Severe Meningococcal Disease Research Articles

Neisseria meningitidis carriage rate, antibiotic susceptibility profile, and associated factors among prisoners at Jimma zonal correction facility in Jimma Town, Southwestern Ethiopia: a cross-sectional study

BackgroundNeisseria meningitidis causes severe life-threatening meningococcal disease with a case fatality rate of 10–15% even with proper treatment. In Ethiopia, particularly in our study area, inadequate information is found on meningococcal disease. So, this study aimed to assess N. meningitidis carriage rate, antibiotic susceptibility profile, and associated factors among prisoners in Jimma Town, Southwestern Ethiopia.MethodsA cross-sectional study was conducted in Jimma town, Southwest Ethiopia, from May to October 2019. A stratified sampling technique was used and proportional allocation was done. A total of 550 oropharyngeal swabs were collected, processed, isolated, and identified N. meningitidis using standard microbiological techniques. Antibiotics susceptibility test was done for isolates using the disk diffusion method. Data on demographic and associated factors for carriage were collected using a structured questionnaire. Data were summarized using frequency, percentage, graph, and table. A logistic regression model was used to see the association between the dependent and independent variables. Variables with a p-value < 0.25 during bivariate analysis were included in multivariate analysis to identify factors significantly associated with the meningococcal carriage and, a p-value < 0.05 was considered statistically significant.ResultOut of the 550 study participants, 76(13.8%) with (CI: 7.20–18.20) were found carriers of N meningitidis. The predominant isolates were non-serogroupable 26(34.2%) and serogroup W/Y 22(28.9%), respectively. N. meningitidis isolates showed highest sensitivity to chloramphenicol 74(97.4%). Meningococcal carriage rate was significantly associated with being age group of 16–20 years; having respiratory symptoms within 3 months and active cigarette smoking within 3 months.ConclusionsThe majority of participants harbor most of the serogroups responsible for invasive cases of meningococcal disease. Respiratory symptoms, active cigarette smoking, and age group of 16–20 years increased the risk of N. meningitidis pharyngeal carriage rate. This study suggests providing better health education to control respiratory symptoms, smoking, and providing antibiotic prophylaxis for prisoners.

Інтенсивна терапія тяжких та блискавичних форм менінгококової інфекції в дітей

У статті наведено сучасні дані щодо інтенсивної терапії тяжких та блискавичних форм менінгококової інфекції в дітей. Детально охарактеризовані актуальні принципи антибактеріальної терапії, інфузійної реанімації, тактики застосування інотропних, симпатоміметичних засобів, вазодилататорів. Наведені цільові показники гомеостазу, що мають бути відновлені засобами інтенсивної терапії. Наведено клінічний приклад реалізації сучасних принципів інтенсивної терапії септичного шоку при менінгококовій інфекції. Також охарактеризовані інші напрямки інтенсивної терапії, а саме: застосування глюкокортикоїдів, принципи корекції водно-електролітного гомео­стазу та кислотно-основного стану, респіраторна підтримка, екстракорпоральні методи терапії, профілактика та лікування некротичного ураження шкіри та м’яких тканин.

Meningococcal Meningitis with Waterhouse-Friderichsen Syndrome.

