genetic polymorphisms in TLR9 and FcγRIIa.

POLYMORPHISMS IN PARP, IL1B, IL4, IL10, C1INH, DEFB1, AND DEFA4 IN MENINGOCOCCAL DISEASE IN THREE POPULATIONS

The pathogenesis of meningococcal infections involves activation of the complement system, proinflammatory and anti-inflammatory mediators, antimicrobial peptides, and apoptosis. We hypothesized that variations in genes encoding these products are involved in the susceptibility to and severity of pediatric meningococcal infections. Polymorphisms in poly (adenosine diphosphate-ribose) polymerase (PARP), serine protease C1 inhibitor (C1INH), IL4, IL10 and IL1B, alpha-defensin 4, and beta-defensin 1 (DEFB1) were analyzed in two independent Caucasian case control cohorts from the United Kingdom and the Netherlands and in a family-based transmission disequilibrium test cohort from the UK. In the UK case control cohort, the DEFB1 -44 G/G homozygous genotype was overrepresented in patients with meningococcal disease compared with the G/C and C/C genotypes when combined (odds ratio, 1.57; 95% confidence interval, 1.12-2.20). The transmission disequilibrium test analysis did not confirm this, but did find an association and linkage of the IL4 -524 and the C1INH 480 polymorphisms with susceptibility to meningococcal infection. Hematological failure was present more often in UK patients with the DEFB1 -44 G/G genotype compared with the C allele carriers (odds ratio, 2.17; 95% confidence interval, 1.22-3.85). Additional studies are necessary to elucidate the conflicting results obtained for the DEFB1, IL4, and C1INH polymorphisms and their role in susceptibility to and severity of meningococcal disease.

Severity of Meningococcal Disease Associated with Genomic Bacterial Load

Severity of Meningococcal Disease Associated with Genomic Bacterial Load

Influence of innate cytokine production capacity on clinical manifestation and severity of pediatric meningococcal disease

Objective: To analyze the role of the innate production capacity for tumor necrosis factor, interleukin-1[beta], interleukin-12, and interleukin-10 in the clinical presentation and severity of meningococcal disease. Design: Whole blood cultures from survivors of severe meningococcal disease obtained median 5.4 yrs after hospitalization were stimulated with meningococcal lipopolysaccharide and heat-killedNeisseria meningitidisbacteria. Setting: Intensive care unit in academic hospital. Patients: A total of 111 children were included. We classified these patients according to clinical manifestation in four groups: shock (n = 43); both shock and meningitis (n = 11); bacteremia (neither shock nor meningitis, n = 24); and distinct meningitis (n = 33). Interventions: None. Measurements and Main Results: The classification into four groups stratifies these patients according to disease severity. No differences in whole blood cytokine production were found between the patients in these four groups. However, within the group of patients who had presented with shock, interleukin-1[beta] and the interleukin-1[beta]/interleukin-10 ratio were negatively correlated with disease severity (R = -.35,p= .03 and R = -.33,p= .04, respectively; Pediatric Risk of Mortality score). Conclusions: Clinical manifestation of meningococcal disease cannot be explained by the innate production capacity of whole blood cultures for the cytokines tumor necrosis factor, interleukin-1[beta], interleukin-10, and interleukin-12. In patients who presented with shock, a low production capacity for interleukin-1[beta] and a low interleukin-1[beta]/interleukin-10 production ratio was associated with more severe disease.

