Blood biomarkers for the differentiation between central and peripheral vertigo in the emergency department: a systematic review and meta-analysis.

BACKGROUND/INTRODUCTION: In patients with acute vestibular syndrome (AVS), differentiating between stroke and nonstroke causes is challenging in the emergency department (ED). Correct diagnosis of vertigo etiology is essential for early optimum treatment and disposition. OBJECTIVES: The aim of this systematic review and meta-analysis was to summarize the published evidence on the potential of blood biomarkers in the diagnosis and differentiation of peripheral from central causes of AVS. METHODS: A literature search was conducted for studies published until January 1, 2023, in PubMed, Ovid Medline, and EMBASE databases analyzing biomarkers for the differentiation between central and peripheral AVS. The Quality Assessment of Diagnostic Accuracy Studies questionnaire 2 was used for quality assessment. Pooled standardized mean difference and 95% confidence intervals were calculated if a biomarker was reported in two or more studies. Heterogeneity among included studies was investigated using the I2 metric. RESULTS: A total of 17 studies with 859 central and 4844 peripheral causes of acute dizziness or vertigo, and analysis of 61 biomarkers were included. The general laboratory markers creatinine, blood urea nitrogen, albumin, C-reactive protein, glucose, HbA1c, leukocyte counts, and neutrophil counts and the brain-derived biomarkers copeptin, S100 calcium-binding protein ß (S100ß), and neuron-specific enolase (NSE) significantly differentiated central from peripheral causes of AVS. CONCLUSIONS: This systematic review and meta-analysis highlights the potential of generalized inflammatory markers and brain-specific blood protein markers of NSE and S100ß as diagnostic biomarkers for central from peripheral differentiation in AVS. These results, as a complement to clinical characteristics, provide guidance for future large-scale diagnostic research, in this challenging ED patient population.

Addition of host genetic variants in a prediction rule for post meningitis hearing loss in childhood: a model updating study.

BACKGROUND: Sensorineural hearing loss is the most common sequela in survivors of bacterial meningitis (BM). In the past we developed a validated prediction model to identify children at risk for post-meningitis hearing loss. It is known that host genetic variations, besides clinical factors, contribute to severity and outcome of BM. In this study it was determined whether host genetic risk factors improve the predictive abilities of an existing model regarding hearing loss after childhood BM. METHODS: Four hundred and seventy-one Dutch Caucasian childhood BM were genotyped for 11 single nucleotide polymorphisms (SNPs) in seven different genes involved in pathogen recognition. Genetic data were added to the original clinical prediction model and performance of new models was compared to the original model by likelihood ratio tests and the area under the curve (AUC) of the receiver operating characteristic curves. RESULTS: Addition of TLR9-1237 SNPs and the combination of TLR2 + 2477 and TLR4 + 896 SNPs improved the clinical prediction model, but not significantly (increase of AUC's from 0.856 to 0.861 and from 0.856 to 0.875 (p = 0.570 and 0.335, respectively). Other SNPs analysed were not linked to hearing loss. CONCLUSIONS: Although addition of genetic risk factors did not significantly improve the clinical prediction model for post-meningitis hearing loss, AUC's of the pre-existing model remain high after addition of genetic factors. Future studies should evaluate whether more combinations of SNPs in larger cohorts has an additional value to the existing prediction model for post meningitis hearing loss.

Single nucleotide polymorphisms in pathogen recognition receptor genes are associated with susceptibility to meningococcal meningitis in a pediatric cohort.