This scenario was developed to educate junior and senior emergency medicine (EM) residents. It can also be cut short to be used for 4th year EM bound medical students. Meningococcal meningitis is a devastating disease that can cause severe neurologic sequelae if not diagnosed early and treated appropriately. In 2017, Centers for Disease Control reports a rate of 350 cases (0.11 cases per 100,000) which makes it an extremely rare disease. The highest reported rate is under the age of 1 (0.69 in 100,000) with second peak in adolescents and young adults between the ages of 16 and 23 (0.29 in 100,000) and third peak in patients above the age of 80 (0.49 in 100,000).1 The presentation for bacterial meningitis includes neck stiffness, fever, vomiting, photophobia, positive Kernig and Brudzinski's sign, and lethargy. In addition, 80% patients with meningococcal meningitis have rash during some stage of their disease.2 A feared and rare complication of severe meningococcal disease is Waterhouse-Friderichsen Syndrome (WFS) which carries a high mortality rate of 20%. Therefore, early diagnosis and rapid management of meningococcal disease is highly imperative.3 This simulation case was written to demonstrate the presentation of meningococcal meningitis and to discuss the management of WFS. By the end of this simulation session, learners will be able to: (1) manage a patient with altered mental status (AMS) with fever while maintaining a broad differential diagnosis, (2) recognize the risk factors for meningococcal meningitis, (3) manage a patient with worsening shock and perform appropriate resuscitation, (4) develop a differential diagnosis for thrombocytopenia and elevated international normalized ratio (INR) in an altered febrile hypotensive patient with rash, (5) manage the bleeding complications from WFS, (6) discuss the complications of meningococcal meningitis including WFS, and (7) review when meningitis prophylaxis is given. This session was conducted using high-fidelity simulation. It was immediately followed by an in-depth debriefing session. The session was conducted on a total of 9 EM residents from various levels of training who actively participated during the case and 25 residents who were observers. There was 1 simulation instructor running the session and 1 simulation technician who acted as a nurse. After the simulation and debriefing session was complete, an online survey was sent via surveymonkey.com to all the learners. The survey collected responses to the following questions: (1) the case was believable, (2) the case had right amount of complexity, (3) the case helped in improving medical knowledge and patient care, (4) the simulation environment gave me a real-life experience and, (5) the debriefing session after simulation helped improve my knowledge. A ten-item Likert scale was used to collect the responses. Ten learners responded to the survey. One hundred percent of them either agreed or strongly agreed that the case was beneficial in learning and improving patient care. They also agreed that it helped in improving medical knowledge. The post-session debrief was found to be very helpful by all the learners.. This high-fidelity simulation case was not only cost-effective but also was very helpful in teaching EM residents how to manage a patient with meningococcal meningitis and WFS. The case was started with the patient presenting with altered mental status and fever, and as the case unfolded, mental status and shock worsened allowing the learners to intubate and resuscitate. Overall, learners also found the discussion of prophylaxis valuable. Meningitis, altered mental status, medical simulation, infectious disease, neurology, septic shock, Waterhouse-Friderichsen Syndrome, hematology.

P034 Parvovirus B19 infection causing vasculitis and hypocomplementemia

Abstract Background/Aims Acquired hypocomplementemia occurs through immune complex-mediated diseases, as seen in systemic lupus erythematosus (SLE), idiopathic membranoproliferative glomerulonephritis (MPGN) and cryoglobulinemia. Infective causes are less common, although chronic bacterial and viral infections causing glomerulonephritis (GN) and vasculitis have been reported. Bacterial infections causing chronic osteomyelitis, endocarditis and visceral abscesses have all been implicated, whilst hepatitis B is the only virus known to cause severe GN/ vasculitis leading to low complement levels. Severe meningococcal disease is an established cause of acquired hypocomplementemia, typically associated with Nisseria Meningitidis. Parvovirus B19 is an infection exclusive to humans, usually manifesting as fifth disease, a mild illness characterised by a rash, fever and runny nose. Less common systemic effects include hydrops fetalis, thrombocytopenia, neutropenia, neurological sequalae (including encephalopathy, aseptic meningitis, neuropathy and neuralgic amyotrophy), myocarditis and hepatitis. Arthropathy is by far the most common manifestation in adults, affecting 60% of females and 30% of males. Methods The literature on Parvovirus B19 and hypocomplementemia is sparse, limited to case reports and comparative studies, the pathogenicity of which stems from glomerulonephritis, consequently resulting in low complement levels. We present a case series of 2 patients with Parvovirus B19 infection and acquired hypocomplementemia between 2016-2020. Results Patient A, a 26-year-old female, presented with a vasculitic rash on her legs and arthralgia affecting her hands and knees, refractory to oral prednisolone and hydroxychloroquine. She was found to have low complement levels (C3 0.61 g/l and C4 0.03 g/l), whilst ANA, ENA and ANCA testing was negative. She also had a negative rheumatoid factor and anti-CCP antibody, and a normal serum protein: creatinine (6 mg/mmol). Immunoglobulins were within normal range (IgG 8.7 g/l, IgA 0.80 g/l, IgM 2.41 g/l) and a serum protein electrophoresis was normal. Hepatitis and HIV serology was also negative. Patient B, a 34-year-old female, 9 weeks pregnant, presented with polyarthralgia, fever and a maculopapular rash, with normal inflammatory markers and a normal serum protein: creatinine (9 mg/mmol). Her complement was low (C3 0.57 g/l and C4 &amp;lt;0.02 g/l), ANA weakly positive, ENA negative and her ANCA screen showed a pANCA pattern with positive anti-PR3 antibodies (4.6 U/ml). She also had weakly positive dsDNA antibodies (37 IU/ml), and smooth muscle antibodies were weakly positive on tissue biopsy. Anti-C1q antibodies were normal. IgM was raised (2.56 g/l), whilst IgG and IgA were normal (10.8 g/l and 1.37 g/l, respectively). Serum protein electrophoresis was normal. HIV, hepatitis B and syphilis serology was all negative. In both cases, Parvovirus B19 IgM antibody was detected. Conclusion We recommend that clinicians consider acute viral illness in patients presenting with vasculitis and hypocomplementemia. If diagnosis and treatment can be established early, patients can avoid the need for long term immunosuppression. Disclosure A. Gharatya: None. C. Nelson: None. S. Melath: None.