Opa Protein Repertoires of Disease-Causing and Carried Meningococci

The meningococcal Opa proteins play an important role in pathogenesis by mediating invasion of human cells. The aim of this investigation was to determine whether carried and disease-associated meningococci possess different Opa repertoires and whether the diversity of these proteins is associated with clinical severity of disease. Opa repertoires in 227 disease-associated meningococci, isolated in the United Kingdom over a period of 6 years, were compared to the repertoires in 190 asymptomatically carried meningococci isolated in the United Kingdom from a contemporary, nonepidemic period. Multidimensional scaling (MDS) was employed to investigate the association between Opa repertoires and multilocus sequence typing (MLST) genotypes. Associations with clinical severity were also analyzed statistically. High levels of diversity were observed in opa alleles, variable regions, and repertoires, and MDS revealed that MLST genotypes were strongly associated with particular Opa repertoires. Individual Opa proteins or repertoires were not associated with clinical severity, though there was a trend toward an association with the opaD locus. Meningococcal Opa repertoire is strongly linked to MLST genotype irrespective of epidemiological sampling and therefore correlates with invasiveness. It is not, however, strongly associated with severity of meningococcal disease.

Neisseria meningitidis, Neisseria lactamica and Moraxella catarrhalis share cross-reactive carbohydrate antigens

Carriage of commensal bacteria species is associated with the development of natural immunity to meningococcal disease, with lipo-oligosaccharides (LOS) of meningococci being one of the main virulence factors associated with severity of meningococcal disease. Meningococcal reference strains and isolates from the commensal species Neisseria lactamica and Moraxella catarrhalis were assessed for the presence of cross-reactive glycoconjugate antigens. Binding of human blood group antibodies of the P and Ii system to meningococcal immunotype reference strains were in accordance with the presence of known LOS carbohydrate structures. Binding studies with meningococcal immunotyping antibodies and blood group phenotyping antibodies to N. lactamica strains from different European countries showed, that a greater number of isolates obtained from native Greek and Scottish adults and children bound anti-meningococcal L(3, 7, 9) immunotyping ( P<0.001), p K ( P=0.035) and paragloboside ( P<0.001) blood group typing antibodies compared to isolates obtained from children of Russian immigrants in Greece. A greater number of M. catarrhalis strains isolated from children in Scotland bound anti-L(3, 7, 9) antibodies (38.2%) compared to strains isolated from adults (22.2%) ( P=0.017). These findings provide evidence that blood group like glycoconjugate antigens found on the commensal species N. lactamica and M. catarrhalis might be involved in the development of natural immunity to meningococcal endotoxins during childhood, and might be exploited as anti-meningococcal vaccine candidates.

Severity of meningococcal disease in children and the angiotensin-converting enzyme insertion/deletion polymorphism.

Critical illness outcome may be causally related to inflammatory response severity. Given that tissue angiotensin-converting-enzyme (ACE) regulates such responses and that the deletion (D) [rather than insertion (I)] variant of the ACE gene is associated with higher tissue ACE levels, DD genotype might be associated with a poorer outcome in a uniform infectious disease state. Illness severity (Pediatric RIsk of Mortality score, the Glasgow Meningococcal Septicaemia Prognostic Score [GMSPS], and clinical course) was recorded for consecutive white patients with meningococcal disease (n = 110, 34 DD genotype, 61 male, aged 49.4 +/- 5.4 months) referred to the Royal Liverpool Children's Hospital, UK. Compared with children with > or = I allele, DD genotype was associated with 14% higher predicted risk of mortality (p = 0.038), higher GMSPS (DD 9.4 +/- 0.5, ID/II 7.7+/- 0.4 [mean +/- SEM], p = 0.013), greater prevalence of inotropic support (76% versus 55%, p = 0.03) and ventilation (82% versus 63%, p = 0.04), and longer Pediatric Intensive Care Unit (PICU) stay (5.8 versus 3.9, p = 0.02). DD genotype frequency was 6% (1 case) for the 18 children who did not require PICU care, 33% for the 84 PICU survivors, and 45% for those who died (p = 0.01). ACE DD is associated with increased illness severity in meningococcal disease.

