Course Of Meningococcal Disease Research Articles

Interactions and Signal Transduction Pathways Involved during Central Nervous System Entry by Neisseria meningitidis across the Blood-Brain Barriers.

The Gram-negative diplococcus Neisseria meningitidis, also called meningococcus, exclusively infects humans and can cause meningitis, a severe disease that can lead to the death of the afflicted individuals. To cause meningitis, the bacteria have to enter the central nervous system (CNS) by crossing one of the barriers protecting the CNS from entry by pathogens. These barriers are represented by the blood–brain barrier separating the blood from the brain parenchyma and the blood–cerebrospinal fluid (CSF) barriers at the choroid plexus and the meninges. During the course of meningococcal disease resulting in meningitis, the bacteria undergo several interactions with host cells, including the pharyngeal epithelium and the cells constituting the barriers between the blood and the CSF. These interactions are required to initiate signal transduction pathways that are involved during the crossing of the meningococci into the blood stream and CNS entry, as well as in the host cell response to infection. In this review we summarize the interactions and pathways involved in these processes, whose understanding could help to better understand the pathogenesis of meningococcal meningitis.

Adolescents at Risk: The Case for Meningococcal Vaccine

<h2>Abstract</h2> The clinical course of meningococcal disease represents a diagnostic challenge because early symptoms are often nonspecific and overlap with those of other common infections before rapidly progressing to a life-threatening condition. Clinicians need to prioritize vaccination of preadolescent, adolescent, and other patients who are at risk of meningococcal disease, using a quadrivalent meningococcal conjugate vaccine at the soonest opportunity.

Naturally Occurring Lipid A Mutants in Neisseria meningitidis from Patients with Invasive Meningococcal Disease Are Associated with Reduced Coagulopathy

Neisseria meningitidis is a major cause of bacterial meningitis and sepsis worldwide. Lipopolysaccharide (LPS), a major component of the Gram-negative bacterial outer membrane, is sensed by mammalian cells through Toll-like receptor 4 (TLR4), resulting in activation of proinflammatory cytokine pathways. TLR4 recognizes the lipid A moiety of the LPS molecule, and the chemical composition of the lipid A determines how well it is recognized by TLR4. N. meningitidis has been reported to produce lipid A with six acyl chains, the optimal number for TLR4 recognition. Indeed, meningococcal sepsis is generally seen as the prototypical endotoxin-mediated disease. In the present study, we screened meningococcal disease isolates from 464 patients for their ability to induce cytokine production in vitro. We found that around 9% of them were dramatically less potent than wild-type strains. Analysis of the lipid A of several of the low-activity strains by mass spectrometry revealed they were penta-acylated, suggesting a mutation in the lpxL1 or lpxL2 genes required for addition of secondary acyl chains. Sequencing of these genes showed that all the low activity strains had mutations that inactivated the lpxL1 gene. In order to see whether lpxL1 mutants might give a different clinical picture, we investigated the clinical correlate of these mutations in a prospective nationwide observational cohort study of adults with meningococcal meningitis. Patients infected with an lpxL1 mutant presented significantly less frequently with rash and had higher thrombocyte counts, consistent with reduced cytokine induction and less activation of tissue-factor mediated coagulopathy. In conclusion, here we report for the first time that a surprisingly large fraction of meningococcal clinical isolates have LPS with underacylated lipid A due to mutations in the lpxL1 gene. The resulting low-activity LPS may have an important role in virulence by aiding the bacteria to evade the innate immune system. Our results provide the first example of a specific mutation in N. meningitidis that can be correlated with the clinical course of meningococcal disease.

