Cerebrospinal-fluid cytokine and chemokine profile in patients with pneumococcal and meningococcal meningitis

BACKGROUND Bacterial meningitis is characterized by an intense inflammatory reaction contributing to neuronal damage. The aim of this study was to obtain a comparative analysis of cytokines and chemokines in patients with pneumococcal (PM) and meningococcal meningitis (MM) considering that a clear difference between the immune response induced by these pathogens remains unclear. METHODS The cyto/chemokines, IL-1beta, IL-2, IL-6, TNF-alpha, IFN-gamma, IL-10, IL-1Ra, CXCL8/IL-8, CCL2/MCP-1, CLL3/MIP-1alpha, CCL4/MIP-1gamma and G-CSF, were measured in cerebrospinal fluid (CSF) samples from patients with PM and MM. Additionally, a literature review about the expression of cytokines in CSF samples of patients with MB was made. RESULTS Concerning cytokines levels, only IFN-gamma was significantly higher in patients with Streptococcus pneumoniae compared to those with Neisseria meningitidis, regardless of the time when the lumbar puncture (LP) was made. Furthermore, when samples were compared considering the timing of the LP, higher levels of TNF-alpha (P <0.05) were observed in MM patients whose LP was made within 48 h from the initial symptoms of disease. We also observed that the index of release of cyto/chemokines per cell was significantly higher in PM. From the literature review, it was observed that TNF-alpha, IL-1beta and IL-6 are the best studied cytokines, while reports describing the concentration of the cytokine IL-2, IL-1Ra, G-CSF and CCL4/MIP-1beta in CSF samples of patients with bacterial meningitis were not found. CONCLUSION The data obtained in this study and the previously published data show a similar profile of cytokine expression during PM and MM. Nevertheless, the high levels of IFN-gamma and the ability to release high levels of cytokines with a low number of cells are important factors to be considered in the pathogenesis of PM and thereby should be further investigated. Moreover, differences in the early response induced by the pathogens were observed. However, the differences observed are not sufficient to trigger changes in the current therapy of corticosteroids adopted in both the PM and MM.

Inhibition of matrix metalloproteinases attenuates brain damage in experimental meningococcal meningitis.

BackgroundApproximately 7% of survivors from meningococcal meningitis (MM) suffer from neurological sequelae due to brain damage in the course of meningitis. The present study focuses on the role of matrix metalloproteinases (MMPs) in a novel mouse model of MM-induced brain damage.MethodsThe model is based on intracisternal infection of BALB/c mice with a serogroup C Neisseria meningitidis strain. Mice were infected with meningococci and randomised for treatment with the MMP inhibitor batimastat (BB-94) or vehicle. Animal survival, brain injury and host-response biomarkers were assessed 48 h after meningococcal challenge.ResultsMice that received BB-94 presented significantly diminished MMP-9 levels (p¿<¿0.01), intracerebral bleeding (p¿<¿0.01), and blood-brain barrier (BBB) breakdown (p¿<¿0.05) in comparison with untreated animals. In mice suffering from MM, the amount of MMP-9 measured by zymography significantly correlated with both intracerebral haemorrhage (p¿<¿0.01) and BBB disruption (p¿<¿0.05).ConclusionsMMPs significantly contribute to brain damage associated with experimental MM. Inhibition of MMPs reduces intracranial complications in mice suffering from MM, representing a potential adjuvant strategy in MM post-infection sequelae.

Bacterial meningitis and living conditions

INTRODUCTION: Bacterial meningitis has great social relevance due to its ability to produce sequelae and cause death. It is most frequently found in developing countries, especially among children. Meningococcal meningitis occurs at a high frequency in populations with poor living conditions. This study describes the temporal evolution of bacterial meningitis in Salvador, Brazil, 1995-2009, and verifies the association between its spatial variation and the living conditions of the population. METHODS: This was an ecological study in which the areas of information were classified by an index of living conditions. It examined fluctuations using a trend curve, and the relationship between this index and the spatial distribution of meningitis was verified using simple linear regression. RESULTS: From 1995-2009, there were 3,456 confirmed cases of bacterial meningitis in Salvador. We observed a downward trend during this period, with a yearly incidence of 9.1 cases/100,000 population and fatality of 16.7%. Children aged <5 years old and male were more affected. There was no significant spatial autocorrelation or pattern in the spatial distribution of the disease. The areas with the worst living conditions had higher fatality from meningococcal disease (β = 0.0078117, p < 0.005). CONCLUSIONS: Bacterial meningitis reaches all social strata; however, areas with poor living conditions have a greater proportion of cases that progress to death. This finding reflects the difficulties for ready access and poor quality of medical care faced by these populations.

