Regulation of Intracellular Triiodothyronine Is Essential for Optimal Macrophage Function.

Innate immune cells, including macrophages, have recently been identified as target cells for thyroid hormone. We hypothesized that optimal intracellular concentrations of the active thyroid hormone triiodothyronine (T3) are essential for proinflammatory macrophage function. T3 is generated intracellularly by type 2 deiodinase (D2) and acts via the nuclear thyroid hormone receptor (TR). In zebrafish embryos, D2 knockdown increased mortality during pneumococcal meningitis. Primary murine D2 knockout macrophages exhibited impaired phagocytosis and partially reduced cytokine response to stimulation with bacterial endotoxin. These effects are presumably due to reduced intracellular T3 availability. Knockdown of the main TR in macrophages, TRα, impaired polarization into proinflammatory macrophages and amplified polarization into immunomodulatory macrophages. Intracellular T3 availability and action appear to play a crucial role in macrophage function. Our data suggest that low intracellular T3 action has an anti-inflammatory effect, possibly due to an effect on macrophage polarization mediated via the TRα. This study provides important insights into the link between the endocrine and innate immune system.

Lack of Toll-like receptor 2 results in higher mortality of bacterial meningitis by impaired host resistance.

Bacterial meningitis is - despite therapeutical progress during the last decades - still characterized by high mortality and severe permanent neurogical sequelae. The brain is protected from penetrating pathogens by both the blood-brain barrier and the innate immune system. Invading pathogens are recognized by so-called pattern recognition receptors including the Toll-like receptors (TLR) which are expressed by glial immune cells in the central nervous system. Among these, TLR2 is responsible for the detection of Gram-positive bacteria such as the meningitis-causing pathogen Streptococcus pneumoniae. Here, we used TLR2-deficient mice to investigate the effects on mortality, bacterial growth and inflammation in a mouse model of pneumococcal meningitis. Our results revealed a significantly increased mortality rate and higher bacterial burden in TLR2-deficient mice with pneumococcal meningitis. Furthermore, infected TLR2-deficient mice suffered from a significantly increased pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and Chemokine (C-C motif) ligand 2 (CCL2) or CCL3 chemokine expression and decreased expression of anti-inflammatory cytokines and antimicrobial peptides. In contrast, glial cell activation assessed by glial cell marker expression was comparable to wildtype mice. Taken together, the results suggest that TLR2 is essential for an efficient immune response against Streptococcus pneumoniae meningitis since lack of the receptor led to a worse outcome by higher mortality due to increased bacterial burden, weakened innate immune response and reduced expression of antimicrobial peptides.

Genetic Variation in NFKBIE Is Associated With Increased Risk of Pneumococcal Meningitis in Children.

BACKGROUND: Streptococcus pneumoniae and Neisseria meningitidis are frequent pathogens in life-threatening infections. Genetic variation in the immune system may predispose to these infections. Nuclear factor-κB is a key component of the TLR-pathway, controlled by inhibitors, encoded by the genes NFKBIA, NFKBIE and NFKBIZ. We aimed to replicate previous findings of genetic variation associated with invasive pneumococcal disease (IPD), and to assess whether similar associations could be found in invasive meningococcal disease (IMD). METHODS: Cases with IPD and IMD and controls were identified by linking Danish national registries. DNA was obtained from the Danish Neonatal Screening Biobank. The association between SNPs and susceptibility to IPD and IMD, mortality and pneumococcal serotypes was investigated. RESULTS: 372 children with pneumococcal meningitis, 907 with pneumococcal bacteremia and 1273 controls were included. We included 406 cases with meningococcal meningitis, 272 with meningococcal bacteremia, and 672 controls. The NFKBIE SNP was associated with increased risk of pneumococcal meningitis (aOR 1.68; 95% CI: 1.20-2.36), but not bacteremia (aOR 1.08; 95% CI: 0.86-1.35). The remaining SNPs were not associated with susceptibility to invasive disease. None of the SNPs were associated with risk of IMD or mortality. CONCLUSIONS: A NFKBIE polymorphism was associated with increased risk of pneumococcal meningitis.

Caracterización de pacientes fallecidos por enfermedad neumocóccica invasiva en la poblacion infantil de Bogotá, Colombia / Characterization of patients who died of invasive pneumococcal disease in the child population of Bogota, Colombia