Systemic manifestations in the course of meningococcal disease

Meningococcal disease most often manifests itself as meningitis or sepsis. During the course of these diseases, other clinical events sometimes develop such as pneumonia, pericarditis, arthritis, and they are referred to as extrameningeal or systemic manifestations of the meningococcal disease. The aim of this study was to investigate the type and the incidence of particular extrameningeal/systemic manifestations among patients with meningococcal meningitis and sepsis, including time of their onset and the influence on the disease outcome. The retrospective study of the medical records of 246 patients treated for meningococcal disease over the 25-year period in the Institute for Infectious and Tropical Diseases, Belgrade was conducted. The patients, aged 3 months to 82 years both sexes, were divided into two groups. Out of 246 patients extrameningeal/systemic manifestations were found in 42 (17.1%) patients: 35 (14.2%) occurred during meningitis, and seven (2.8%) during sepsis. Pulmonary manifestations (mostly pneumonia) were the most prevalent, found in 12 (4.9%) patients, followed by heart involvement in nine (3.6%) patients (mostly pericarditis, in seven or 2.8% patients). Various ophthalmic manifestations occurred in seven (2.8%), arthritis in 4 (1.6%) and sinusitis in six (2.4%) patients. Otitis, multiple renal embolisms with hematuria, osteomyelitis and thrombophlebitis were evidenced in one patient, each. Most of the systemic manifestations (30 patients or 71.4%), developed within the initial three days of the disease (p < 0.01), suggesting direct pathogenic mechanism induced by meningococci per se, while only three (7.1%) developed after seven days, when immune-mediated disease was more likely. Even though these manifestations complicate and prolong treatment of the meningococcal disease, they had no major influence on the disease outcome. Lethal outcome occurred in 2 (4.76%) patients, both with the meningococcal type of the disease. Extrameningeal or systemic manifestations are uncommon complications during the course of both meningococcal meningitis and sepsis. The onset of pneumonia, pericarditis, eye involvement, and arthritis, within the initial seven days of the disease, were most prevalent in the course of meningitis. They had no major influence on the disease outcome.

Pre-admission clinical course of meningococcal disease and opportunities for the earlier start of appropriate intervention: a prospective epidemiological study on 752 patients in the Netherlands, 2003–2005

To improve the timeliness of health care delivery to patients with meningococcal disease, the early disease evolution and clinical manifestation at admission were studied in all 752 patients with invasive meningococcal disease in the Netherlands in 2003-2005. Eighty-eight percent (88%) had serogroup B disease. The case fatality rate (CFR) was 6.7% overall, but reached 16% among adults over 50 years of age. The CFR was similar for serogroups B (6.3%) and C (5.2%). Admission followed 17 h (median) after the onset of symptoms. The CFR in patients admitted within 12 h, 12-18 h, 18-36 h or >36 h after the first symptoms was 10.2, 7.8, 3.5 and 2.2%, respectively. Only 60% of patients had skin lesions, and admission followed 2 h (median) later. Earlier recognition can be achieved when non-petechial clues are included in the diagnosis. A short duration of disease before admission is a simple tool in the recognition of patients with severe disease.

Diagnosing Meningococcal Disease

Infectious Diseases/Senior Members| May 01 2006 Diagnosing Meningococcal Disease AAP Grand Rounds (2006) 15 (5): 56–57. https://doi.org/10.1542/gr.15-5-56 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Diagnosing Meningococcal Disease. AAP Grand Rounds May 2006; 15 (5): 56–57. https://doi.org/10.1542/gr.15-5-56 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search nav search search input Search input auto suggest search filter All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: meningococcal infections Source: Thompson MJ, Ninis N, Perera R, et al. Clinical recognition of meningococcal disease in children and adolescents. Lancet. 2006;367:397–403. Meningococcal disease occurs worldwide; in developed countries during endemic periods, the mortality can be as great as 10%.1,–5 A practitioner’s experience with meningococcal disease is often quite limited. The potential for extremely rapid progression to a severe or fatal outcome requires that physicians recognize the signs and symptoms of meningococcal disease as early in the clinical course as possible. Most pediatricians rely on textbook descriptions of classic features that usually occur relatively late in the course of meningococcal disease – purpura, meningismus, and shock – to signal the need to consider meningococcal disease when evaluating a child who is ill. This study from the University of Oxford, United Kingdom, is a retrospective review designed to assess the sequence, development, and timing... You do not currently have access to this content.

Changing the diagnostic framework of meningococcal disease

In todays Lancet Matthew Thompson and colleagues show that leg pain cold extremities and abnormal skin colour which are symptoms and signs of sepsis and shock are seen in the first 12 h of meningococcal disease whereas the classic features of haemorrhagic rash--meningism and impaired consciousness--are relatively late signs with a median onset of 13-22 h. The authors recommend that the diagnostic framework is changed to emphasise recognition of the early symptoms of sepsis (panel). Thompson and colleagues study pioneers the description of the presentation and time course of meningococcal disease in children and adolescents before admission to hospital. (excerpt)

Severe meningococcal disease in childhood

Severe meningococcal disease in childhood

Procalcitonin as a prognostic marker in meningococcal disease.

