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Usefulness of analytes comprising the previously established adult 7-marker serum protein biosignature in the diagnosis of TBM in children.
Source publication
Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis and results in high morbidity and mortality in children. Diagnostic delay contributes to the poor outcome. There is an urgent need for new tools for the rapid diagnosis of TBM, especially in children.
Methods: We collected serum samples from children in whom TBM was su...
Contexts in source publication
Context 1
... the concentrations of the six available markers (CRP, IFN-γ, IP-10, CFH, Apo-A1, and SAA), from the adult pulmonary TB seven-marker signature (28) were evaluated in serum samples from children with TBM vs. those without TBM individually, significant differences were obtained for CFH only. After ROC curve analysis, the most useful individual marker from this signature, as determined by AUC was CFH ( Table 3). When used in combination, the AUC for this 6-marker model in the diagnosis of TBM was 0.75 (95% CI, 0.61-0.90); ...Context 2
... the concentrations of the six available markers (CRP, IFN-γ, IP-10, CFH, Apo-A1, and SAA), from the adult pulmonary TB seven-marker signature (28) were evaluated in serum samples from children with TBM vs. those without TBM individually, significant differences were obtained for CFH only. After ROC curve analysis, the most useful individual marker from this signature, as determined by AUC was CFH ( Table 3). When used in combination, the AUC for this 6-marker model in the diagnosis of TBM was 0.75 (95% CI, 0.61-0.90); ...Citations
... However, children often have numerous health care visits within complex care pathways before a lumbar puncture is considered, contributing to diagnostic delays and poor outcomes [ 21 ]. Host biomarker signatures in blood to diagnose and treat TB meningitis at peripheral levels of care or to expedite referral to tertiary level care show promise but require validation [ 22 ]. Non-invasive sampling techniques for Xpert Ultra testing and digital CXR are feasible and acceptable at decentralized levels of care for prompt diagnosis and treatment initiation in high-risk children, such as those with severe pneumonia or severe malnutrition [ 19 , 23 ]. ...
... Previous studies have found that M2 macrophages significantly enhanced their activity in active tuberculosis and played a leading role in the occurrence and development of tuberculous granulomas, and sCD163 can be used as a marker of M2 macrophage activation 9,10 , suggesting that the level of sCD163 can be used as an important indicator to assess the severity of active tuberculosis. Studies have reported that TBM can also cause nerve cell damage, leading to reduced synthesis of NCAM1 11 , and the lack of NCAM1 in cerebrospinal fluid is related to the onset and progression of TBM, NCAM1 is expected to be a potential marker for the prognosis of TBM. In summary, the levels of cerebrospinal fluid sCD163, MMP-9 and serum NCAM1 are closely related to the pathogenesis and prognosis of TBM. ...
Tuberculous meningitis (TBM) is the most serious type of tuberculosis infection, and there is a lack of accurate diagnostic targets for TBM. Therefore, it is of great clinical and public health significance to find a specific target for early diagnosis and prediction of the prognosis of TBM. From January 2021 to February 2024, 110 TBM patients and 122 patients with non-tumor, non-infectious headaches were admitted to Hunan Chest Hospital. To compare the two groups, cerebrospinal fluid (CSF) levels of sCD163 and MMP-9, as well as serum NCAM1 protein levels, were detected by ELISA. Multivariate logistic regression analysis or Spearman analysis was then performed to investigate the correlation between these protein levels and the MRC (Medical Research Council) stage or the short-term prognosis in TBM patients. sCD163 and MMP-9 were elevated in the CSF of TBM patients compared to controls. Oppositely, the protein levels of serum NCAM1 was decreased. The levels of CSF sCD163, MMP-9 and serum NCAM1 are associated with MRC stage and short-term prognosis of TBM patients, and the combined CSF sCD163, MMP-9 and serum NCAM1 have the best value in predicting the short-term prognosis of TBM patients.
... Some of the studies apart from the CRP and PCT analyses also included additional markers and usually compared their effectiveness; therefore, we decided to describe them in a separate paragraph [40][41][42][43]. Moreover, other researchers investigated completely novel parameters without comparison to CRP or PCT [43][44][45][46]. ...
