Review of the epidemiology, diagnosis and management of invasive meningococcal disease in Vietnam.

Invasive meningococcal disease (IMD), caused by Neisseria meningitidis, is life-threatening with a high case fatality rate (CFR) and severe sequelae. We compiled and critically discussed the evidence on IMD epidemiology, antibiotic resistance and disease management in Vietnam, focusing on children. PubMed, Embase and gray literature searches for English, Vietnamese and French publications, with no date restrictions, retrieved 11 eligible studies. IMD incidence rate (/100,000 population) was 7.4 [95% confidence interval 3.6-15.3] in children under 5 years of age; driven by high rates in infants (e.g. 29.1 [8.0-106.0] in 7-11 month-olds). Serogroup B IMD was predominant. Neisseria meningitidis strains may have developed resistance to streptomycin, sulfonamides, ciprofloxacin, and possibly ceftriaxone. There was a lack of current data on diagnosis and treatment of IMD, which remain challenging. Healthcare professionals should be trained to rapidly recognize and treat IMD. Preventive measures, such as routine vaccination, could help address the medical need.

Development of a simple and cost-effective gel-based duplex PCR method to identify both encapsulated and unencapsulated Neisseria meningitidis applicable under resource-limited conditions.

Tens of thousands of cases of invasive meningococcal diseases (IMD) with thousands of deaths are reported annually worldwide; however, only approximately 40 cases occur each year in Japan. Therefore, the majority of medical technologists in Japan have never performed or prepared for analyses of the causative agent, Neisseria meningitidis. Since IMD outbreaks have been reported at mass gathering events, the risk of IMD will increase in Japan in 2021 because of the Olympics. In the present study, we developed a new simple gel-based duplex PCR method that may be employed by the majority Japanese clinical laboratories. It is simple to perform and time- and cost-effectively identifies encapsulated and unencapsulated N. meningitidis by detecting the encapsulated N. meningitidis-specific ctrB and N. meningitidis-specific ggt genes. We consider this simple and cost-effective identification method to compensate for the lack of experience and resource-poor conditions in most Japanese laboratories in which N. meningitidis has rarely been examined.

The "Petechiae in children" (PiC) study: evaluating potential clinical decision rules for the management of feverish children with non-blanching rashes, including the role of point of care testing for Procalcitonin & Neisseria meningitidis DNA - a study protocol.

BACKGROUND: Children commonly present to Emergency Departments (ED) with a non-blanching rash in the context of a feverish illness. While most have a self-limiting viral illness, this combination of features potentially represents invasive serious bacterial infection, including meningococcal septicaemia. A paucity of definitive diagnostic testing creates diagnostic uncertainty for clinicians; a safe approach mandates children without invasive disease are often admitted and treated with broad-spectrum antibiotics. Conversely, a cohort of children still experience significant mortality and morbidity due to late diagnosis. Current management is based on evidence which predates (i) the introduction of meningococcal B and C vaccines and (ii) availability of point of care testing (POCT) for procalcitonin (PCT) and Neisseria meningitidis DNA. METHODS: This PiC study is a prospective diagnostic accuracy study evaluating (i) rapid POCT for PCT and N. meningitidis DNA and (ii) performance of existing clinical practice guidelines (CPG) for feverish children with non-blanching rash. All children presenting to the ED with a history of fever and non-blanching rash are eligible. Children are managed as normal, with detailed prospective collection of data pertinent to CPGs, and a throat swab and blood used for rapid POCT. The study is running over 2 years and aims to recruit 300 children. PRIMARY OBJECTIVE: Report on the diagnostic accuracy of POCT for (i) N. meningitidis DNA and (ii) PCT in the diagnosis of early MD Report on the diagnostic accuracy of POCT for PCT in the diagnosis of Invasive bacterial infection Secondary objectives: Evaluate the performance accuracy of existing CPGs Evaluate cost-effectiveness of available diagnostic testing strategies Explore views of (i) families and (ii) clinicians on research without prior consent using qualitative methodology Report on the aetiology of NBRs in children with a feverish illness DISCUSSION: The PiC study will provide important information for policy makers regarding the value of POCT and on the utility and cost of emerging diagnostic strategies. The study will also identify which elements of existing CPGs may merit inclusion in any future study to derive clinical decision rules for this population. TRIAL REGISTRATION: NCT03378258 . Retrospectively registered on December 19, 2017.

Value of the eazyplex® CSF direct assay in rapid diagnosis of invasive meningococcal disease - Case report.