Introducción: El Streptococcus pneumoniae (S. pneumoniae), también denominado neumococo, es una de las principales bacterias asociadas a mortalidad en menores de 2 años, con una incidencia de morbimortalidad variable de acuerdo a la demografía y exposición a factores protectores o de riesgo. Objetivo: Caracterizar los pacientes fallecidos por enfermedad neumocóccica invasiva (ENI) entre el 2008-2014 en la población infantil de 8 instituciones de salud en Bogotá, Colombia. Pacientes y método: Estudio observacional descriptivo tipo serie de casos, en pacientes fallecidos por ENI, mayores de 28 días hasta los 18 años, en 8 instituciones de tercer nivel de atención en Bogotá, Colombia. Periodo del estudio del 1 de enero de 2008 al 15 de enero de 2014. Tamaño de la muestra: 239 pacientes. Resultados: Se revisaron 239 casos registrados de ENI, presentando una mortalidad del 7,5% (n = 18). La edad promedio de los pacientes que fallecieron fue de 43,7 meses, con un rango de edad entre 2 y 176 meses (14 años); el 66% de los casos era de sexo masculino. Se identificaron serotipos en 8 pacientes, encontrando: 6A, 6B, 10A, 14, 18C, 23B, 23F, 35B. La presentación clínica más frecuente de los casos de mortalidad fue meningitis con el 33% (6 casos), seguida por bacteriemia sin foco en el 28% (5 casos) y neumonía con el 27% (5 casos). Se presentaron situaciones clínicas combinadas como neumonía y meningitis en el 11% (2 casos). Dos de los pacientes tenían factores de riesgo para ENI claramente documentados (asplenia y enfermedad respiratoria crónica). Conclusiones: La mortalidad por ENI es especialmente alta en los menores de 2 años y en pacientes de sexo masculino, especialmente cuando presenta foco meníngeo (44%). La serotipificación no fue posible en todos los pacientes fallecidos, ya que no se envió la cepa aislada al Instituto Nacional de Salud. Se requiere una vigilancia continua y sistemática para evaluar el impacto de la vacunación y las posibles modificaciones en el patrón de presentación de la enfermedad.

Introduction: Streptococcus pneumoniae (S. pneumoniae), also known as pneumococcus, is one of the main bacteria associated with mortality in children under 2 years of age, with a morbidity and mortality incidence that varies according to demographics and exposure to risk, or protective factors. Objective: To describe the child mortality due to invasive pneumococcal disease (IPD) between 2008 -2014 (6 years), in 8 Medical Centres in Bogotá, Colombia. Patients and method: Descriptive observational case series of patients who died of IPD, aged 28 days to 18 years, in 8 tertiary care institutions in Bogota, Colombia. The study period was from 1 January 2008 to 15 January 2014. Sample size: 239 patients. Results: A total of 239 registered cases of IPD were reviewed, showing a mortality of 8% (n 18). The mean age of patients that died was 43.7 months, with an age range from 2 to 176 months (14 years), with 66% of the cases being male. Serotypes were identified in 8 patients, finding: 6A, 6B, 10A, 14, 18C, 23B, 23F, and 35B. The most common clinical presentation of the cases was meningitis with mortality of 33% (6 cases), followed by bacteraemia without focus in 28% (5 cases), and pneumonia with 27% (5 cases). Combined clinical situations were presented, such as pneumonia and meningitis in 11% (2 cases). Two of the patients had clearly documented risk factors for IPD (asplenia and chronic respiratory disease). Conclusions: IPD mortality is particularly high in children under 2 years in male patients, especially when presented with a meningeal focus (44%). Serotyping was not possible in all patients who died, since no strain isolated was sent to the National Institute of Health. Continuous and systematic vigilance is required to evaluate the impact of vaccination and possible changes in the pattern of presentation of disease.

Interferon-γ-Induced Nitric Oxide Synthase-2 Contributes to Blood/Brain Barrier Dysfunction and Acute Mortality in Experimental Streptococcus pneumoniae Meningitis.

The proinflammatory cytokine interferon-gamma (IFNγ) recently was shown to play a crucial role in experimental pneumococcal meningitis (PM) pathogenesis, and we aimed in this study to investigate IFNγ-driven nitric oxide synthase-2 (NOS2)-mediated pathogenesis of murine PM. We demonstrate that costimulation of toll-like receptors and IFNγ receptors was synergistic for NOS2 expression in cultured murine microglia. Using an experimental PM model, wild-type mice treated with anti-IFNγ antibody, as well as IFNγ and NOS2 gene knockout (GKO) mice, were inoculated intracerebroventricularly with 10(3) colony-forming units of Streptococcus pneumoniae (WU2 strain). Mice were monitored daily during a 200-h disease course to assess survival rate and blood-brain barrier (BBB) permeability measured at 48 h. IFNγ deficiency was protective in PM, with an approximate 3-fold increase in survival rates in both antibody-treated and IFNγ GKO mice compared to controls (P < 0.01). At 48 h postinoculation, brain NOS2 mRNA expression was significantly increased in an IFNγ-dependent manner. Mortality was significantly delayed in NOS2 GKO mice compared to controls (P < 0.01), and BBB dysfunction was reduced by 54% in IFNγ GKO mice and abolished in NOS2 GKO. These data suggest that IFNγ-dependent expression of NOS2 in the brain contributes to BBB breakdown and early mortality in murine PM.