... Therefore, PAR and LAR were shown as a notable facilitation of the refractory suppurative meningitis diagnosis. Manyelo et al. explored the effectiveness of cytokine screening platforms, focusing specifically on the diagnosis of TBM [41]. The study involved the use of a modified version of adult pulmonary TB 7-marker signature (including CRP, interferon-gamma (IFN-γ), CXCL-10, complement factor H (CFH), apolipoprotein A1 (Apo-A1), serum amyloid A (SAA), and neural cell adhesion molecule 1 (NCAM1)) and a specific 3-marker biosignature (comprising adipsin, amyloid-beta 42 (Aβ42), and IL-10) in a population of children suspected to have meningitis. ...
Meningitis is an inflammation of the meninges that can sometimes be a life-threatening disease. Therefore, fast and proper diagnosis with the implementation of adequate treatment is crucial in its management. Treatment depends on etiology, which can be viral, bacterial, fungal, and parasitic. Diagnosis is based on thorough clinical examination with a performance of lumbar puncture in the case of meningitis suspicion. This procedure, however, remains invasive with several contraindications and a need for a patient’s consent, which is not always given due to the patient’s fear of it, for instance. Thus, this systematic review aimed to summarize the available literature on the topic of blood biomarkers in meningitis differentiation. A selection process was performed by two authors independently in accordance with the Preferred Research Items for Systematic Reviews and Meta-analyses. Two databases were screened. It led to the identification of 863 articles, of which 43 were eventually included in the systematic review. The analysis resulted in identifying blood biomarkers in both adult and pediatric meningitis. Most studies focused on inflammatory markers, such as C-reactive protein and procalcitonin, from which procalcitonin showed better utility. Among other analyzed molecules were, for instance, interleukins, apolipoproteins, and microRNAs. Moreover, many researchers suggested that combining biomarkers or implementing novel technologies may lead to the best accuracy. However, many suggested methods lack validation, which stands in the way of making them widely used.
... Metabolomic approaches are also showing promise. A recent study by Manyelo et al. identified a 7-marker serum metabolomic biosignature that showed 80% sensitivity and 89% specificity for TB diagnosis in children [67]. While these biomarker-based approaches are still in the discovery or early validation phases, they offer the potential for rapid, non-sputum-based diagnostics with turnaround times potentially as short as a few hours once fully developed [68]. ...
Pediatric tuberculosis (TB) is still challenged by several diagnostic bottlenecks, imposing a high TB burden in low- and middle-income countries (LMICs). Diagnostic turnaround time (TAT) and ease of operation to suit resource-limited settings are critical aspects that determine early treatment and influence morbidity and mortality. Based on TAT and ease of operation, this article reviews the evolving landscape of TB diagnostics, from traditional methods like microscopy and culture to cutting-edge molecular techniques and biomarker-based approaches. We examined the benefits of efficient rapid results against potential trade-offs in accuracy and clinical utility. The review highlights emerging molecular methods and artificial intelligence-based detection methods, which offer promising improvements in both speed and sensitivity. The review also addresses the challenges of implementing these technologies in resource-limited settings, where most pediatric TB cases occur. Gaps in the existing diagnostic methods, algorithms, and operational costs were also reviewed. Developing optimal diagnostic strategies that balance speed, performance, cost, and feasibility in diverse healthcare settings can provide valuable insights for clinicians, researchers, and policymakers.
... Recent research has discovered gene signatures that can forecast the development of active TB months prior to symptom appearance, signatures for predicting the transition from latent TB infection to active TB, and for monitoring responses to TB treatment 16 7,19 . Additional research on pediatric TBM revealed that heightened concentrations of the CSF brain biomarkers S100B, glial fibrillary acidic protein (GFAP), and neuron-specific enolase (NSE) are linked to brain imaging infracts in early detection 20 . ...
The global disease burden remains greatly influenced by tuberculosis. Its most critical form, Tuberculosis meningitis (TBM) affects both adults and children who face high rates of mortality and morbidity. As many as 50% of paediatric TBM cases lead to mortality, and nearly 53.9 percent of those who survive endure neurological consequences. The primary reasons for unsatisfactory TBM results are late diagnosis and the postponement of anti-tuberculosis therapy. Thus, improved case identification and prompt administration of effective treatments are crucial for controlling tuberculosis in children. The primary aim of this research is to identify new biomarkers for the early diagnosis of Tuberculosis meningitis in children by conducting RNA sequencing on data obtained from various samples. This research emphasizes the use of bioinformatics, machine learning, and diverse statistical methods, including the evaluation of fixed threshold values or p-values, which facilitate the identification of Differentially Expressed Genes (DEGs). Consequently, three new biomarkers were identified by combining the findings from RNASeq and machine learning, utilizing algorithms like multi-layer perceptron, support vector machine (SVM), and random forest (RF) to suggest the optimal model with high accuracy and performance for the identification of the new biomarkers. It was understood that the RF model surpassed the other classifiers by achieving an accuracy score of 1.0 in identifying new biomarkers of Tuberculosis meningitis in children. Then computational analysis of these genes was done with the potential drugs used for treating Tuberculosis meningitis using AutodockTools software.