Severity of meningococcal disease

Severity of meningococcal disease

Outcome of a complex interaction

Infections caused by Neisseria meningitidis provoke considerable anxiety. Meningococcal disease is transmittable and can affect young and previously healthy people. The course of the disease can be rapid, because meningococci shed large amounts of endotoxin, a constituent of the meningococcal outer membrane that induces fever and shock. Patients can die within hours after the onset of non-specific symptoms, and those who survive often have amputations, hearing loss, and renal failure. Although in Europe only one case arises in every 100 000 inhabitants every year, most individuals are probably colonised by a meningococcal strain at least once a year. Host and bacterial factors regulate the outcome of a complex interaction. The risk of development of disease after nasopharyngeal colonisation is high if protective antibody titres, which vary throughout life, are low at the time of acquisition of a pathogenic strain (figure). The protective antibodies that bind to meningococci are induced by nasopharyngeal colonisation with neisserial species that express cross-reactive antigens. Some individuals are also more susceptible to meningococcal disease because of their genetic makeup. A few patients are at high risk because of deficiencies of complement proteins, which mediate phagocytosis and lyse the bacteria immediately after they enter the bloodstream. Some of these complement deficiencies make the patient susceptible to recurrent episodes of mild meningococcal disease, and others are associated with severe and often lethal forms of the disease. Mutations in the mannose binding lectin, which is also involved in complement activation, enhance susceptibility to the disease. Coagulopathy, an important feature of severe disease, occurs most frequently in patients with polymorphisms in genetic elements that drive the expression of a regulator of the coagulation cascade. The same has been reported for the gene of a cytokine, termed tumour necrosis factor , whose degree of expression correlates with the severity of meningococcal disease. A polysaccharide capsule surrounds pathogenic isolates and prevents phagocytosis and lysis of the bacteria. The chemical composition of the lipopolysaccharide has been identified, as have host cell receptors that interact with meningococci. Researchers are trying to understand how bacteria enter the cerebrospinal fluid. Complete sequencing of the genomes of three genetically different pathogenic meningococcal strains is a driving force in research of meningococcal pathogenicity, because each of the 2100 genes can now be analysed for its contribution. Because of the genetic and antigenetic variability of meningococci, however, we still do not know what cocktail of bacterial factors is sufficient to render a strain dangerous. To answer this question, molecular epidemiologists are studying the distribution of meningococcal lineages in healthy carriers and in patients. Meningococcal sequence types (STs) and their phylogenetic relations are defined by DNA sequence comparisons of housekeeping genes, whose variation is independent of immune selection. Related STs are summarised in meningococcal lineages or complexes. The genetic background of a strain largely determines risk of disease. For example, some meningococcal lineages are frequently found in healthy carriers but never cause disease—ie, the ST-53 complex. Strains of the ST-53 complex are avirulent because they lack capsule synthesis genes. Other lineages also frequently colonise healthy individuals, but can cause meningococcal disease—ie, the ST-22 and ST-23 complexes. These lineages are characterised by expression of the capsular serogroups W-135 and Y, respectively. By contrast, strains of the ST-11 complex are rare in healthy carriers, but cause many instances of serogroup C disease. Therefore, non-immune people who acquire an ST-11 strain are at risk of developing meningitis or severe meningococcal disease. Monitoring such pathogenic lineages is warranted, since new clones are constantly evolving, which can cause meningococcal disease in human populations that lack herd immunity. There are various meningococcal pathogenicity patterns made up of different variants of the capsule, the lipopolysaccharide, outer membrane porins, adhesins, iron-binding proteins, and other unknown virulence factors. This natural variety can be exploited to understand in detail the pathogenicity of N meningitidis, since we now have the tools for the job; molecular epidemiology, human and bacterial genome sequences, and sophisticated pathogenicity research. A human host is colonised by a meningococcal strain The outcome of this interaction is affected by the virulence of the strain, and by the natural immunity and genetic predisposition of the host. Usually an asymptomatic commensal lifestyle of the bacterium results, but sometimes disease occurs.

A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease.