Pacientes con infección del sistema nervioso central / Patients with central nervous system infection

INTRODUCCIÓN: las infecciones del sistema nervioso central constituyen un importante problema de salud. La aparición brusca de la sintomatología, el desenlace fatal en pocas horas o la permanencia de secuelas hace que estas enfermedades tengan un gran impacto social. OBJETIVO: caracterizar las infecciones del sistema nervioso central, su comportamiento y relación con la mortalidad. MÉTODOS: estudio observacional descriptivo y transversal en una muestra de 100 pacientes atendidos en el Hospital Militar Central "Dr. Carlos J. Finlay", entre enero de 2009 y diciembre de 2013. La información se recogió a través de las historias clínicas con diagnóstico al egreso de cualquier tipo de sepsis del sistema nervioso central y de los informes de necropsia. Se realizaron análisis estadísticos univariados y bivariados, y se hallaron las distribuciones de frecuencia absoluta y relativa. RESULTADOS: la edad media fue de 44,4 años. Predominó el sexo masculino en el grupo de ≤ 39 años (54,7 %); en el femenino prevaleció el grupo de 40-59 años (34,9 %). En los fallecidos predominó el grupo de 60-79 años (47,8 %) y en los egresados vivos los de ≤ 39 años (53,2 %). Los factores de riesgo se presentaron en el 64 % de los pacientes; las meningoencefalitis bacterianas y virales constituyeron el 77 %. El estudio citoquímico se indicó al 98 % de los pacientes y la positividad fue de 88,8 %. El agente causal más frecuente resultó el Streptococcus pneumoniae (33,3 %). El 33,7 % de los pacientes presentó complicaciones. La mortalidad fue del 23 %. CONCLUSIONES: la mortalidad por infección el sistema nervioso central fue elevada y resultó escaso el aislamiento de microorganismos. El hecho de que más de un tercio de los pacientes se hayan complicado, justifica la alta mortalidad presente en el estudio.

INTRODUCTION: central nervous system infections are a major health problem. The sudden onset of symptoms, the fatal outcome within a few hours or the remaining sequels makes these diseases have a major social impact. OBJECTIVE: characterize the central nervous system infections, their behavior and relationship to mortality at "Dr. Carlos J. Finlay" Hospital from January 2009 to December 2013. METHODS: an observational descriptive transversal study was carried out with 100 patients at "Dr. Carlos J. Finlay" Hospital from January 2009 to December 2013. Information was collected through medical records with diagnosis any type of sepsis central nervous system at discharge and from autopsy reports. Univariate and Bivariate statistical analyzes were conducted, and the distributions of absolute and relative frequencies were found. RESULTS: the average age was 44.4 years, there was male predominance in the group ≤ 39 years (54.7 %), but 40-59 years (34.9 %) prevailed in the female group. the deceased group, 60-79 years (47.8 %) majored and those living at discharge, the predominance was ≤ 39 years (53.2 %).Risk factors occurred in the 64 % of patients. Bacterial and viral meningencephalitis accounted for the 77 %. Citochemical testing was performed in 98 % of the patients and it proved positive in the 88, 8 %. The most frequent ethiological agent was Streptococcus pneumoniae(33, 3 %). Complications were present in 33, 7 % of the patients. The rate mortality reached 23 %. CONCLUSIONS: mortality due to CNS infection was high and the isolation of microorganisms was low. The fact that more than a third of patients have complicated substantiates the high mortality in the study.

Matrix metalloproteinase inhibition lowers mortality and brain injury in experimental pneumococcal meningitis.

Pneumococcal meningitis (PM) results in high mortality rates and long-lasting neurological deficits. Hippocampal apoptosis and cortical necrosis are histopathological correlates of neurofunctional sequelae in rodent models and are frequently observed in autopsy studies of patients who die of PM. In experimental PM, inhibition of matrix metalloproteinases (MMPs) and/or tumor necrosis factor (TNF)-converting enzyme (TACE) has been shown to reduce brain injury and the associated impairment of neurocognitive function. However, none of the compounds evaluated in these studies entered clinical development. Here, we evaluated two second-generation MMP and TACE inhibitors with higher selectivity and improved oral availability. Ro 32-3555 (Trocade, cipemastat) preferentially inhibits collagenases (MMP-1, -8, and -13) and gelatinase B (MMP-9), while Ro 32-7315 is an efficient inhibitor of TACE. PM was induced in infant rats by the intracisternal injection of live Streptococcus pneumoniae. Ro 32-3555 and Ro 32-7315 were injected intraperitoneally, starting at 3 h postinfection. Antibiotic (ceftriaxone) therapy was initiated at 18 h postinfection, and clinical parameters (weight, clinical score, mortality rate) were recorded. Myeloperoxidase activities, concentrations of cytokines and chemokines, concentrations of MMP-2 and MMP-9, and collagen concentrations were measured in the cerebrospinal fluid. Animals were sacrificed at 42 h postinfection, and their brains were assessed by histomorphometry for hippocampal apoptosis and cortical necrosis. Both compounds, while exhibiting disparate MMP and TACE inhibitory profiles, decreased hippocampal apoptosis and cortical injury. Ro 32-3555 reduced mortality rates and cerebrospinal fluid TNF, interleukin-1ß (IL-1ß) and collagen levels, while Ro 32-7315 reduced weight loss and cerebrospinal fluid TNF and IL-6 levels.

Cost-effectiveness of new adult pneumococcal vaccination strategies in Italy.