Acute kidney injury in a mouse model of meningococcal disease

IntroductionMeningococcal disease is associated with high mortality. When acute kidney injury (AKI) occurs in patients with severe meningococcal disease, it is typically attributable to sepsis, although meningococcal disease and lipopolysaccharide release are rarely investigated. Therefore, we evaluated renal tissue in a mouse model of meningococcal disease.MethodsFemale BALB/c mice were induced to AKI by meningococcal challenge. Markers of renal function were evaluated in infected and control mice.ResultsIn the infected mice, serum concentrations of tumor necrosis factor alpha, interferon gamma, interleukins (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12), and granulocyte–macrophage colony-stimulating factor were elevated, as was renal interstitial infiltration with lymphocytes and neutrophils (p < 0.01 for the latter). Histological analysis showed meningococcal microcolonies in the renal interstitium, without acute tubular necrosis. Infected mice also showed elevated renal expression of toll-like receptor 2, toll-like receptor 4, and Tamm–Horsfall protein. The expression of factors in the intrinsic pathway of apoptosis was equal to or lower than that observed in the control mice. Urinary sodium and potassium were also lower in infected mice, probably due to a tubular defect.ConclusionOur findings corroborate those of other studies of AKI in sepsis. To our knowledge, this is the first time that meningococci have been identified in renal interstitium and that the resulting apoptosis and inflammation have been evaluated. However, additional studies are needed in order to elucidate the mechanisms involved.

A mixed-methods study to identify factors associated with MenACWY vaccine uptake, barriers and motivations towards vaccination among undergraduate students