Bacterial meningitis (BM) is a serious infection of the central nervous system, frequently occurring in childhood and often resulting in hearing loss, learning disabilities, and encephalopathy. Previous studies showed that genetic variation in innate immune response genes affects susceptibility, severity, and outcome of BM. The aim of this study is to describe whether single nucleotide polymorphisms (SNPs) in pathogen recognition gene products are associated with susceptibility to develop BM in single genes analysis as well as SNP combinations. Genotype frequencies of seven SNPs, in five immune response genes encoding for Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD) proteins and caspase-1 (CASP1), in 391 children with meningococcal meningitis (MM) and 82 children with pneumococcal meningitis were compared with a large cohort of 1141 ethnically matched healthy controls. Carriage of TLR4 +896 GG mutant predisposed to susceptibility to develop MM (p = 1.2*10(-5), OR  = 9.4, 95% CI  = 3.0-29.2). The NOD2 SNP8 mutant was significantly more frequent in MM patients compared to controls (p = 0.0004, OR  = 12.2, 95% CI  = 2.6-57.8). Combined carriage of TLR2 +2477 and TLR4 +896 mutants was strongly associated with MM (p = 4.2*10(-5), OR  = 8.6, 95% CI  = 2.7-27.3). A carrier trait of TLR4 +896 and NOD2 SNP8 mutants was also strongly associated with susceptibility to develop MM (p = 4.2*10(-5), OR  = 10.6, 95% CI  = 2.9-38.6). This study associates SNPs in TLR4 and NOD2 with susceptibility to develop MM.

Independent validation of an existing model enables prediction of hearing loss after childhood bacterial meningitis.

OBJECTIVE: This study aimed external validation of a formerly developed prediction model identifying children at risk for hearing loss after bacterial meningitis (BM). Independent risk factors included in the model are: duration of symptoms prior to admission, petechiae, cerebral spinal fluid (CSF) glucose level, Streptococcus pneumoniae and ataxia. Validation helps to evaluate whether the model has potential in clinical practice. STUDY DESIGN: 116 Dutch school-age BM survivors were included in the validation cohort and screened for sensorineural hearing loss (>25 dB). Risk factors were obtained from medical records. The model was applied to the validation cohort and its performance was compared with the development cohort. Validation was performed by application of the model on the validation cohort and by assessment of discrimination and goodness of fit. Calibration was evaluated by testing deviations in intercept and slope. Multiple imputation techniques were used to deal with missing values. RESULTS: Risk factors were distributed equally between both cohorts. Discriminative ability (Area Under the Curve, AUC) of the model was 0.84 in the development and 0.78 in the validation cohort. Hosmer-Lemeshow test for goodness of fit was not significant in the validation cohort, implying good fit concerning the similarity of expected and observed cases. There were no significant differences in calibration slope and intercept. Sensitivity and negative predicted value were high, while specificity and positive predicted value were low which is comparable with findings in the development cohort. CONCLUSIONS: Performance of the model remained good in the validation cohort. This prediction model might be used as a screening tool and can help to identify those children that need special attention and a long follow-up period or more frequent auditory testing.

Polymorphisms in Toll-like receptors 2, 4, and 9 are highly associated with hearing loss in survivors of bacterial meningitis.

Genetic variation in innate immune response genes contributes to inter-individual differences in disease manifestation and degree of complications upon infection. We recently described an association of single nucleotide polymorphisms (SNPs) in TLR9 with susceptibility to meningococcal meningitis (MM). In this study, we investigate the association of SNPs in multiple pathogen recognition and immune response genes with clinical features that determine severity and outcome (especially hearing loss) of childhood MM and pneumococcal meningitis (PM). Eleven SNPs in seven genes (TLR2, TLR4, TLR9, NOD1, NOD2, CASP1, and TRAIL) were genotyped in 393 survivors of childhood bacterial meningitis (BM) (327 MM patients and 66 PM patients). Genotype distributions of single SNPs and combination of SNPs were compared between thirteen clinical characteristics associated with severity of BM. After correction for multiple testing, TLR4+896 mutant alleles were highly associated with post-meningitis hearing loss, especially MM (p= 0.001, OR 4.0 for BM, p= 0.0004, OR 6.2 for MM). In a multigene analysis, combined carriership of the TLR2+2477 wild type (WT) with TLR4+896 mutant alleles increases the risk of hearing loss (p<0.0001, OR 5.7 in BM and p= 0.0001, OR 7.6 in MM). Carriage of one or both mutant alleles in TLR4+896 and TLR9 -1237 increases the risk for hearing loss (p = 0.0006, OR 4.1 in BM). SNPs in immune response genes contribute to differences in clinical severity and outcome of BM. The TLR system seems to play an important role in the immune response to BM and subsequent neuronal damage as well as in cochlear inflammation. Genetic markers may be used for identification of high-risk patients by creating prediction rules for post-meningitis hearing loss and other sequelae, and provide more insight in the complex immune response in the CNS possibly resulting in new therapeutic interventions.