To assess the prognostic value of procalcitonin levels during the clinical course of meningococcal disease in children. A retrospective, descriptive study. University paediatric intensive care unit. Nine patients with meningococcal sepsis and 55 patients with meningococcal septic shock were included in the study, giving a total of 64. Procalcitonin (PCT), C-reactive protein (CRP), cytokines (IL-6, IL-8 and TNF-alpha), plasminogen activator inhibitor-1 (PAI-1) and several routine laboratory parameters were determined and expressed as medians (ranges). PCT levels on hospitalisation were elevated in all children as compared to normal values. Median PCT levels on admission were significantly higher in children with septic shock than in children with sepsis (270 ng/ml (5.7-672.3) versus 64.4 (20.6-283.7); p<0.01). When the patients were categorised to severity using the Pediatric Risk of Mortality (PRISM) score (group 1: <15 points, group 2: 16-30, group 3: >30), the PCT levels were significantly different in the three groups. All markers, with the exception of PCT (p=0.056), were significantly different between survivors and non-survivors. When the duration of petechiae was taken into account, the difference in PCT levels became significant (p=0.04). Procalcitonin levels on admission are related to severity. In the case of a short disease history (duration of petechiae), PCT levels are also related to mortality. Although PCT levels are elevated in all patients, the levels per se do not allow a prediction about survival versus non-survival, this is in contrast to other markers and scores (PRISM).

Bench-to-bedside review: genetic influences on meningococcal disease.

This review discusses the possible involvement of a variety of genetic polymorphisms on the course of meningococcal disease. It has been shown that several common genetic polymorphisms can either influence the susceptibility to meningococcal disease or can account for a higher mortality rate in patients. Gene polymorphisms concerning antibody receptors, lipopolysaccharide (LPS) binding receptors or proteins, innate complement proteins as well as cytokines and hemostatic proteins are described. The study of genetic polymorphisms might provide important insights in the pathogenesis of meningococcal disease and could make it possible to identify individuals who are at risk of either contracting or dying from meningococcal disease.

Molecular typing methods for Neisseria meningitidis.

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

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.

Acute Abdomen as an Atypical Presentation of Meningococcal Septicaemia

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

Clinical manifestations and course of meningococcal disease in 562 patients.

To describe the clinical manifestations and course of meningococcal disease (MD) data were collected on patients with culture-proven MD, reported in the Netherlands between April 1, 1989 and April 30, 1990 by means of a questionnaire completed by the specialist in attendance. During the study period, 562 patients (295 males, 267 females) were reported. The age of the patients ranged from 2 weeks to 88 years. Of the patients, 57.8% were classified as meningitic, 20.3% as bacteraemic and 21.9% as both meningitic and bacteraemic. In 4.6% of the patients a predisposing factor was present, and in 1.4% a previous episode of meningitis had occurred. A positive family history of meningitis was reported in 12.9% of the patients. On admission, 65.2% of the patients had haemorrhagic skin lesions, 7.9% coma and 4.2% seizures. During admission, 17.8% of the patients developed serious complications. The fatality rate was 7.7%. In 73.2% of the deceased, death occurred within 2 days after admission. Of the survivors, 8.5% recovered with serious sequelae. In conclusion, 16% of the patients with meningococcal disease either died or became severely disabled. Prevention of this putative life-threatening disease seems to be the only means of circumventing the problems caused by this serious condition.

Humoral immune response to class 1 outer membrane protein during the course of meningococcal disease.