Background: In response to an outbreak of severe meningococcal disease caused by serogroup W, the UK introduced the meningococcal ACWY (MenACWY) for adolescents and new university students as a control measure. Objective: To estimate MenACWY vaccine uptake and identify factors associated with uptake, barriers and motivations towards vaccination among university students. Design: Mixed methods including a cross-sectional survey, 7 interviews and 1 focus group. Setting: A Scottish university between April and May 2016. Methods: Inclusion criteria were &lt;25 years and attending university for the first time (MenACWY eligible). All first-year undergraduates ( n = 5,808) were invited to take part in the survey via email, and qualitative participants were recruited through the survey. The final sample consisted of 768 students, representing 13% (768/5,808) of the target population. Results: MenACWY uptake among the sample was 71.5% (549/768). Older students (22–24 years) were less likely than younger students (18 years) to have been vaccinated [adjusted odds ratio (aOR) = 0.21; 95% confidence interval (CI) = 0.06–0.77], and male students were less likely to be vaccinated than female students (aOR = 0.667; 95% CI = 0.45–0.96). In comparison to international students, domestic students had a significantly higher odds of vaccination (aOR = 3.89; 95% CI = 2.64–5.72). Communication barriers were most frequently identified as reasons for non-vaccination. Most vaccination occurred before starting university (76.7%, 421/549), highlighting access barriers. Meningococcal disease knowledge was low; a significant association ( p &lt; 0.001) was found between knowledge and vaccination uptake. Some participants were unaware of their vaccination history. They perceived meningococcal disease as severe, but disease risk as low. Key motivations were knowledge of the benefits of vaccines, influence of others and social responsibility. Conclusion: Students outside main UK-based, core age cohorts were under-immunised and focused efforts are needed to improve vaccination rates. Future student vaccination programmes could focus on raising awareness of the serious implications of meningococcal disease. Additional benefit may be gained from emphasising the benefits of vaccinations for society as a whole.

An outbreak of severe invasive meningococcal disease due to a capsular switched Neisseria meningitidis hypervirulent strain B:cc11

ObjectivesThe aim was to investigate an outbreak of invasive meningococcal disease (IMD) in Southern Sardinia. MethodsEpidemiological and microbiological investigations were performed. The latter included antimicrobial susceptibility testing and whole-genome sequencing (WGS). ResultsSeven individuals with severe IMD were found to be infected with serogroup B (MenB) Neisseria meningitidis in the first quarter of 2018. Five of the seven cases (five males; mean age 19 years; range 18–21 years; CFR 40%) were due to a unique strain B:P1.5-1,10-8:F3-6:ST-11(cc11), probably switched from the hypervirulent C-cc11, as confirmed by WGS. All five patients had attended the same nightclub in the 2 weeks prior to symptom onset. Public health measures, including chemoprophylaxis of contacts and active immunization against MenB, were implemented. ConclusionsWe observed five IMD cases due to the same switched MenB strain. The hypervirulent B:P1.5-1,10-8:F3-6:ST-11(cc11) strain, probably switched from C-cc11, is of concern due to the observed high virulence and case fatality rates. All the patients shared the same place of probable exposure. The molecular characterization of the invasive strain allowed the outbreak to be confirmed, which was then controlled through timely public health action.

Effectiveness of a Serogroup B and C Meningococcal Vaccine Developed in Cuba.

INTRODUCTION Serogroup B meningococcal outer membrane vesicle vaccines have been effective against vaccine-type strains, but their effectiveness against heterologous strains has been controversial. The Cuban VA-MENGOC-BC vaccine is of this type, but also includes meningococcus C capsular polysaccharide. OBJECTIVES Assess the effectiveness of VA-MENGOC-BC in reducing meningococcal disease caused by homologous or heterologous serogroup B strains and its serological effectiveness against meningococcus C. METHODS A review of studies of VA-MENGOC-BC's application in Cuba, Brazil, Uruguay and Colombia was carried out to examine the vaccine's effectiveness in reducing meningococcal disease during serogroup B outbreaks. Serological effectiveness against serogroup C determined in these studies (indicated by bactericidal antibody titers before and after vaccination) was also analyzed. RESULTS VA-MENGOC-BC's effectiveness against homologous serogroup B strains has consistently been greater than 80% in all age groups. Effectiveness in heterologous contexts was also above 80% in individuals aged >4 years. Lower effectiveness in heterologous contexts was found in Brazilian children aged 50%. Effectiveness increased when assessed based on mortality rates, as well as in cases of clinically severe meningococcal disease. The carrier-state pattern was modified after vaccination with reduction of hypervirulent lineages. Some 60% of infants (aged <1 year) attained protective bactericidal antibody titers against serogroup C. Higher protection rates were achieved in older children. CONCLUSIONS In addition to prevention of meningococcal disease caused by homologous serogroup B strains, VA-MENGOC-BC should be considered for heterologous contexts. It is protective against serogroup C in all age groups. KEYWORDS Neisseria meningitidis, meningococcal disease, meningococcal vaccines, serogroup B meningococcus, serogroup C meningococcus, immunogenicity, bacterial outer membrane proteins, heterologous effects of vaccines, acellular vaccines, Cuba.