Human Toll-like receptor 4 (TLR4) transduces proinflammatory cytokine release by human cells in response to lipopolysaccharide (LPS). This study tested the hypothesis that, if TLR4 is rate limiting for a successful response to bacterial LPS in humans, a human gene polymorphism that results in the amino acid substitution Asp299Gly and causes reduced expression and function of TLR4 should influence susceptibility to or severity of natural gram-negative infection. The allele frequency of the Asp299Gly polymorphism was 5.9% among 879 blood donors, 6.5% among 1047 patients with microbiologically proven meningococcal disease, and 4.1% among 86 patients who died of meningococcal disease. No significant differences were observed, including those analyzed after stratification of the infected population by age and by meningococcal serogroup. Therefore, this functional TLR4 polymorphism does not influence susceptibility to or severity of meningococcal disease.

Effect of the Factor V Leiden mutation on the severity of meningococcal disease.

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

Association of Human FcγRIIa (CD32) Polymorphism with Susceptibility to and Severity of Meningococcal Disease

Phagocytosis of bacteria constitutes an important defense mechanism against invasive bacterial diseases. Efficacy of phagocytosis by polymorphonuclear neutrophils is known to vary between allotypes of Fc gamma RIIa (a class of Fc receptors for immunoglobulins that is constitutively expressed on neutrophils). We compared the distribution of Fc gamma RIIa-R131 and Fc gamma RIIa-H131 allotypes in 98 Slavic complement-sufficient patients with meningococcal disease with that of the allotypes in 107 healthy controls. A strong association was found between the IIa-R/R131 allotype and the development of meningococcal disease after the age of 5 years, compared with IIa-R/H131 and IIa-H/H131 allotypes (P < .03; odds ratio [OR], 2.9). A severe course of meningococcal disease was observed in 21 (68%) of 31 episodes in patients with IIa-R/R131 genotype and in 22 (54%) of 41 episodes in patients with IIa-R/H131 genotype, in contrast to eight (31%) of 26 episodes in patients with IIa-H/H131 genotype (P < .02; OR, 4.7). Our data show that individuals older than 5 years of age who have the IIa-H/H131 allotype are less susceptible to severe meningococcal disease than are individuals with the IIa-R/R131 or IIa-R/H131 genotype.

Meningococcal disease and influenza-like syndrome: a new approach to an old question.

The temporal and spatial association of meningococcal disease and influenza-like syndrome (ILS) was assessed from surveillance data on these diseases in France for a 6-year period (1985-1990). Using time series methods to account for the usual seasonal pattern meningococcal disease, the incidence of meningococcal disease in a given week was found to be linked to incidence of ILS in the 5 previous weeks but not to that in subsequent weeks. Geographic spread of meningococcal disease correlated with spread of ILS. This study also suggests that meningococcal disease is more severe for a 2-month period during and after an ILS epidemic: The proportion of cases with purpura fulminans increased by 24% and those resulting in death by 26% during this period. No shift in the age distribution was observed. When an ILS epidemic is identified, medical practitioners should be informed of the likelihood of an increased incidence and severity of meningococcal disease.

Severity of Meningococcal Disease: Assessment by Factors and Scores and Implications for Patient Management

Results from our own and other published series of cases of meningococcal disease were used to study prognostic factors and to compose scores for assessment of severity of disease on admission to the hospital. The difference in risk for fatality was designated the factor fatality difference (FFD); the FFD was determined by subtracting the percent fatality for factor-negative patients from the percent fatality for factor-positive patients. FFD was useful for selection of good indicators of severity of disease. Blood pH of less than 7.35 was the best single factor; low platelet count came next, followed by low blood pressure, cyanosis, ecchymosis, and low blood leukocyte count. New scores were constructed based on multiple regression analyses. Several older and new scores seemed to be comparable. By combining age-adjusted systolic blood pressure (less than 100 mm Hg), cyanosis, ecchymosis, diarrhea before or at admission, cold extremities, absence of nuchal or back rigidity, and rectal temperature of greater than or equal to 40 degrees C, a simple bedside percentage score, the MenOPP bedside clinical score (MOC), was devised. Cross-evaluations on test materials generally confirmed the choice of score. The simplicity of this score made it more clinically suitable than laboratory or mixed laboratory and bedside scores.