LTA4H genotype is associated with susceptibility to bacterial meningitis but is not a critical determinant of outcome.
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ABSTRACT:
SUBMITTER: Dunstan SJ
PROVIDER: S-EPMC4370666 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
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LTA4H genotype is associated with susceptibility to bacterial meningitis but is not a critical determinant of outcome.
Dunstan Sarah J SJ Tram Trinh Thi Bich TT Thwaites Guy E GE Chau Tran Thi Hong TT Phu Nguyen Hoan NH Hien Tran Tinh TT Farrar Jeremy J JJ Wolbers Marcel M Mai Nguyen Thi Hoang NT
PloS one 20150323 3
Adjunctive dexamethasone saves lives in the treatment of tuberculous meningitis but this response is influenced by the patient's LTA4H genotype. Despite less certain benefit, adjunctive dexamethasone is also frequently used in the treatment of pyogenic bacterial meningitis, but the influence of LTA4H genotype on outcomes has not been previously investigated. We genotyped the LTA4H promoter region SNP (rs17525495) in 390 bacterial meningitis patients and 751 population controls. rs17525495 was as ...[more]
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| S-EPMC5426370 | biostudies-literature
Project description:BackgroundCommunity acquired bacterial meningitis (CABM) is a condition associated with significant morbidity and mortality. Treatment delay remains an area of concern and might be improved by awareness of meningitis among health care professionals.MethodsRetrospective observational study of patients with CABM between 2016 and 2021 in Eastern Denmark with a population of 2,700,000. Data was extracted from electronic health records. Treatment delay and mortality was analyzed using multivariate logistic regression and expressed as odds ratio (OR) with 95% confidence intervals (CI).ResultsOf 369 patients 226 (61%) had treatment delayed more than 2 hours. Old age (OR 2.42, CI 1.22;4.77), comorbidity (OR 1.30, CI 1.00;1.70), suspicion of other infections than meningitis (OR 65.93, CI 20.68;210.20), stroke (OR 7.24, CI 3.11;16.86) and other diagnoses (OR 13.00, CI 5.07;33.31) were associated with delayed treatment. Treatment delay was associated with increased 30-day mortality (OR 3.07, 95% CI 1.09;8.67). Most of the treatment delay (82%) was due lack of suspicion of CABM.ConclusionsTreatment delay is a common problem associated with 30-day mortality in CABM. Awareness of CABM in undiagnosed patients is vital to achieve timely initiation of appropriate treatment. Special care should be shown for patients suspected of stroke or other infections.
| S-EPMC10139896 | biostudies-literature
Project description:UnlabelledIn sub-Saharan Africa, cryptococcal meningitis (CM) continues to be a predominant cause of AIDS-related mortality. Understanding virulence and improving clinical treatments remain important. To characterize the role of the fungal strain genotype in clinical disease, we analyzed 140 Cryptococcus isolates from 111 Ugandans with AIDS and CM. Isolates consisted of 107 nonredundant Cryptococcus neoformans var. grubii strains and 8 C. neoformans var. grubii/neoformans hybrid strains. Multilocus sequence typing (MLST) was used to characterize genotypes, yielding 15 sequence types and 4 clonal clusters. The largest clonal cluster consisted of 74 isolates. The results of Burst and phylogenetic analysis suggested that the C. neoformans var. grubii strains could be separated into three nonredundant evolutionary groups (Burst group 1 to group 3). Patient mortality was differentially associated with the different evolutionary groups (P = 0.04), with the highest mortality observed among Burst group 1, Burst group 2, and hybrid strains. Compared to Burst group 3 strains, Burst group 1 strains were associated with higher mortality (P = 0.02), exhibited increased capsule shedding (P = 0.02), and elicited a more pronounced Th(2) response during ex vivo cytokine release assays with strain-specific capsule stimulation (P = 0.02). The results of these analyses suggest that cryptococcal strain variation can be an important determinant of human immune responses and mortality.ImportanceCryptococcus neoformans is a common life-threatening human fungal pathogen that is responsible for an estimated 1 million cases of meningitis in HIV-infected patients annually. Virulence factors that are important in human disease have been identified, yet the impacts of the fungal strain genotype on virulence and outcomes of human infection remain poorly understood. Using an analysis of strain variation based on in vitro assays and clinical data from Ugandans living with AIDS and cryptococcal infection, we report that strain genotype predicts the type of immune response and mortality risk. These studies suggest that knowledge of the strain genotype during human infections could be used to predict disease outcomes and lead to improved treatment approaches aimed at targeting the specific combination of pathogen virulence and host response.