... Tuberculous meningitis is very important in the central nervous system (especially in children) and has a high mortality rate. Manyelo et al. reported an incidence rate of tuberculous meningitis of 23 (48.9%) among 47 children [26]. A study in Germany showed that tuberculous meningitis was 3.9% in children under 5 years old, 2.2% in children 5-9 years old, and 1.3% in children 10-14 years old [27]. ...
Background
Worldwide, tuberculosis (TB) is among the most common causes of death. To our knowledge, there has been no study showing the prevalence of EPTB in Khuzestan province. Therefore, the objective of this research was to investigate the prevalence of EPTB in patients with or without pulmonary TB in different cities of Khuzestan province from 2002 to 2023. Additionally, the correlation between patient’s gender, and age groups with the disease was also investigated.
Methods
In this retrospective study, the existing records in Tuberculosis Regional Reference Laboratory of Khuzestan province related to patients were used. The research was carried out by investigating the archive information in 19 years (from 1st January 2002 to December 30, 2023). All confirmed cases of EPTB and simultaneous EPTB and PTB, based on laboratory results and medical examination were included in the study. Patients with incomplete information and military TB were excluded from the study. Information collected from patients includes age, gender, involved organ, place of residence, and year of disease.
Results
A total of 12,900 EPTB-related medical records were extracted from Tuberculosis Regional Reference Laboratories in southwest Iran, Ahvaz. After excluding records, 12,836 clinically diagnosed or laboratory-confirmed tuberculosis patients were included in this study, including 5991 patients with simultaneous PTB and EPTB, and 6845 patients with EPTB only. The mean age of male EPTB patients was 37.5 years (SD ± 14.6), while the mean age of male patients with simultaneous PTB and EPTB was 45.8 years (SD ± 15.3). The mean age of female patients with EPTB only, and with simultaneous PTB and EPTB was 31.2 years (SD ± 12.6), and 31.5 years respectively.
Discussion
tuberculosis is a systemic disease with different clinical manifestations. This study described different epidemiologic patterns of concurrent EPTB. The proportion of different types of EPTB was simultaneously determined for a group of hospitalized patients and shown to be different with gender and age. This study will likely increase clinicians’ awareness of the disease and help them better address diagnostic challenges and improve treatment outcomes for patients with EPTB.
... Plasma and CSF VEGF-A concentrations are significantly higher in TBM patients than controls although not associated with outcome (40). In a study looking for a CSF biosignature for TBM using proteomics in HIVuninfected children, a combination of VEGF-A, IFNg and myeloperoxidase had a sensitivity and specificity of 91.3% and 100% respectively compared to a heterogeneous non-TBM group, suggesting VEGF-A as an important contributor in TBM pathogenesis (41). Studies have also shown that VEGF-A increases MMP-9 activation (42). ...
Tuberculous meningitis (TBM), the most severe form of tuberculosis, causes death in approximately 25% cases despite antibiotic therapy, and half of survivors are left with neurological disability. Mortality and morbidity are contributed to by a dysregulated immune response, and adjunctive host-directed therapies are required to modulate this response and improve outcomes. Developing such therapies relies on improved understanding of the host immune response to TBM. The historical challenges in TBM research of limited in vivo and in vitro models have been partially overcome by recent developments in proteomics, transcriptomics, and metabolomics, and the use of these technologies in nested substudies of large clinical trials. We review the current understanding of the human immune response in TBM. We begin with M. tuberculosis entry into the central nervous system (CNS), microglial infection and blood-brain and other CNS barrier dysfunction. We then outline the innate response, including the early cytokine response, role of canonical and non-canonical inflammasomes, eicosanoids and specialised pro-resolving mediators. Next, we review the adaptive response including T cells, microRNAs and B cells, followed by the role of the glutamate-GABA neurotransmitter cycle and the tryptophan pathway. We discuss host genetic immune factors, differences between adults and children, paradoxical reaction, and the impact of HIV-1 co-infection including immune reconstitution inflammatory syndrome. Promising immunomodulatory therapies, research gaps, ongoing challenges and future paths are discussed.