We have determined the amounts of specific anti-class 1 outer membrane protein antibodies in sera from 25 patients during the course of systemic meningococcal disease, using purified class 1 protein as the sensitizing antigen in an enzyme-linked immunosorbent assay. The class 1 protein was obtained from a variant of strain 44/76 (B:15:P1.7,16) lacking class 3 and class 4 outer membrane proteins. Specific anti-class 1 (serosubtype P1.7,16) outer membrane protein immunoglobulin G (IgG) antibody levels increased significantly in 12 patients (12 of 25; 48%), regardless of the serotype of the infecting strain, indicating that the antibodies reacted in part with epitopes not determined by the monoclonal antibodies used for serotyping. Most patients had low levels of anti-class 1 IgG antibodies during the acute illness. The antibody levels peaked during the second week of disease and returned to near baseline levels in sera collected 6 weeks to 12 months after the onset of the disease. The majority of the specific anti-class 1 IgG antibodies bound to surface-exposed epitopes on whole bacteria and belonged to the IgG1 and IgG3 subclasses. Anti-class 1 IgA and IgM antibodies were not detected in any of the patient sera. Prior to disease, seven patients had been immunized with a meningococcal outer membrane vesicle vaccine developed from strain 44/76 (P1.7,16). None of these patients was infected with meningococcal strains containing class 1 protein homologous or partly homologous to that of the vaccine strain, indicating serosubtype-specific protection. The highest anti-class 1 IgG antibody peak levels were seen in immunized patients infected with strains of heterologous serotype, suggesting an anamnestic response. However, these patients were not protected from meningococcal disease after immunization.

Humoral immune response to the class 3 outer membrane protein during the course of meningococcal disease

We have determined the amounts of specific anti-class 3 outer membrane protein antibodies of immunoglobulin G (IgG), IgM, and IgA isotypes in patient sera during the course of meningococcal disease by using purified class 3 protein as the sensitizing antigen in an enzyme-linked immunosorbent assay. The class 3 protein was obtained from a variant of strain 44/76 (B:15:P1.7,16) lacking class 1 and class 4 outer membrane proteins. Serum samples from 25 patients with systemic meningococcal disease caused by organisms of various serotypes were collected during the course of disease. Seven of these patients had been immunized with a meningococcal outer membrane vesicle vaccine made from strain 44/76 prior to disease. An increase in specific anti-class 3 (type 15) outer membrane protein IgG antibodies was demonstrated in 22 of 25 patients (88%), regardless of the serotype of the infecting strain. This indicates that the specific anti-class 3 antibodies were reacting in part with epitopes not determined by the monoclonal antibodies used for serotyping. A considerable heterogeneity in antibody levels and IgG subclass response was seen. Most patients had low levels of anti-class 3 antibodies during the acute illness, with antibodies peaking during the second week of disease and returning to near baseline in sera collected 6 to 12 months after the onset of the disease. The majority of the specific anti-class 3 IgG antibodies were shown to bind to surface-exposed epitopes on the whole bacteria and to belong to IgG1 and IgG3. The highest anti-class 3 IgG peak levels were seen in patients infected with strains of the homologous serotype after vaccination with the meningococcal outer membrane vesicle vaccine, suggesting an anamnestic response. However, these patients were not protected from meningococcal disease after immunization.

Meningococcal Pericarditis

A diagnosis of pericarditis was made in five patients with acute meningococcal infections, including three from a recent series of 97 cases. Evidence for pericarditis was present in four of the five patients upon admission to the hospital, and all demonstrated the typical features of pericardial involvement, including electrocardiographic abnormalities, cardiac silhouette enlargement on x-ray film, and pericardial friction rubs. The course was uncomplicated in three patients, while two developed cardiac tamponade, necessitating pericardiocentesis. Reaccumulation of fluid was felt to be prevented by the administration of corticosteroids. A review of the past and present cases suggests that the pericarditis occurring early in the course of meningococcal disease is due to invasion of the pericardium by the organism, while its appearance later in the illness is a hypersensitivity reaction, initiated by the earlier bacterial invasion.

Meningococcal pericarditis. Clinical features andd therapy in five patients

A diagnosis of pericarditis was made in five patients with acute meningococcal infections, including three from a recent series of 97 cases. Evidence for pericarditis was present in four of the five patients upon admission to the hospital, and all demonstrated the typical features of pericardial involvement, including electrocardiographic abnormalities, cardiac silhouette enlargement on x-ray film, and pericardial friction rubs. The course was uncomplicated in three patients, while two developed cardiac tamponade, necessitating pericardiocentesis. Reaccumulation of fluid was felt to be prevented by the administration of corticosteroids. A review of the past and present cases suggests that the pericarditis occurring early in the course of meningococcal disease is due to invasion of the pericardium by the organism, while its appearance later in the illness is a hypersensitivity reaction, initiated by the earlier bacterial invasion.