Epidemiological profile of meningococcal disease in the State of Minas Gerais and in the Central, North, and Triângulo Mineiro regions, Brazil, during 2000-2009

INTRODUCTION: Infection by Neisseria meningitidis, termed as meningococcal disease, can cause meningococcal meningitis and septicemia with or without meningitis. Meningococcal disease is endemic in Brazil and has a high potential to cause large-scale epidemics; therefore, it requires the immediate notification of cases to the Information System for Notifiable Diseases (SINAN) in Brazil. The aim of this study was to describe an epidemiological profile using data from notified and confirmed cases in the State of Minas Gerais, Brazil, from January 2000 to December 2009, obtained from the investigation records of individuals with meningitis registered with SINAN. METHODS: This was a retrospective, population-based study. Descriptive analysis of the data was made using the simple and relative frequencies of the categorical variables in the investigation records. RESULTS: There were 1,688 confirmed patients in Minas Gerais of which 45.5% lived in the Central, North, and Triângulo Mineiro regions. The highest frequencies of cases were in the 1-4-years age group (26.3%), males (54.7%), caucasian (36.4%), and lived in an urban area (80%). In the patients with specified education, 650 (60.9%) patients had secondary education. Serogrouping of meningococci had been performed in 500 (29.6%) patients by age and gender; 285 (57%) belonged to serogroup C, 67 (13.4%) were in the 1-to 4-years age group, and 168 (33.6%) were male. CONCLUSIONS: The epidemiological profiles of patients in the Central, North, and Triângulo Mineiro regions were not significantly different from the profile of patients in Minas Gerais.

Meningococcal disease in the Sorocaba region, Sao Paulo State, Brazil, 1999-2008

The objective of this study was to describe the occurrence of meningococcal disease reported to the Regional Health Department in Sorocaba, Sao Paulo State, Brazil, from 1999 to 2008. Annual incidence of the disease was two cases per 100,000 inhabitants, with an increase from 2006 to 2008. Annual incidence rates were highest in the 0 to 4 year age bracket. Case-fatality was 21.8%, higher in the 0 to 4 year age bracket (26.4%), which also showed the highest incidence of the disease, and in the over 30-year age bracket (28%). Diagnosis was confirmed by laboratory test in 71% of cases (culture in 45.3%) and by clinical and epidemiological criteria in 22%. Serological groups were B in 45.7%, C in 47.3%, W135 in 3.7%, and Y in 1.5% of the identified cases, with a predominance of B from 1999 to 2003 and C from 2004 to 2008. The most frequent phenotypes were B:4, 7:P1.19,15 and C:23:P1.14-6. The results emphasize the need for regional surveillance of trends in the disease for early detection of outbreaks and monitoring circulating strains.

[Invasive meningococcal infections: two cases that demonstrate the broad spectrum in clinical manifestation and outcome]

Invasive meningococcal infections show a broad clinical picture including sepsis and meningitis. Here we report on a case of sepsis and a case of meningitis, two clinical manifestations of meningococcal infections with striking differences in the clinical presentation and outcome. Meningococcal sepsis is characterized by a systemic release of endotoxins, that triggers an intense cytokine response of the host that can lead to shock and multi organ failure and death within hours. Meningococcal meningitis occurs when bacteria breach into the subarachnoidal and ventricular space during bacteremia and mortality is much lower that in sepsis. Thus meningitis may be seen as a consequence of lower pathogenicity and/or more efficient host control of the meningococci compared to sepsis.

Strategies to prevent neuronal damage in paediatric bacterial meningitis

PURPOSE OF REVIEW: The mortality of bacterial meningitis can reach 30%, and up to 50% of survivors suffer from persisting neurological deficits as a consequence of the disease. The incidence of neurological sequelae of bacterial meningitis has not improved over the last decade. Adjunctive therapeutic options are limited, and ongoing research into the pathophysiology of brain damage in bacterial meningitis aims at providing the scientific basis for future development of more efficient adjunctive options. RECENT FINDINGS: In a population with good access to health care, dexamethasone given before or at the time of initiation of antibiotic therapy acts beneficially in paediatric pneumococcal meningitis, but not in meningococcal meningitis. In experimental animal models, brain-derived neurotrophic factor protected against brain injury and improved hearing while melatonin, which has antioxidant properties among other effects, reduced neuronal death. Transgene technology can be used to provide new insights into the pathophysiology of the disease and to identify potential therapeutic targets. SUMMARY: Although dexamethasone improves outcome of bacterial meningitis under defined circumstances, the morbidity of bacterial meningitis still remains unacceptably high. Experimental models may help to identify new therapeutic strategies to further improve the neurological outcome in young children suffering from bacterial meningitis.