There is a need for easy-to-use molecular assays for diagnosis of invasive meningococcal disease. Here, we report the rapid identification of Neisseria meningitidis in a cerebrospinal fluid sample from a patient with purulent meningitis using a commercially available loop-mediated isothermal amplification assay, resulting in a prompt de-escalation of the initial empiric antibiotic therapy.

A retrospective assessment of the completeness and timeliness of meningococcal disease notifications in the Republic of Ireland over a 16-year period, 1999-2015.

OBJECTIVES: To assess how invasive meningococcal disease (IMD) records held by the Irish Meningitis & Sepsis Reference Laboratory (IMSRL) compare to records of IMD notifications reported on the national integrated electronic Computerised Infectious Disease Reporting (CIDR) system. STUDY DESIGN: We assessed the completeness, data quality and timeliness of IMD notifications and reference laboratory records for the period between 01 July 1999 and 30 June 2015 by identifying discrepant and/or missing data items in a matched case data set and by measuring the timeliness of case reporting. METHODS: We matched anonymised cases notified to CIDR to records based at the IMSRL using birth, reporting and onset dates with gender and laboratory parameters of meningococcal strain characteristics and method of confirmation. Completeness, data quality and the timeliness of notifications were assessed by a stratified sensitivity-based technique and by calculating the average difference between IMSRL and CIDR reporting dates. RESULTS: CIDR recorded a total of 3163 notifications, of which 2759 (87.2%) were matched to IMSRL records. Completeness of IMD case classification as confirmed was estimated to be >99%. Examining the levels of discrepant or missing data in both matched CIDR and IMSRL records as a measure of data quality, recording of demographic items and meningococcal group showed least differences, recording of laboratory case confirmation method and meningococcal strain characteristics were less well recorded, with detail on clinical presentation/diagnosis least well recorded. Overall average annual difference between CIDR and IMSRL recording dates was 3.2 days (95% confidence interval 2.6-3.8). CONCLUSIONS: A high quality of IMD surveillance in Ireland was demonstrated, but scope for improvements in timeliness and capture of enhanced surveillance data regarding date of onset and strain-specific characteristics were identified.

The Burden of Pediatric Invasive Meningococcal Disease in Spain (2008-2013).

BACKGROUND: Invasive meningococcal disease remains a rare infectious disease not only with high mortality but also with important morbidity. Until recently no universal vaccine existed against serogroup B, which explains most of the cases in settings like Europe. The objective of this study was to analyze the clinical course and sequelae of meningococcal disease in Spain. METHODS: Retrospective review of all children younger than 15 years admitted to any of the 36 hospitals in the MENDICOS Spanish network (www.mendicos.org) with confirmed or probable invasive meningococcal disease in children between January 2008 and December 2013. RESULTS: A total of 458 cases were identified across the country, most of them occurring in previously healthy children (91.5%; n = 419/458). Median (interquartile range) age was 1.7 (0.7 and 4.6) years, with 53.1% of the cases occurring in children younger than 2 years; 82.1% (n = 368) were laboratory confirmed cases; 95.2% (n = 256) of those serogrouped were serogroup B. The diagnosis was meningitis in 24.9% (n = 114) of the cases, sepsis in 37.1% (n = 170) and both in 38.0% (n = 174). Mean hospital length of stay was 11.6 (10.9) days; 79.2% (n = 354) of the patients required pediatric intensive care unit admission, with a mean pediatric intensive care unit stay of 3.9 (4.9) days; 3.5% (n = 16) died; 12.9% (n = 59) of the survivors were discharged with some kind of physical sequelae, mainly neurological (n = 23). CONCLUSIONS: Serogroup B invasive meningococcal infection explains substantial morbidity and mortality in Spain, occurring mainly in infants. The recent availability of a vaccine against serogroup B may change this scenario. Given that the vast majority of the cases occur in otherwise healthy children, inclusion of the meningococcal B vaccine in the national immunization program should be carefully considered.

Clinical and Cost-Effectiveness of Procalcitonin Test for Prodromal Meningococcal Disease-A Meta-Analysis.