In silico Homology Modeling and Epitope Prediction of NadA as a Potential Vaccine Candidate in Neisseria meningitidis.

Neisseria meningitidis is a facultative pathogen bacterium which is well founded with a number of adhesion molecules to facilitate its colonization in human nasopharynx track. Neisseria meningitidis is a major cause of mortality from severe meningococcal disease and septicemia. Neisseria meningitidis adhesion, NadA, is a trimeric autotransporter adhesion molecule which is involved in cell adhesion, invasion, and antibody induction. It is identified in approximately 50% of N. meningitidis isolates, and is established as a vaccine candidate due to its antigenic effects. In the present study, we exploited bioinformatics tools to better understand and determine the 3D structure of NadA and its functional residues to select B cell epitopes, and provide information for elucidating the biological function and vaccine efficacy of NadA. Therefore, this study provided essential data to close gaps existing in biological areas. The most appropriate model of NadA was designed by SWISS MODEL software and important residues were determined using the subsequent epitope mapping procedures. Locations of important linear and conformational epitopes were determined and conserved residues were identified to broaden our knowledge of efficient vaccine design to reduce meningococcal infectioun in population. These data now provide a theme to design more broadly cross-protective antigens.

Effectiveness of a Serogroup B and C Meningococcal Vaccine Developed in Cuba.

INTRODUCTION Serogroup B meningococcal outer membrane vesicle vaccines have been effective against vaccine-type strains, but their effectiveness against heterologous strains has been controversial. The Cuban VA-MENGOC-BC vaccine is of this type, but also includes meningococcus C capsular polysaccharide. OBJECTIVES Assess the effectiveness of VA-MENGOC-BC in reducing meningococcal disease caused by homologous or heterologous serogroup B strains and its serological effectiveness against meningococcus C. METHODS A review of studies of VA-MENGOC-BC's application in Cuba, Brazil, Uruguay and Colombia was carried out to examine the vaccine's effectiveness in reducing meningococcal disease during serogroup B outbreaks. Serological effectiveness against serogroup C determined in these studies (indicated by bactericidal antibody titers before and after vaccination) was also analyzed. RESULTS VA-MENGOC-BC's effectiveness against homologous serogroup B strains has consistently been greater than 80% in all age groups. Effectiveness in heterologous contexts was also above 80% in individuals aged >4 years. Lower effectiveness in heterologous contexts was found in Brazilian children aged <2 years, although still >50%. Effectiveness increased when assessed based on mortality rates, as well as in cases of clinically severe meningococcal disease. The carrier-state pattern was modified after vaccination with reduction of hypervirulent lineages. Some 60% of infants (aged <1 year) attained protective bactericidal antibody titers against serogroup C. Higher protection rates were achieved in older children. CONCLUSIONS In addition to prevention of meningococcal disease caused by homologous serogroup B strains, VA-MENGOC-BC should be considered for heterologous contexts. It is protective against serogroup C in all age groups. KEYWORDS Neisseria meningitidis, meningococcal disease, meningococcal vaccines, serogroup B meningococcus, serogroup C meningococcus, immunogenicity, bacterial outer membrane proteins, heterologous effects of vaccines, acellular vaccines, Cuba.

Structure of the meningococcal vaccine antigen NadA and epitope mapping of a bactericidal antibody.