Inhibition of meningitis-associated neutrophil apoptosis by TNF-α depends on functional PI3-kinase in monocytes

In bacterial meningitis, neutrophils cope with bacterial infection but also lead to tissue damage. The balance of beneficial and harmful effects may depend on the lifespan of the neutrophils in the CNS. Here, we show that CSF of patients with meningococcal meningitis contains a neutrophil apoptosis-inhibiting capacity that correlates with TNF-α content. In vitro experiments show that Neisseria meningitidis as well as LPS derived from these bacteria regulated neutrophil apoptosis mainly by stimulating TNF-α production in monocytes. Whereas LPS-induced PI3K-dependent survival signals in monocytes are critical for neutrophil survival, PI3K signaling in granulocytes did not contribute to the increased lifespan of neutrophils. We conclude that LPS-driven PI3K signaling in monocytes regulates neutrophil apoptosis and thereby, may be crucial in the initiation of secondary brain damage in bacterial meningitis.

Use of sodC versus ctrA for real-time polymerase chain reaction-based detection of Neisseria meningitidis in sterile body fluids

We evaluated the use of a newly described sodC-based real-time-polymerase chain reaction (RT-PCR) assay for detecting Neisseria meningitidis in normally sterile sites, such as cerebrospinal fluid and serum. The sodC-based RT-PCR assay has an advantage over ctrA for detecting nongroupable N. meningitidis isolates, which are commonly present in asymptomatic pharyngeal carriage. However, in our study, sodC-based RT-PCR was 7.5% less sensitive than ctrA. Given the public health impact of possible false-negative results due to the use of the sodC target gene alone, sodC-based RT-PCR for the diagnosis of meningococcal meningitis should be used with caution.

False-negative PCR result due to gene polymorphism: the example of Neisseria meningitidis.

Early treatment of meningococcal meningitis is mandatory but may negate the cerebrospinal fluid culture. Etiological diagnosis then mainly relies on PCR. Here, we report a case of false-negative results for real-time PCR for a Neisseria meningitidis serogroup B isolate with a polymorphism in the ctrA gene.

Skipping of exon 30 in C5 gene results in complete human C5 deficiency and demonstrates the importance of C5d and CUB domains for stability

The deficiency of complement C5 is rare and frequently associated with severe and recurrent infections, especially caused by Neisseria spp. We observed the absence of component C5 in the serum of 3 siblings from a Brazilian family with history of consanguinity. The patients had suffered from recurrent episodes of meningitis and other less severe infections. Sera from these patients were unable to mediate hemolytic activity either by the classical or alternative pathways and presented extremely low levels of C5 protein (13, 0.9 and 1.0 mu g/ml-normal range: 45-190 mu g/ml). Hemolytic activity could be restored by the addition of purified C5 to deficient serum. Sequencing of sibling C5 cDNA revealed a homozygous 153 bp deletion that corresponds precisely to exon 30. The parents carried the same deletion but only in one allele. Sequencing of the corresponding region in the genomic DNA revealed a C to C substitution within intron 30 and, most significantly, the substitution of GAG(4028) for GAA(4028) at the 3` end of exon 30 which is most likely responsible for skipping of exon 30. The resulting in-frame deletion in the C5 mRNA codes for a mutant C5 protein lacking residues 1289-1339. These residues map to the CUB and C5d domains of the C5 alpha chain. This deletion is expected to produce a non-functional and unstable C5 protein which is more susceptible to degradation. (C) 2009 Published by Elsevier Ltd.