BACKGROUND: Despite vaccines and improved medical intensive care, clinicians must continue to be vigilant of possible Meningococcal Disease in children. The objective was to establish if the procalcitonin test was a cost-effective adjunct for prodromal Meningococcal Disease in children presenting at emergency department with fever without source. METHODS AND FINDINGS: Data to evaluate procalcitonin, C-reactive protein and white cell count tests as indicators of Meningococcal Disease were collected from six independent studies identified through a systematic literature search, applying PRISMA guidelines. The data included 881 children with fever without source in developed countries.The optimal cut-off value for the procalcitonin, C-reactive protein and white cell count tests, each as an indicator of Meningococcal Disease, was determined. Summary Receiver Operator Curve analysis determined the overall diagnostic performance of each test with 95% confidence intervals. A decision analytic model was designed to reflect realistic clinical pathways for a child presenting with fever without source by comparing two diagnostic strategies: standard testing using combined C-reactive protein and white cell count tests compared to standard testing plus procalcitonin test. The costs of each of the four diagnosis groups (true positive, false negative, true negative and false positive) were assessed from a National Health Service payer perspective. The procalcitonin test was more accurate (sensitivity=0.89, 95%CI=0.76-0.96; specificity=0.74, 95%CI=0.4-0.92) for early Meningococcal Disease compared to standard testing alone (sensitivity=0.47, 95%CI=0.32-0.62; specificity=0.8, 95% CI=0.64-0.9). Decision analytic model outcomes indicated that the incremental cost effectiveness ratio for the base case was £-8,137.25 (US $ -13,371.94) per correctly treated patient. CONCLUSIONS: Procalcitonin plus standard recommended tests, improved the discriminatory ability for fatal Meningococcal Disease and was more cost-effective; it was also a superior biomarker in infants. Further research is recommended for point-of-care procalcitonin testing and Markov modelling to incorporate cost per QALY with a life-time model.

Severe meningococcal infection: a review of epidemiology, diagnosis, and management.

Neisseria meningitidis, also known as meningococcus, is a relatively uncommon cause of invasive infection, but when it occurs it is frequently severe and potentially life threatening. Meningococcus should be considered and investigated promptly as a potentially etiologic pathogen in any patient with meningitis, or sepsis accompanied by a petechial rash. Suspected patients should receive early appropriate antimicrobial therapy concomitantly with confirmatory invasive diagnostic tests. Vaccines have reduced the incidence of infection with certain non-B meningococcal serogroups, and new serotype B vaccines are on the horizon. This article reviews the epidemiology, diagnosis, and management of severe meningococcal infections.

Meningococcal B disease: assessment and management.

Serogroup B meningococcal disease is the last main cause of bacterial meningitis and septicaemia in the UK. There is currently no vaccine against this serogroup. This article outlines the nature of meningococcal disease and highlights recent guidance from the National Institute for Health and Clinical Excellence on recognising and managing the disease in primary and secondary care. An update on progress towards a preventive vaccine is also discussed.

Meningococcal infections in hospitalised patients in Pretoria.

We report on 13 patients diagnosed with meningococcal infections in patients attending state-owned hospitals serving an indigent population in Pretoria in 2009. The case fatality rate was 27%. Ceftriaxone was the main antibiotic (9 out of 13 patients) for therapy. Five isolates (39%) were serogroup B and 4 (31%) serogroup W135. Most isolates (12/13) were fully susceptible to penicillin (MIC range 0.016 - 0.047 µg/ml). A single isolate was intermediately resistant to penicillin (MIC, 0.125 µg/ml) while all isolates were uniformly susceptible to ceftriaxone, ciprofloxacin and rifampicin. This pattern reveals a shift in serogroups with an increase of serogroup B disease in the Pretoria region, and the need for ongoing monitoring of antimicrobial susceptibility profiles and the value of ceftriaxone for favourable therapeutic outcome.

The burden of vaccine-preventable invasive bacterial infections and pneumonia in children admitted to hospital in urban Nepal.

BACKGROUND: Protein-polysaccharide vaccines have made a significant impact on the burden of disease caused by encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and have the potential to do so for Salmonella Typhi. Nepal is one of many resource-poor nations with limited information on the epidemiology of childhood infections caused by these pathogens. METHODS: Over a 21-month period, we studied children aged ≤12 years admitted to an urban hospital in Nepal with suspected bacteremia, meningitis, or pneumonia. Patan Hospital is a non-profit hospital with the second largest pediatric unit in the Kathmandu Valley. RESULTS: Of 2039 children enrolled in the study, 142 (7.5%) included in the analysis had positive blood cultures. The agents of enteric fever, Salmonella Typhi and Salmonella Paratyphi, accounted for 59/142 (42%) of all bacteremias and were the most frequently cultured pathogens in children ≥1 year of age. S. pneumoniae was isolated in 16% of positive blood cultures and was the most common cause of bacteremia in children <1 year of age. Pneumonia accounted for 51% of admissions in children ≥2 months, with 44% of these children having radiographically defined primary endpoint pneumonia. S. pneumoniae was the most commonly identified pathogen in cases of pneumonia and meningitis. The S. pneumoniae serotype distribution indicated that the 10-valent and 13-valent pneumococcal conjugate vaccines would cover 44% and 47%, respectively, of all S. pneumoniae cultured from blood or cerebrospinal fluid (CSF) isolates and 62% and 67%, respectively, of isolates associated with pneumonia. H. influenzae type b was isolated infrequently from blood or CSF cultures, but is likely to be more important as a cause of pneumonia. CONCLUSIONS: The data on the burden of invasive bacterial infections and pneumonia from this study suggest that vaccines in development against Salmonella Typhi and the pneumococcus have the potential to significantly improve the health of children in Nepal.