Community-acquired pneumonia (CAP) and invasive pneumococcal disease (IPD) are very relevant pathologies among elderly people (≥ 65 y old), with a consequent high disease burden. Immunization with the 23-valent pneumococcal polysaccharide vaccine (PPV23) has been differently implemented in the Italian regions in the past years, reaching overall low coverage rates even in those with medical indications. In 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) became available and recommended in the universal Italian infant immunization program. Since October 2012, indications for use of PCV13 were extended to subjects ≥ 50 y to prevent invasive pneumococcal diseases. The Italian decision makers should now revise regional indications for the prevention of pneumococcal diseases in the elderly. Pharmaco-economic analyses represent a useful tool to value the feasibility of new immunization programs and their sustainability. Therefore, an ad hoc population model was developed in order to value the clinical and economic impact of an adult pneumococcal vaccination program in Italy.   Particularly, different immunization scenarios were modeled: vaccination of 65 y-olds (1 cohort strategy), simultaneous vaccination of people aged 65 and 70 y (double cohort strategy) and, lastly, immunization of people aged 65, 70 and 75 y (triple cohort strategy), thus leading to the vaccination of 5, 10 and 15 cohorts during the 5 y of the program. In addition, the administration of a PPV23 dose one year after PCV13 was evaluated, in order to verify the economic impact of the supplemental serotype coverage in elderly people. The mathematical model valued the clinical impact of PCV13 vaccination on the number of bacteraemic pneumococcal pneumonia (BPP) and pneumococcal meningitis (PM) cases, and related hospitalizations and deaths. Although PCV13 is not yet formally indicated for the prevention of pneumococcal CAP by the European Medicine Agency (differently from FDA, whose indications include all pneumococcal diseases in subjects ≥ 50 y), the model calculated also the possible impact of vaccination on CAP cases (non-bacteraemic), considering the rate of this disease due to S. pneumoniae. The results of the analysis show that, in Italy, an age-based PCV13 vaccination program in elderly people is cost-effective from the payer perspective, with costs per QALY ranging from 17,000 to 22,000 Euro, according to the adopted vaccination strategy. The subsequent PPV23 offer results in an increment of costs per QALY (from 21,000 to 28,000 Euro, according to the vaccination strategy adopted). Pneumococcal vaccination using the conjugate vaccine turned out to be already favorable in the second year of implementation, with incremental costs per QALY comparable to those of other already adopted prevention activities in Italy (for instance, universal HPV vaccination of 12 y-old girls), with further benefits obtained when extending the study period beyond the 5-y horizon of our analysis.

Genetic variation in inflammasome genes is associated with outcome in bacterial meningitis.

Bacterial meningitis is a severe and deadly disease, most commonly caused by Streptococcus pneumoniae. Disease outcome has been related to severity of the inflammatory response in the subarachnoid space. Inflammasomes are intracellular signaling complexes contributing to this inflammatory response. The role of genetic variation in inflammasome genes in bacterial meningitis is largely unknown. In a prospective nationwide cohort of patients with pneumococcal meningitis, we performed a genetic association study and found that single-nucleotide polymorphisms in the inflammasome genes CARD8 (rs2043211) and NLRP1 (rs11621270) are associated with poor disease outcome. Levels of the inflammasome associated cytokines interleukin (IL)-1ß and IL-18 in cerebrospinal fluid also correlated with clinical outcome, but were not associated with the CARD8 and NLRP1 polymorphisms. Our results implicate an important role of genetic variation in inflammasome genes in the regulation of inflammatory response and clinical outcome in patients with bacterial meningitis.

Invasive pneumococcal disease after routine pneumococcal conjugate vaccination in children, England and Wales.

We assessed known risk factors, clinical presentation, and outcome of invasive pneumococcal disease (IPD) in children 3-59 months of age after introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in England and Wales. During September 2006-March 2010, a total of 1,342 IPD episodes occurred in 1,332 children; 14.9% (198/1,332) had comorbidities. Compared with IPD caused by PCV7 serotypes (44/248; 17.7%), comorbidities were less common for the extra 3 serotypes in the 10-valent vaccine (15/299; 5.0%) but similar to the 3 additional PCV13 serotypes (45/336; 13.4%) and increased for the 11 extra serotypes in 23-valent polysaccharide vaccine (PPV23) (39/186; 21.0%) and non-PPV23 serotypes (38/138; 27.5%). Fifty-two (3.9%) cases resulted from PCV7 failure; 9 (0.7%) case-patients had recurrent IPD. Case-fatality rate was 4.4% (58/1,332) but higher for meningitis (11.0%) and children with comorbidities (9.1%). Thus, comorbidities were more prevalent in children with IPD caused by non-PCV13 serotypes and were associated with increased case fatality.

Hospitalization rates for pneumococcal disease in Brazil, 2004 - 2006 / Hospitalizações por doença pneumocócica no Brasil, 2004 - 2006 / Hospitalizaciones por enfermedad neumocócica en Brasil, 2004-2006

OBJECTIVE: To estimate hospitalization rates for pneumococcal disease based on the Brazilian Hospital Information System (SIH). METHODS: Descriptive study based on the Hospital Information System of Brazilian National Health System data from January 2004 to December 2006: number of hospitalizations and deaths for pneumococcal meningitis, pneumococcal sepsis, pneumococcal pneumonia and Streptococcus pneumoniae as the cause of diseases reported in Brazil. Data from the 2003 Brazilian National Household Survey were used to estimate events in the private sector. Pneumococcal meningitis cases and deaths reported to the Notifiable Diseases Information System during the study period were also analyzed. RESULTS: Pneumococcal disease accounted for 34,217 hospitalizations in the Brazilian National Health System (0.1 percent of all hospitalizations in the public sector). Pneumococcal pneumonia accounted for 64.8 percent of these hospitalizations. The age distribution of the estimated hospitalization rates for pneumococcal disease showed a "U"-shape curve with the highest rates seen in children under one (110 to 136.9 per 100,000 children annually). The highest hospital case-fatality rates were seen among the elderly, and for sepsis and meningitis. CONCLUSIONS: PD is a major public health problem in Brazil. The analysis based on the SIH can provide an important input to pneumococcal disease surveillance and the impact assessment of immunization programs.