An economic assessment of the impact of climate change on the health sector in Montserrat

Climate change has the potential to impact on global, regional, and national disease burdens both directly and indirectly. Projecting and valuing these health impacts is important not only in terms of assessing the overall impact of climate change on various parts of the world, but also in terms of ensuring that national and regional decision-making institutions have access to the data necessary to guide investment decisions and future policy design. This report contributes to the research focusing on projecting and valuing the impacts of climate change in the Caribbean by projecting the climate change-induced excess disease burden for two climate change scenarios in Montserrat for the period 2010 - 2050, and by estimating the monetary value associated with this excess disease burden. The diseases initially considered in this report are variety of vector and water-borne impacts and other miscellaneous conditions; specifically, malaria, dengue fever, gastroenteritis/diarrheal disease, schistosomiasis, leptospirosis, ciguatera poisoning, meningococcal meningitis, and cardio-respiratory diseases. Disease projections were based on derived baseline incidence and mortality rates, available dose-response relationships found in the published literature, climate change scenario population projections for the A2 and B2 IPCC SRES scenario families, and annual temperature and precipitation anomalies as projected by the downscaled ECHAM4 global climate model. Monetary valuation was based on a transfer value of statistical life approach with a modification for morbidity. Using discount rates of 1%, 2% and 4%, results show mean annual costs (morbidity and mortality) ranges of $0.61 million (in the B2 scenario, discounted at 4% annually) – $1 million (in the A2 scenario, discounted at 1% annually) for Montserrat. These costs are compared to adaptation cost scenarios involving increased direct spending on per capita health care. This comparison reveals a high benefit-cost ratio suggesting that moderate costs will deliver significant benefit in terms of avoided health burdens in the period 2010-2050. The methodology and results suggest that a focus on coordinated data collection and improved monitoring represents a potentially important no regrets adaptation strategy for Montserrat. Also the report highlights the need for this to be part of a coordinated regional response that avoids duplication in spending.

An assessment of the economic impact Of climate change on the health sector in Saint Lucia

Climate change has the potential to impact on global, regional, and national disease burdens both directly and indirectly. Projecting and valuing these health impacts is important not only in terms of assessing the overall impact of climate change on various parts of the world, but also of ensuring that national and regional decision-making institutions have access to the data necessary to guide investment decisions and future policy design. This report contributes to the research focusing on projecting and valuing the impacts of climate change in the Caribbean by projecting the climate change-induced excess disease burden for two climate change scenarios in Saint Lucia for the period 2010 - 2050, and by estimating the non-market, statistical life-based costs associated with this excess disease burden. The diseases initially considered in this report are a variety of vector and water-borne impacts and other miscellaneous conditions; specifically, malaria, dengue fever, gastroenteritis/diarrhoeal disease, schistosomiasis, leptospirosis, ciguatera poisoning, meningococcal meningitis, and cardio-respiratory diseases. Disease projections were based on derived baseline incidence and mortality rates, available dose-response relationships found in the published literature, climate change scenario population projections for the A2 and B2 IPCC SRES scenario families, and annual temperature and precipitation anomalies as projected by the downscaled ECHAM4 global climate model. Monetary valuation was based on a transfer value of statistical life approach with a modification for morbidity. Using discount rates of 1, 2, and 4%, results show mean annual costs (morbidity and mortality) ranges of $80.2 million (in the B2 scenario, discounted at 4% annually) -$182.4 million (in the A2 scenario, discounted at 1% annually) for St. Lucia.1 These costs are compared to adaptation cost scenarios involving direct and indirect interventions in health care. This comparison reveals a high benefit-cost ratio suggesting that moderate costs will deliver significant benefit in terms of avoided health costs from 2010-2050. In this context indirect interventions target sectors other than healthcare (e.g. water supply). It is also important to highlight that interventions can target both the supply of health infrastructure (including health status and disease monitoring), and households. It is suggested that a focus on coordinated data collection and improved monitoring represents a potentially important no regrets adaptation strategy for St Lucia. Also, the need for this to be part of a coordinated regional response that avoids duplication in spending is highlighted.

THE INTERNATIONAL CLASSIFICATION OF PUBLIC HEALTH NURSING PRACTICES - CIPESC (R): A PEDAGOGICAL TOOL FOR EPIDEMIOLOGICAL STUDIES

The CIPESC (R) is a tool that informs the work of nurses in Public Health and assists in prioritizing their care in practice, management and research. It is also a powerful pedagogical instrument for the qualification of nurses within the Brazilian healthcare system. In the teaching of infectious diseases, using the CIPESC (R) assists in analyzing the interventions by encouraging clinical and epidemiological thinking regarding the health-illness process. With the purpose in mind of developing resources for teaching undergraduate nursing students and encouraging reflection regarding the process of nursing work, this article presents an experimental application of CIPESC (R), using meningococcal meningitis as an example.