Toll-like receptor 9 polymorphisms are associated with severity variables in a cohort of meningococcal meningitis survivors.

BACKGROUND: Genetic variation in immune response genes is associated with susceptibility and severity of infectious diseases. Toll-like receptor (TLR) 9 polymorphisms are associated with susceptibility to develop meningococcal meningitis (MM). The aim of this study is to compare genotype distributions of two TLR9 polymorphisms between clinical severity variables in MM survivors. METHODS: We used DNA samples of a cohort of 390 children who survived MM. Next, we determined the genotype frequencies of TLR9 -1237 and TLR9 +2848 polymorphisms and compared these between thirteen clinical variables associated with prognostic factors predicting adverse outcome of bacterial meningitis in children. RESULTS: The TLR9 -1237 TC and CC genotypes were associated with a decreased incidence of a positive blood culture for Neisseria (N.) meningitidis (p = 0.014, odds ratio (OR) 0.5. 95% confidence interval (CI) 0.3 - 0.9). The TLR9 +2848 AA mutant was associated with a decreased incidence of a positive blood culture for N. meningitidis (p = 0.017, OR 0.6, 95% CI 0.3 - 0.9). Cerebrospinal fluid (CSF) leukocytes per µL were higher in patients carrying the TLR9 -1237 TC or CC genotypes compared to carriers of the TT wild type (WT) (p = 0.024, medians: 2117, interquartile range (IQR) 4987 versus 955, IQR 3938). CSF blood/glucose ratios were lower in TLR9 -1237 TC or CC carriers than in carriers of the TT WT (p = 0.017, medians: 0.20, IQR 0.4 versus 0.35, IQR 0.5). CSF leukocytes/µL were higher in patients carrying the TLR9 +2848 AA mutant compared to carriers of GG or GA (p = 0.0067, medians: 1907, IQR 5221 versus 891, IQR 3952). CONCLUSIONS: We identified TLR9 genotypes associated with protection against meningococcemia and enhanced local inflammatory responses inside the central nervous system, important steps in MM pathogenesis and defense.

Single nucleotide polymorphisms in TLR9 are highly associated with susceptibility to bacterial meningitis in children.

BACKGROUND: Bacterial meningitis (BM) is a severe infection mainly caused by Streptococcus pneumoniae and Neisseria meningitidis (NM). However, genetically determined susceptibility to develop severe infections by these microorganisms is variable between individuals. Toll-like receptor 9 (TLR9) recognizes bacterial DNA leading to intracellular inflammatory signaling. Single nucleotide polymorphisms (SNPs) within the TLR9 gene are associated with susceptibility to several diseases, no such association with meningitis has been described. METHODS: We studied the role of TLR9 SNPs in host defense against BM. Two TLR9 SNPs and 4 TLR9 haplotypes were determined in 472 survivors of BM and compared to 392 healthy controls. RESULTS: Carriage of the TLR9+2848-A mutant was significantly decreased in meningococcal meningitis (MM) patients compared with controls (p: .0098, odds ratio [OR]: .6, 95% confidence interval [CI]: .4-.9). TLR9 haplotype I was associated with an increased susceptibility to MM (p: .0237, OR 1.3, 95% CI: 1.0-1.5). In silico analysis shows a very strong immunoinhibitory potential for DNA of NM upon recognition by TLR9 (CpG index of -106.8). CONCLUSIONS: We report an association of TLR9 SNPs with susceptibility to BM, specifically MM indicating a protective effect for the TLR9+2848-A allele. We hypothesize that the TLR9+2848-A mutant results in an up-regulation of TLR9 induced immune response compensating the strong inhibitory potential of NM CpG DNA.