Serogroup B Neisseria meningitidis (MenB) is a major cause of severe sepsis and invasive meningococcal disease, which is associated with 5-15% mortality and devastating long-term sequelae. Neisserial adhesin A (NadA), a trimeric autotransporter adhesin (TAA) that acts in adhesion to and invasion of host epithelial cells, is one of the three antigens discovered by genome mining that are part of the MenB vaccine that recently was approved by the European Medicines Agency. Here we present the crystal structure of NadA variant 5 at 2 Å resolution and transmission electron microscopy data for NadA variant 3 that is present in the vaccine. The two variants show similar overall topology with a novel TAA fold predominantly composed of trimeric coiled-coils with three protruding wing-like structures that create an unusual N-terminal head domain. Detailed mapping of the binding site of a bactericidal antibody by hydrogen/deuterium exchange MS shows that a protective conformational epitope is located in the head of NadA. These results provide information that is important for elucidating the biological function and vaccine efficacy of NadA.

Structure-based Vaccine Development (Structural Vaccinology)

Structural biology is playing an increasingly important role in vaccine development, as it can facilitate the rational design of vaccines by allowing an atomic-level control of their antigenic and immunogenic properties. Several cases are now available that demonstrate the potential of structure-based methods for vaccine development. Here, I will present an overview of the insights we gained at Novartis Vaccines from studying two protein antigens of the recently approved vaccine against serogroup B meningococcus (MenB), and their impact for vaccine design and development. MenB causes severe sepsis and invasive meningococcal disease (IMD), particularly affecting young children and adolescents. In 2013, the first genome-derived vaccine, which targets MenB (4CMenB), was approved for use in Europe, and it is expected to become widely implemented in Europe beginning in 2014. The vaccine contains 3 previously unknown recombinant proteins discovered by genome mining. For one of the antigens, Factor H Binding Protein (FHBP), we recently generated a broadly protective chimera by a structure-based approach that consisted in grafting multiple immunodominant regions onto a single scaffold. Also, co-crystal structures of FHBP with Fabs from monoclonal antibodies provided insights into the molecular bases of the immune recognition and bactericidal activity. The structure of a second antigen, Neisserial adhesin A (NadA), a member of the Trimeric Autotransporter Adhesins (TAA), revealed a novel fold, while epitope mapping by Hydrogen-Deuterium Exchange Mass Spectrometry showed that in addition to being the receptor-binding domain, the head domain of NadA is also the target of a bactericidal monoclonal antibody. Overall, the structural information on the MenB antigens presented here provides important details on the pathogenesis and vaccine-induced immunity against meningococcus, and especially informs the engineering of improved immunogens by structure-based design.

Glutamine depletion and heat shock protein 70 (HSP70) in children with meningococcal disease

Heat shock proteins are classified into six main families, of which HSP70 is the best studied. HSP70 is postulated to modulate the immune/inflammatory response in critical illness. Glutamine promotes HSP70 release, however, little is known about the relationship between glutamine and HSP70 in paediatric critical illness. We therefore aimed to describe plasma levels of HSP70, inflammatory mediators and glutamine in critically ill children. A clinical audit identified 143 children with severe meningococcal disease, 78 convalescent children, in addition to 35 healthy paediatric controls. Stored plasma was used to measure plasma concentrations of HSP70, inflammatory mediators and glutamine. HSP70 was significantly increased on admission (n = 143, mean 26.7 ng/ml; ±SD 79.95) compared with convalescence (n = 78, mean 3.16 ng/ml; ±SD 5.67). Glutamine levels were low (n = 132, mean 0.31 mmol/l; ±SD 0.13), which continued in convalescence (n = 65, mean 0.40 mmol/l; ±SD 0.14). Enteral glutamine provided only 28% of the recommendations. Glutamine was inversely correlated with length-of-stay (n = 98, r = -0.520, p < 0.001), ventilation (n = 98, r = -0.513, p < 0.001), lactate (n = 98, r = -0.41, p < 0.001) and CRP (n = 98, r = -0.51, p < 0.001). HSP70 was correlated with length-of-stay (n = 99, r = 0.30, p < 0.001), ventilation (n = 99, r = 0.31, p < 0.001), lactate (n = 99, r = 0.26, p < 0.001) and CRP (n = 99, r = 0.29, p < 0.001) and inflammatory mediators. There was no relationship between glutamine and HSP70 or inflammatory mediators. During acute illness HSP70/inflammatory mediators are significantly increased, and glutamine is significantly depleted. However, glutamine and HSP70 were not correlated. Enteral feeds only provided a small proportion of the ASPEN/ESPEN recommendations for glutamine.