OBJETIVO: Estimar as hospitalizações por doença pneumocócica com base em dados do Sistema de Informações Hospitalares (SIH). MÉTODOS: Estudo descritivo com base em dados do SIH de janeiro de 2004 a dezembro de 2006: números de hospitalizações e mortes por meningite pneumocócica, sepse pneumocócica, pneumonia pneumocócicca e Streptococcus pneumoniae como causa de doenças ocorridas no Brasil. Dados da Pesquisa Nacional por Amostras de Domicílios 2003 foram utilizados para o setor privado. Casos e mortes por meningite pneumocócica notificados no Sistema Nacional de Agravos de Notificação no mesmo período também foram analisados. RESULTADOS: A doença pneumocócica foi responsável por 34.217 hospitalizações no Sistema Único de Saúde (0,1 por cento de todas as hospitalizações). Pneumonia pneumocócica foi responsável por 64,8 por cento dessas hospitalizações. A distribuição das estimativas de hospitalizações segundo faixa etária mostrou curva em "U", com maior freqüência entre crianças < 1 ano (110-136,9/100.000 crianças/ano). A letalidade hospitalar foi mais alta entre idosos, e entre casos de meningite e sepse. CONCLUSÕES: Doença pneumocócica é importante problema de saúde pública no Brasil. Análise baseada no SIH pode contribuir para a vigilância epidemiológica da doença pneumocócica e para a avaliação do impacto do programa de vacinação.

OBJETIVO: Estimar las hospitalizaciones por enfermedad neumocócica con base en datos del Sistema de Informaciones Hospitalarias (SIH). MÉTODOS: Estudio descriptivo con base en datos del SIH de enero de 2004 a diciembre de 2006: números de hospitalizaciones y muertes por meningitis neumocócica, sepsis neumocócica, neumonía neumocócica y Streptococcus pneumoniae como causa de enfermedades ocurridas en Brasil. Datos de la Investigación Nacional por Muestras de Domicilios 2003 fueron utilizados para el sector privado. Casos y muertes por meningitis neumocócica notificados en el Sistema Nacional de Agravios de Notificación en el mismo período también fueron analizados. RESULTADOS: La enfermedad neumocócica fue responsable por 34.217 hospitalizaciones en el Sistema Único de Salud, (0,1 por ciento de todas las hospitalizaciones). Neumonía neumocócica fue responsable por 64,8 por ciento de tales hospitalizaciones. La distribución de las estimaciones de hospitalizaciones según grupo etáreo mostró curva en "U", con mayor frecuencia entre niños < 1 año (110-136,9/100.000 niños/año). La letalidad hospitalaria fue más alta entre ancianos, y entre casos de meningitis y sepsis. CONCLUSIONES: Enfermedad neumocócica es importante problema de salud pública en Brasil. Análisis basado en el SIH puede contribuir para la vigilancia epidemiológica de la enfermedad neumocócica y para la evaluación del impacto del programa de vacunación.

Long-term mortality in patients diagnosed with pneumococcal meningitis: a Danish nationwide cohort study.

The objective of the study was to determine the long-term mortality and the causes of death in patients diagnosed with pneumococcal meningitis. The authors performed a nationwide, population-based cohort study including all Danish patients diagnosed with pneumococcal meningitis from 1977 through 2006 and alive 1 year after diagnosis. Data were retrieved from medical databases in Denmark. The absolute and relative risks of all-cause and cause-specific death were analyzed by using Kaplan-Meier survival curves, Poisson regression analysis, Cox regression analysis, and cumulative incidence functions. The authors identified 2,131 pneumococcal meningitis patients and an age- and gender-matched, population-based cohort of 8,524 individuals. Compared with the background population, the pneumococcal meningitis patients had an increased long-term mortality varying from an 8-fold increased mortality in the age category 0-<20 years to a 1.5-fold increased mortality in those aged 60-<80 years. The increased risk of death stemmed from neoplasms, liver diseases, and nervous system diseases. The excess mortality due to neoplasms stemmed mainly from a 5-fold increased risk of death due to hematologic neoplasms. To improve survival in patients surviving the acute phase of pneumococcal meningitis, physicians should meticulously screen this patient population for neurologic sequelae and comorbidity predisposing to the disease.