| S-EPMC3448160 | biostudies-literature
Project description:Recently, the biased ?2-adrenoceptor/?-arrestin pathway was shown to play a pivotal role in crossing of the blood brain barrier by Neisseria meningitidis. We hypothesized that genetic variation in the ?2-adrenoceptor gene (ADRB2) may influence susceptibility to bacterial meningitis. In a prospective genetic association study we genotyped 542 patients with CSF culture proven community acquired bacterial meningitis and 376 matched controls for 2 functional single nucleotide polymorphisms in the ?2-adrenoceptor gene (ADRB2). Furthermore, we analyzed if the use of non-selective beta-blockers, which bind to the ?2-adrenoceptor, influenced the risk of bacterial meningitis. We identified a functional polymorphism in ADRB2 (rs1042714) to be associated with an increased risk for bacterial meningitis (Odds ratio [OR] 1.35, 95% confidence interval [CI] 1.04-1.76; p?=?0.026). The association remained significant after correction for age and was more prominent in patients with pneumococcal meningitis (OR 1.52, 95% CI 1.12-2.07; p?=?0.007). For meningococcal meningitis the difference in genotype frequencies between patients and controls was similar to that in pneumococcal meningitis, but this was not statistically significant (OR 1.43, 95% CI 0.60-3.38; p?=?0.72). Patients with bacterial meningitis had a lower frequency of non-selective beta-blockers use compared to the age matched population (0.9% vs. 1.8%), although this did not reach statistical significance (OR 1.96 [95% CI 0.88-4.39]; p?=?0.09). In conclusion, we identified an association between a genetic variant in the ?2-adrenoceptor and increased susceptibility to bacterial meningitis. The potential benefit of pharmacological treatment targeting the ?2-adrenoceptor to prevent bacterial meningitis in the general population or patients with bacteraemia should be further studied in both experimental studies and observational cohorts.
| S-EPMC3356289 | biostudies-literature
Project description:Leukotriene A(4) hydrolase (LTA(4)H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene B(4) (LTB(4)). LTA(4)H also possesses aminopeptidase activity with unknown substrate and physiological importance; we identified the neutrophil chemoattractant proline-glycine-proline (PGP) as this physiological substrate. PGP is a biomarker for chronic obstructive pulmonary disease (COPD) and is implicated in neutrophil persistence in the lung. In acute neutrophil-driven inflammation, PGP was degraded by LTA(4)H, which facilitated the resolution of inflammation. In contrast, cigarette smoke, a major risk factor for the development of COPD, selectively inhibited LTA(4)H aminopeptidase activity, which led to the accumulation of PGP and neutrophils. These studies imply that therapeutic strategies inhibiting LTA(4)H to prevent LTB(4) generation may not reduce neutrophil recruitment because of elevated levels of PGP.
| S-EPMC3072752 | biostudies-literature
Project description:The aim of the study was to determine the effect of chronic alcohol abuse on the course and outcome of bacterial meningitis (BM). We analyzed records of patients with BM who were hospitalized between January 2010 and December 2017 in the largest neuroinfection center in Poland. Out of 340 analyzed patients, 45 (13.2%) were alcoholics. Compared with non-alcoholics, alcoholics were more likely to present with seizures (p < 0.001), scored higher on the Sequential Organ Failure Assessment (SOFA) (p = 0.002) and lower on the Glasgow Coma Scale (GCS) (p < 0.001), and had worse outcome as measured by the Glasgow Outcome Score (GOS) (p < 0.001). Furthermore, alcoholics were less likely to complain of headache (p < 0.001) and nausea/vomiting (p = 0.005) and had lower concentration of glucose in cerebrospinal fluid (CSF) (p = 0.025). In the multiple logistic regression analysis, alcoholism was associated with lower GCS (p = 0.036), presence of seizures (p = 0.041), male gender (p = 0.042), and absence of nausea/vomiting (p = 0.040). Furthermore, alcoholism (p = 0.031), lower GCS score (p = 0.001), and higher blood urea concentration (p = 0.018) were independently associated with worse outcome measured by GOS. Compared with non-alcoholics, chronic alcohol abusers are more likely to present with seizures, altered mental status, and higher SOFA score and have an increased risk of unfavorable outcome. In multivariate analysis, seizures and low GCS were independently associated with alcoholism, while alcoholism was independently associated with worse outcome.
| S-EPMC6800865 | biostudies-other
Project description:Purpose of reviewCommunity-acquired bacterial meningitis is a continually changing disease. This review summarises both dynamic epidemiology and emerging data on pathogenesis. Updated clinical guidelines are discussed, new agents undergoing clinical trials intended to reduce secondary brain damage are presented.Recent findingsConjugate vaccines are effective against serotype/serogroup-specific meningitis but vaccine escape variants are rising in prevalence. Meningitis occurs when bacteria evade mucosal and circulating immune responses and invade the brain: directly, or across the blood-brain barrier. Tissue damage is caused when host genetic susceptibility is exploited by bacterial virulence. The classical clinical triad of fever, neck stiffness and headache has poor diagnostic sensitivity, all guidelines reflect the necessity for a low index of suspicion and early Lumbar puncture. Unnecessary cranial imaging causes diagnostic delays. cerebrospinal fluid (CSF) culture and PCR are diagnostic, direct next-generation sequencing of CSF may revolutionise diagnostics. Administration of early antibiotics is essential to improve survival. Dexamethasone partially mitigates central nervous system inflammation in high-income settings. New agents in clinical trials include C5 inhibitors and daptomycin, data are expected in 2025.SummaryClinicians must remain vigilant for bacterial meningitis. Constantly changing epidemiology and emerging pathogenesis data are increasing the understanding of meningitis. Prospects for better treatments are forthcoming.