Autoantibody stabilization of the classical pathway C3 convertase leading to C3 deficiency and Neisserial sepsis: C4 nephritic factor revisited

C3 deficiency is a rare disorder that leads to recurrent pyogenic infections. Here we describe a previously healthy 18 y/o Caucasian male with severe meningococcal disease. Total hemolytic activity was zero secondary to an undetectable C3. The C3 gene was normal by sequencing. Mixing the patient's serum with normal human serum led to C3 consumption. An IgG autoantibody in the patient's serum was identified that stabilized the classical pathway C3 and C5 convertases, thus preventing decay of these enzyme complexes. This autoantibody is an example of a C4 nephritic factor, with an additional feature of stabilizing the C5 convertase. Previous patients with C4 nephritic factor had membranoproliferative glomerulonephritis. Two years after presentation, this patient's C3 remains undetectable with no evidence of renal disease. We revisit the role of autoantibodies to classical pathway convertases in disease, review the literature on C4-NeF and comment on its detection in the clinical laboratory.

Changes in the sublingual microcirculation and endothelial adhesion molecules during the course of severe meningococcal disease treated in the paediatric intensive care unit

The sublingual microcirculation can be visualised in real time using sidestream dark-field (SDF) imaging. Endothelial activation mediated through adhesion molecules may alter flow patterns in the microcirculation. We studied sublingual microcirculatory disturbances in children with meningococcal disease (MCD) and simultaneously measured plasma levels of adhesion molecules. Twenty children admitted to the paediatric intensive care unit (PICU) with MCD were studied. Forty healthy children were controls. The sublingual microcirculation was assessed at admission and at timed intervals until extubation. The microvascular flow index (MFI), capillary density (CD), proportion of perfused vessels (PPV) and perfused vessel density (PVD) were measured using SDF imaging. Plasma intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin and P-selectin were measured at admission and at timed intervals during the course of PICU treatment. Significant reductions in MFI, CD, PPV and PVD were found in children with MCD compared with controls (p<0.005). These differences had resolved prior to extubation. Initial MFI values predicted the duration of mechanical ventilation, irrespective of the stage of illness at the time of presentation to PICU. There were negative correlations between the ICAM-1, VCAM-1 and E-selectin levels and the microcirculatory MFI and PPV values at the time of admission to PICU (p<0.005). Microcirculatory dysfunction is present in children with severe MCD with improvement alongside clinical recovery. Microcirculatory dysfunction correlated with markers of endothelial activation. Sublingual SDF imaging is feasible in children ventilated on PICU for severe sepsis and may prove useful in studies assessing illness severity and therapy.

Meningococcal Disease and Future Drug Targets

Neisseria meningitidis (N. meningitidis) causes sepsis, epidemic meningitis, and sometimes also meningoencephalitis. Despite early antibiotic treatment, mortality and morbidity remain significant. We present recent studies on meningococcal disease with focus on the pathophysiology caused by bacterial virulence factors and the host immune responses. The bacterial outer membrane lipopolysaccharide and non-lipopolysaccharide components are related to meningococcal adhesion and invasion, while the host immune reactions propagate inflammation and neurodegeneration. Hence, bacterium-host interactions are key determinants of the clinical course and risk of fatal outcome. Accordingly, successful treatment of severe meningococcal disease requires not only antibiotics but also adjuvants targeting the released endotoxins and the host immune/inflammatory responses. This review highlights the most recent data and current knowledge on molecular mechanisms of meningococcal disease and explains how host immune responses ultimately may aggravate neuropathology and the clinical prognosis. Within this context, particular importance is paid to the endotoxic components that provide potential drug targets for novel neuroprotective adjuvants, which are needed in order to improve the clinical management of meningoencephalitis and patient prognosis.