Pneumococcal meningitis in Jamaican children / La meningitis pneumocócica en niños jamaicanos

OBJECTIVE: To describe the clinical features and outcome of pneumococcal meningitis in Jamaican children. METHODS: All patients admitted to the Bustamante Hospital for Children, during the period 1995-1999, who had pneumococcus isolated from cerebrospinal fluid (CSF) or pleocytosis in association with a blood culture isolate of pneumococcus were selected. Demographic, clinical and laboratory data were collected. RESULTS: Twenty-five (23%) of 111 patients with pneumococcal infections satisfied criteria for meningitis. The median age was 8 months (range 0.5-60 months). There were 4 (16%) cases of sickle cell disease, 2 (50%) of whom were first diagnosed during the current illness. This represents a 53-fold increased risk of pneumoccocal meningitis in patients with Sickle-cell disease based on population prevalence rates. Oxacillin resistance occurred in 3 (12%) patients, one of whom died. Mortality rate was 12% (3) with all deaths occurring in infants < 1 year. Poor outcome occurred in 36% (9) of the patients. Of the (35%) 8 survivors who had follow-up evaluation, (38%) 3 had documented hearing loss. CONCLUSIONS: Meningitis is a common clinical syndrome of invasive pneumococcal disease, occurring in 23% of cases resulting in mortality and high morbidity among Jamaican children. Local seroepidemiological studies are urgently needed to inform national vaccine decisions. As an interim plan, policymakers should consider a risk-based strategy to vaccine prophylaxis that will ensure that high risk groups such as children with sickle cell disease are offered currently available conjugate pneumococcal vaccines.

OBJETIVO: Describir las características clínicas y evolución de la meningitis meningocócica en niños jamaicanos. MÉTODOS: Se escogieron todos los pacientes que ingresaron al Hospital Infantil Bustamante, durante el período de 1995-1999, y que tuvieron pneumococos aislados del líquido cefalorraquídeo (LCR) o pleocitosis asociada con un aislado de pneumococos en un cultivo de sangre. Se recogieron los datos demográficos y clínicos, así como los datos de laboratorio. RESULTADOS: Veinticinco (23%) de los pacientes con infecciones pneumocócicas correspondían a los criterios de la meningitis. La edad promedio fue de 8 meses (rango 0.5 - 60 meses). Hubo 4 (16%) casos de anemia falciforme, 2 (50%) de los cuales fueron diagnosticados primeramente durante la enfermedad corriente. Esto representa un aumento de riesgo de meningitis meningocócica 53 veces mayor en pacientes con anemia ciclémica, teniendo en cuenta las tasas de prevalencia poblacional. Se halló resistencia a la oxacilina en 3 (12%) pacientes, uno de los cuales murió. La tasa de mortalidad fue del 12% (3), correspondiendo todas las muertes a infantes < 1 año. Resultados pobres se produjeron en (9) 36% de los pacientes. De los 8 (35%) supervivientes que tuvieron evaluación de seguimiento, 3 (38%) tuvieron pérdida de la audición documentada. CONCLUSIONES: La meningitis es un síndrome clínico común de la enfermedad pneumocócica invasiva, que tiene lugar en 23 % de los casos, y que trae por consecuencia mortalidad y una alta morbilidad entre los niños jamaicanos. Se requieren con urgencia estudios seroepidemiológicos locales a fin de tener información para las decisiones nacionales sobre las vacunas. A modo de plan provisional, los encargados de trazar las políticas deben considerar una estrategia de riesgo para la profilaxis de vacuna, a fin de asegurar que los grupos de alto riesgo, tales como los niños con anemia falciforme, puedan tener a su alcance las vacunas pneumocócicas conjugadas actualmente disponibles.

Effects of Toll-like receptor 2 agonist Pam(3)CysSK(4) on inflammation and brain damage in experimental pneumococcal meningitis.

TLR2 signaling participates in the pathogenesis of pneumococcal meningitis. In infant rats, the TLR2 agonist Pam(3)CysSK(4) was applied intracisternally (0.5 microg in 10 microl saline) alone or after induction of pneumococcal meningitis to investigate the effect of TLR2 activation on cerebrospinal fluid (CSF) inflammation and hippocampal apoptosis. A dose effect of Pam(3)CysSK(4) on apoptosis was investigated by intracisternal application of 0.5 microg in 10 microl saline and 40 microg in 20 microl saline. Pam(3)CysSK(4) neither induced apoptosis in sham-operated mice nor aggravated apoptosis in acute infection. However, Pam(3)CysSK(4) induced pleocytosis, TNF-alpha and MMP-9 in CSF in sham-infection but not during acute meningitis. We conclude that TLR2 signaling triggered by Pam(3)CysSK(4) at a dosage capable to induce a neuroinflammatory response does not induce hippocampal apoptosis in the infant rat model of experimental pneumococcal meningitis.

[Pneumococcal meningitis in children--9 1/2-year-experience at Szent László Hospital, Budapest, Hungary]. / Pneumococcus-meningitis gyermekkorban--kilenc és fél év tapasztalata a Szent László kórházban.