Diagnostic value of clinical features at presentation to identify serious infection in children in developed countries: a systematic review.

BACKGROUND: Our aim was to identify which clinical features have value in confirming or excluding the possibility of serious infection in children presenting to ambulatory care settings in developed countries. METHODS: In this systematic review, we searched electronic databases (Medline, Embase, DARE, CINAHL), reference lists of relevant studies, and contacted experts to identify articles assessing clinical features of serious infection in children. 1939 potentially relevant studies were identified. Studies were selected on the basis of six criteria: design (studies of diagnostic accuracy or prediction rules), participants (otherwise healthy children aged 1 month to 18 years), setting (ambulatory care), outcome (serious infection), features assessed (assessable in ambulatory care setting), and sufficient data reported. Quality assessment was based on the Quality Assessment of Diagnostic Accuracy Studies criteria. We calculated likelihood ratios for the presence (positive likelihood ratio) or absence (negative likelihood ratio) of each clinical feature and pre-test and post-test probabilities of the outcome. Clinical features with a positive likelihood ratio of more than 5.0 were deemed red flags (ie, warning signs for serious infection); features with a negative likelihood ratio of less than 0.2 were deemed rule-out signs. FINDINGS: 30 studies were included in the analysis. Cyanosis (positive likelihood ratio range 2.66-52.20), rapid breathing (1.26-9.78), poor peripheral perfusion (2.39-38.80), and petechial rash (6.18-83.70) were identified as red flags in several studies. Parental concern (positive likelihood ratio 14.40, 95% CI 9.30-22.10) and clinician instinct (positive likelihood ratio 23.50, 95 % CI 16.80-32.70) were identified as strong red flags in one primary care study. Temperature of 40 degrees C or more has value as a red flag in settings with a low prevalence of serious infection. No single clinical feature has rule-out value but some combinations can be used to exclude the possibility of serious infection-for example, pneumonia is very unlikely (negative likelihood ratio 0.07, 95% CI 0.01-0.46) if the child is not short of breath and there is no parental concern. The Yale Observation Scale had little value in confirming (positive likelihood ratio range 1.10-6.70) or excluding (negative likelihood ratio range 0.16-0.97) the possibility of serious infection. INTERPRETATION: The red flags for serious infection that we identified should be used routinely, but serious illness will still be missed without effective use of precautionary measures. We now need to identify the level of risk at which clinical action should be taken. FUNDING: Health Technology Assessment and National Institute for Health Research National School for Primary Care Research.

[Hospital admissions for meningococcal infections in Madrid, Spain (1997-2005)]. / Ingresos hospitalarios por infecciones meningocócicas en la Comunidad de Madrid (1997-2005).

BACKGROUND AND OBJECTIVES: Neisseria meningitidis infection causes an important morbidity and mortality in Spain. Our study aims to estimate the burden of hospital admissions for meningococcal infection in Spain during a nine-year period (1997-2005) by analyzing the Spanish hospital surveillance system. METHODS: An epidemiological retrospective study was conducted. Data were obtained from the national surveillance system for hospital data (Conjunto Mínimo Básico de Datos) maintained by the Ministry of Health. Information about hospitalizations, age, length of stay in hospital, mortality and cost per patient was obtained. RESULTS: There were 1137 hospital discharges for meningococcal disease (International Classification of Diseases 9th Clinical Modification: ICD 9 CM code 036 in any listed diagnosis) during the study period. Annual incidence was 2.41 cases per 100,000 individuals. Mortality rate and case-fatality rate were 0.19 cases per 100,000 population and 7.7%, respectively. The average length of hospitalization was 12 days. The youngest age group showed the highest hospitalizations incidence (24.42 hospitalizations per 100,000 population in those under 4 years of age) but the case-fatality rate was higher in the oldest group (11% in patients over 30 years). These hospitalizations imply an annual cost of 592,980 euro to the Madrid Health System. CONCLUSIONS: Our study shows that meningococcal infection is still an important cause of hospital admissions and mortality in Madrid, resulting in a high cost to the Health Care System.