Von Willebrand factor activation, granzyme-B and thrombocytopenia in meningococcal disease.

During invasive meningococcal disease, severe thrombocytopenia is strongly associated with a poor outcome. In order to elucidate the pathophysiological mechanism behind the development of thrombocytopenia, we studied the role of von Willebrand factor (VWF) in meningococcal disease. Thirty-two children with severe meningococcal disease admitted to our university hospital were included in this study. VWF and related parameters were measured and results were correlated with the development of shock and thrombocytopenia. At admission, all patients had increased levels of (active) VWF and VWF propeptide. The highest VWF propeptide levels were observed in patients with shock, indicating acute endothelial activation. Although VWF propeptide levels in patients with shock, with or without thrombocytopenia, were similar, increased active VWF was significantly lower in patients with thrombocytopenia as compared with patients without thrombocytopenia. ADAMTS13 was moderately decreased. However, the VWF multimeric pattern was minimally increased. We assume that these findings are explained by VWF consumption and perhaps by granzyme B (GrB). In vitro experiments showed that GrB is able to cleave VWF multimers in plasma, whereas GrB was high in patients with shock, who developed thrombocytopenia. Our results demonstrate that consumption of VWF, derived from endothelial cells, could be a key feature of meningococcal disease and primary to the development of thrombocytopenia during shock.

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

To analyze the role of the innate production capacity for tumor necrosis factor, interleukin-1beta, interleukin-12, and interleukin-10 in the clinical presentation and severity of meningococcal disease. Whole blood cultures from survivors of severe meningococcal disease obtained median 5.4 yrs after hospitalization were stimulated with meningococcal lipopolysaccharide and heat-killed Neisseria meningitidis bacteria. Intensive care unit in academic hospital. 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). : None. 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-1beta and the interleukin-1beta/interleukin-10 ratio were negatively correlated with disease severity (R = -.35, p = .03 and R = -.33, p = .04, respectively; Pediatric Risk of Mortality score). Clinical manifestation of meningococcal disease cannot be explained by the innate production capacity of whole blood cultures for the cytokines tumor necrosis factor, interleukin-1beta, interleukin-10, and interleukin-12. In patients who presented with shock, a low production capacity for interleukin-1beta and a low interleukin-1beta/interleukin-10 production ratio was associated with more severe disease.

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.

PENTRAXIN 3 AND C-REACTIVE PROTEIN IN SEVERE MENINGOCOCCAL DISEASE

The long pentraxin 3 (PTX3) is an important element of the innate immune system and has potential as a diagnostic tool in inflammatory conditions. We studied PTX3 in patients admitted to an intensive care unit with severe meningococcal disease and compared it with the short pentraxin C-reactive protein (CRP). Twenty-six patients with meningococcal disease were studied, 17 patients presented with meningococcal septic shock (shock group), and 9 patients presented with meningococcal meningitis or bacteremia (no-shock group). Pentraxin 3 and CRP were measured by enzyme-linked immunosorbent assay. High plasma concentrations of PTX3 (median, 579 microg/L) were seen at admission in patients with meningococcal disease. Concentrations were significantly higher in patients with shock compared with patients without shock (medians, 801 and 256 microg/L, respectively; P = 0.006). In contrast, CRP at admission was lower in the shock group as compared with the no-shock group (medians, 58 and 165 mg/L, respectively; P = 0.008). High PTX3 and low CRP concentration at admission discriminated between presence and absence of shock (area under the receiver operating characteristic curve, 0.85; P = 0.007 for PTX3 and area under the receiver operating characteristic curve, 0.84; P = 0.01 for CRP). PTX3 did not correlate with disease severity (pediatric risk of mortality) and days spent in the intensive care unit. PTX3 at admission and PTX3 peak concentration both showed a negative correlation with plasma fibrinogen concentrations. C-reactive protein concentration at admission correlated negatively with disease severity. In conclusion, PTX3 was an early indicator of shock in patients with severe meningococcal disease that followed a pattern of induction distinct from CRP.