BACKGROUND AND OBJECTIVE: No recent publications are available about pneumococcal meningitis in Hungarian children. The aim of this study was to collect data of epidemiological, clinical and prognostic features of pneumococcal meningitis in children treated at Szent László Hospital, Budapest, Hungary. METHODS: We conducted a retrospective review of medical charts and follow-up records of patients aged 1 to 18 years admitted to our Pediatric and Pediatric Intensive Care Units due to pneumococcal meningitis between 1st Jan 1998 and 30th Jun 2007. RESULTS: 31 children with 34 cases of pneumococcal meningitis were admitted to our hospital in the study period. Two children developed recurrent illness. The mean age was 6 years, 26% were under 1 year of age. The mean duration of hospital stay was 21 days, 97% required intensive care. Frequent clinical symptoms were fever (100%), nuchal rigidity and vomiting (78%), altered mental status (71%), Kernig's and Brudzinski's signs (58%) and seizures (41%). Otitis media, sinusitis, mastoiditis were present in 44%, 58%, 41%, respectively. Subdural effusion, parenchymal cerebral lesion and sinus thrombosis were documented in 5, 3 and 2 cases, respectively. One third of the patients received ceftriaxon, two thirds were administered ceftriaxon and vancomycin. Adjunctive therapy with dexamethasone was given to 91% of the children. 70% of patients required mechanical ventilation. 9 patients (25%) required endoscopic sinus surgery. In 13 cases (38%) mastoidectomy, in 5 children (15%) neurosurgery was performed. The case fatality rate was 23.5%. 8 (23.5%) patients had mild or moderate, 1 child (3%) developed severe neurological sequelae. CONCLUSION: Pneumococcal meningitis in children remains a source of substantial morbidity and mortality in childhood. The long hospital stay, the frequent need for intensive care and severe neurologic sequelae emphasize the importance of early diagnosis, early treatment and prevention with pneumococcal conjugate vaccines.

Doença pneumocócica invasiva em crianças e adolescentes soropositivos para HIV / Invasive pneumococcal disease in HIV seropositive children and adolescents

OBJETIVO: Doença Invasiva Pneumocócica (DPI) afeta crianças principalmente menores de 5 anos, idosos e grupos de risco, especialmente pessoas infectadas pelo vírus da Imunodeficiência Humana (HIV). O objetivo deste trabalho foi analisar as doenças pneumocócicas invasivas (DPI) em crianças e adolescentes infectados pelo vírus da imunodeficiência humana (HIV), de acordo com morbiletalidade, sorotipos, sensibilidade à penicilina e ceftriaxona e distribuição de Streptococcus pneumoniae (Sp) sensíveis e resistentes presentes na vacina antipneumocócica conjugada 7-valente, já licenciada. MÉTODOS: Foram identificados 19 casos de DPI entre pacientes HIV soropositivos com idade entre 1 mês e 20 anos hospitalizados de 1993 a 2000. Os dados foram registrados em fichas padronizadas, contendo informações sobre idade, diagnóstico clínico e evolução, sorotipos e perfil de sensibilidade para penicilina e ceftriaxona das cepas de Sp isoladas em cultura. Sp com concentração inibitória mínima < 0,1 mcg/mL foi considerado sensível à penicilina (SpSPn), e as demais cepas como não sensíveis (SpNSPn). RESULTADOS: Dos 19 casos de DPI em HIV soropositivos, 16 (84 por cento) tinham pneumonia e três (16 por cento), meningite; 13 (68 por cento) ocorreram em crianças menores de 2 anos e 16 (84 por cento) em menores de 5 anos. A letalidade foi de 10 por cento. Dos 13 casos em menores de 2 anos, sete (54 por cento) foram SpNSPn e 10 (77 por cento) foram causados por sorotipos contemplados na vacina antipneumocócica conjugada 7-valente. Foram isolados 10 sorotipos, sendo mais freqüentes o 14, 6B e 23F, todos sensíveis à ceftriaxona. Dos três casos de meningite, dois foram causados por SpNSPn. CONCLUSÃO: A maioria das DPI ocorreu em menores de 2 anos de idade; 77 por cento das cepas e 86 por cento dos sorotipos de SpNSPn estão contemplados pela vacina antipneumocócica conjugada 7-valente.

OBJECTIVE: Invasive pneumococcal disease (IPD) primarily affects children less than 5 years old, the elderly and certain at-risk groups; especially people infected by the human immunodeficiency virus (HIV). The objective of this study was to analyze invasive pneumococcal diseases (IPD) in children and adolescents infected by the human immunodeficiency virus (HIV), with relation to morbidity, the case fatality ratio, pneumococcus serotypes, susceptibility to penicillin and ceftriaxone and to the proportion of susceptible and resistant Streptococcus pneumoniae (Sp) included in the 7-valent pneumococcal conjugate vaccine that has already been licensed. METHODS: A total of 19 cases of IPD were identified among HIV seropositive patients aged from 1 month to 20 years and hospitalized between 1993 and 2000. Data were recorded on standardized charts containing information on age, clinical diagnosis and progression, serotypes and the susceptibility to penicillin and ceftriaxone of the Sp strains identified in cultures. When the minimum inhibitory concentration was < 0.1 mcg/mL, Sp were defined as susceptible to penicillin (SpSPn), and all other strains were defined as not susceptible (SpNSPn). RESULTS: Of the 19 HIV seropositive cases with IPD, 16 (84 percent) had pneumonia and three (16 percent), had meningitis; 13 (68 percent) cases were children less than 2 years old and 16 (84 percent) were less than 5 years old. The case fatality ratio was 10 percent. Seven (54 percent) of the 13 cases less than 2 years old were SpNSPn and 10 (77 percent) were caused by serotypes covered by the 7-valent pneumococcal conjugate vaccine. From the 10 isolated serotypes the most frequent were 14, 6B and 23F, all them susceptible to ceftriaxone. From the three patients with meningitis, two were caused by SpNSPn. CONCLUSION: In this study most of the IPD occurred in children less than 2 years old; 77 percent of the strains and 86 percent of the serotypes of SpNSPn...