| S-EPMC7610733 | biostudies-literature
Project description:OBJECTIVE: In bacterial meningitis, a decreased level of consciousness is predictive for unfavorable outcome, but the clinical features and outcome in patients presenting with a minimal score on the Glasgow Coma Scale are unknown. METHODS: We assessed the incidence, clinical characteristics, and outcome of patients with bacterial meningitis presenting with a minimal score on the Glasgow Coma Scale from a nationwide cohort study of adults with community-acquired bacterial meningitis in the Netherlands from 2006 to 2012. RESULTS: Thirty of 1,083 patients (3%) presented with a score of 3 on the Glasgow Coma Scale. In 22 of 30 patients (73%), the minimal Glasgow Coma Scale score could be explained by use of sedative medication or complications resulting from meningitis such as seizures, cerebral edema, and hydrocephalus. Systemic (86%) and neurologic (47%) complications occurred frequently, leading to a high proportion of patients with unfavorable outcome (77%). However, 12 of 30 patients (40%) survived and 7 patients (23%) had a good functional outcome, defined as a score of 5 on the Glasgow Outcome Scale. Patients presenting with a minimal Glasgow Coma Scale score on admission and bilaterally absent pupillary light responses, bilaterally absent corneal reflexes, or signs of septic shock on admission all died. CONCLUSIONS: Patients with community-acquired bacterial meningitis rarely present with a minimal score on the Glasgow Coma Scale, but this condition is associated with high rates of morbidity and mortality. However, 1 out of 5 of these severely ill patients will make a full recovery, stressing the continued need for aggressive supportive care in these patients.
| S-EPMC4202677 | biostudies-literature
Project description:Exposure to Mycobacterium tuberculosis produces varied early outcomes, ranging from resistance to infection to progressive disease. Here we report results from a forward genetic screen in zebrafish larvae that identify multiple mutant classes with distinct patterns of innate susceptibility to Mycobacterium marinum. A hypersusceptible mutant maps to the lta4h locus encoding leukotriene A(4) hydrolase, which catalyzes the final step in the synthesis of leukotriene B(4) (LTB(4)), a potent chemoattractant and proinflammatory eicosanoid. lta4h mutations confer hypersusceptibility independent of LTB(4) reduction, by redirecting eicosanoid substrates to anti-inflammatory lipoxins. The resultant anti-inflammatory state permits increased mycobacterial proliferation by limiting production of tumor necrosis factor. In humans, we find that protection from both tuberculosis and multibacillary leprosy is associated with heterozygosity for LTA4H polymorphisms that have previously been correlated with differential LTB(4) production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.
| S-EPMC2907082 | biostudies-literature
Project description:BACKGROUND: Bacterial meningitis (BM) is an infectious disease that results in high mortality and morbidity. Despite efficacious antibiotic therapy, neurological sequelae are often observed in patients after disease. Currently, the main challenge in BM treatment is to develop adjuvant therapies that reduce the occurrence of sequelae. In recent papers published by our group, we described the associations between the single nucleotide polymorphisms (SNPs) AADAT +401C?>?T, APEX1 Asn148Glu, OGG1 Ser326Cys and PARP1 Val762Ala and BM. In this study, we analyzed the associations between the SNPs TNF -308G?>?A, TNF -857C?>?T, IL-8 -251A?>?T and BM and investigated gene-gene interactions, including the SNPs that we published previously. METHODS: The study was conducted with 54 BM patients and 110 healthy volunteers (as the control group). The genotypes were investigated via primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) or polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. Allelic and genotypic frequencies were also associated with cytokine and chemokine levels, as measured with the x-MAP method, and cell counts. We analyzed gene-gene interactions among SNPs using the generalized multifactor dimensionality reduction (GMDR) method. RESULTS: We did not find significant association between the SNPs TNF -857C?>?T and IL-8 -251A?>?T and the disease. However, a higher frequency of the variant allele TNF -308A was observed in the control group, associated with changes in cytokine levels compared to individuals with wild type genotypes, suggesting a possible protective role. In addition, combined inter-gene interaction analysis indicated a significant association between certain genotypes and BM, mainly involving the alleles APEX1 148Glu, IL8 -251 T and AADAT +401 T. These genotypic combinations were shown to affect cyto/chemokine levels and cell counts in CSF samples from BM patients. CONCLUSIONS: In conclusion, this study revealed a significant association between genetic variability and altered inflammatory responses, involving important pathways that are activated during BM. This knowledge may be useful for a better understanding of BM pathogenesis and the development of new therapeutic approaches.
| S-EPMC4593216 | biostudies-literature