Acute bacterial meningitis in HIV, pacients in southern Brazil: Curitiba, Paraná, Brazil

Acute communitarian bacterial meningitis and AIDS are prevalent infectious disease in Brazil. The objective of this study was to evaluate the frequency of acute communitarian bacterial meningitis in AIDS patients, the clinical and cerebrospinal fluid (CSF) characteristics. It was reviewed the Health Department data from city of Curitiba, Southern Brazil, from 1996 to 2002. During this period, 32 patients with AIDS fulfilled criteria for acute bacterial meningitis, representing 0.84 percent of the AIDS cases and 1.85 percent of the cases of bacterial meningitis. S. pneumoniae was the most frequent bacteria isolated. The number of white blood cells and the percentage of neutrophils were higher and CSF glucose was lower in the group with no HIV co-infection (p 0.12; 0.008; 0.04 respectively). Bacteria not so common causing meningitis can occur among HIV infected patients. The high mortality rate among pneumococcus meningitis patients makes pneumococcus vaccination important.

A meningite bacteriana aguda comunitária e a AIDS são doenças prevalentes no Brasil. O objetivo desse estudo foi avaliar a freqüência de meningite bacteriana aguda comunitária entre os pacientes com AIDS e as características clínicas e do líquido cefalorraquidiano (LCR). Foram revistos os dados da Secretaria Municipal da Saúde, Curitiba, Paraná, Brasil, nos anos de 1996 a 2002. Nesse período, 32 pacientes com AIDS preencheram os critérios para meningite bacteriana aguda, representando 0,84 por cento dos casos com AIDS e 1,85 por cento dos casos com meningite bacteriana aguda. A bactéria mais freqüentemente isolada foi S. pneumoniae. A celularidade total e a porcentagem de neutrófilos no LCR foi mais elevada e a glicose foi mais baixa no grupo sem co-infecção (p 0,12; 0,008; 0,04 respectivamente). Bactérias menos freqüentes como agentes etiológicos de meningite podem ocorrer. A taxa de mortalidade elevada entre pacientes com meningite por pneumococo torna a vacinação importante.

High pneumococcal DNA loads are associated with mortality in Malawian children with invasive pneumococcal disease.

BACKGROUND: In bacteremia owing to Streptococcus pneumoniae, high bacterial counts at presentation have been shown to be predictive of the development of serious invasive disease. Using real-time PCR, we aimed to determine pneumococcal DNA loads in blood and CSF, and their relationship to cytokine concentrations, clinical presentation and outcome. METHODS: Children with confirmed meningitis (n = 82) or pneumonia (n = 13) were prospectively recruited, and blood and CSF samples taken for pneumococcal bacterial DNA loads and cytokine determination. RESULTS: At the time of admission, the median bacterial load in blood was 1.6 x 10 DNA copies/mL (range 0.00-1.54 x 10) and in CSF it was 5.77 x 10 DNA copies/mL (range 4.42 x 10 to 6.15 x 10). Median blood and CSF bacterial loads (log DNA copies/mL) were significantly higher in nonsurvivors than in survivors; blood (3.80 vs. 2.97, P = 0.003), CSF (8.17 vs. 7.50, P = 0.03). In HIV-infected children (n = 59), blood and CSF loads and plasma tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), IL-6 and IL-10 were all significantly higher in nonsurvivors than in survivors, but in HIV-uninfected children (n = 36) this difference was not significant. Blood bacterial loads and plasma cytokine concentrations were significantly associated, and were all significantly higher in children with meningitis than in those with pneumonia. In children with meningitis, median CSF cytokine concentrations were significantly higher than median plasma cytokine concentrations (P < 0.001) and CSF bacterial loads were significantly associated with CSF IL-1beta (P = 0.002) and IL-10 (P = 0.001) concentrations. CONCLUSIONS: Pneumococcal DNA loads are associated with plasma cytokine concentrations, and are higher in meningitis than in pneumonia. High blood and CSF pneumococcal DNA loads are associated with a fatal outcome.

Doxycycline reduces mortality and injury to the brain and cochlea in experimental pneumococcal meningitis.

Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 microM in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats.

Neumoencéfalo, otitis media y meningitis a neumococo / Pneumocephalus, middle otitis and meningococcic meningitis

La meningitis bacteriana es una enfermedad con alta morbi-mortalidad, el germen prevalente es el Strep pneumoniae y constituye la complicación intracraneal más frecuente de la otitis media aguda en el adulto. La TAC de cerebro es de indicación habitual ante su sospecha, previa a la realización de la punción lumbar, y en el 13 por ciento de los casos, los hallazgos son compatibles con una disrupción de la barrera dural, de la que el neumoencéfaloi (NE) es una de las consecuencias. Se presenta un paciente con meningitis bacteriana aguda por neumococo, otitis media y NE, sin traumatismo, malformación, tumor o cirugía previa