... It has been observed that excessive intracerebral inflammation contributes to the mortality rate of TBM, and corticosteroids, which act as broad anti-inflammatory drugs, are now administered adjunctively with anti-tubercu lar antibiotics to reduce the production of proinflammatory cytokines (2,8). Conse quently, the identification of specific cytokines as disease-specific biomarkers could have diagnostic significance and provide new insights into the pathophysiology of TBM (9)(10)(11)(12). Cytokines, signaling molecules produced by various cells, regulate immune responses, inflammation, cell proliferation, and differentiation. ...
Tuberculous meningitis (TBM) is a severe infectious disease affecting the central nervous system, causing high mortality and disability. However, current diagnostic methods for TBM using cerebrospinal fluid (CSF) lack sensitivity and predictive biomarkers for prognosis. We conducted a study on cytokine profiles in CSF and serum samples from TBM patients to identify disease-specific biomarkers. Patients were categorized into three groups: TBM ( n = 17), cryptococcal meningitis ( n = 10), and non-infection ( n = 6), and cytokine levels were quantified using a 48-plex panel. After treatment, we observed a significant reduction in the levels of 12 cytokines, indicating their potential use as biomarkers for treatment monitoring. Among them, monokine induced by interferon-γ (MIG) and interleukin-18 showed significant differences in serum or CSF cytokine levels compared to the control groups. CSF levels of MIG in TBM patients were negatively correlated with the CSF/blood glucose ratio ( r = −0.4728, P = 0.0475). Positive correlations were found between CSF leukocyte counts and several cytokines, including fibroblast growth factor-basic, granulocyte colony-stimulating factor (G-CSF), monocyte chemotactic protein-3, macrophage inflammatory protein 1 alpha (MIP-1α), and tumor necrosis factor alpha. G-CSF and MIP-1α were also positively correlated with CSF protein levels. Receiver operating characteristic curve analysis revealed that MIG exhibited the highest area under the curve of 0.92 [95% confidence interval (CI) 0.82–1.00] with a sensitivity of 0.85 (95% CI 0.58–0.97) and a specificity of 0.87 (95% CI 0.62–0.98), making it a promising diagnostic biomarker for TBM. Our study provides valuable insights into TBM’s pathogenesis and identifies potential biomarkers for diagnosis and evaluating treatment monitoring.
IMPORTANCE
Tuberculous meningitis is a life-threatening infection with high mortality and disability rates. Current diagnostic methods using cerebrospinal fluid (CSF) samples have limited sensitivity and lack predictive biomarkers for evaluating prognosis. This study’s findings reveal excessive activation of the immune response during tuberculous meningitis (TBM) infection. Notably, a strong negative correlation was observed between CSF levels of monokine induced by interferon-γ (MIG) and the CSF/blood glucose ratio in TBM patients. MIG also exhibited the highest area under the curve with high sensitivity and specificity. This study suggests that MIG may serve as a novel biomarker for differentiating TBM infection in CSF or serum, potentially leading to improved diagnostic accuracy and better patient outcomes.
... Although the complement pathway in tuberculosis infection is not fully understood, pathogens in Mycobacterium activate the complement pathway [7]. However, the association of the complement system with TBM has rarely been evaluated, and data on clinical implications are scarce [8]. ...
... As with BM, data on serum complement levels in TBM are scarce, and studies including serial blood sampling to determine complement activation profiles in acute TBM are lacking. In a study that included 23 children with TBM and 24 with non-TBM meningitis, serum complement was evaluated as a potential surrogate marker in the diagnosis of TBM, but no significant results were obtained [8]. However, our study included a much larger study population, with 97 cases of TBM and 588 cases of non-TBM meningitis, and revealed a significant decrease in serum C3 and C4 levels in TBM compared to in VM. ...
PurposeWe evaluated the associations between serum complement levels and tuberculous meningitis (TBM), bacterial meningitis (BM), and viral meningitis (VM), as well as the association between serum complement levels and mortality in TBM. Methods
Background information and blood/cerebrospinal fluid analysis results were collected from 2009 to 2019. Patients who had serum complement level data collected at admission and who were diagnosed with TBM (n = 97), BM (n = 31), or VM (n = 557) were enrolled. ResultsInitial serum complement levels were significantly lower in the TBM group than the VM group in both the total population and the propensity score-matched population. In the TBM and VM groups, compared to patients with initial highest-quartile C4 level, patients in the lowest quartile (C4 < 24.3 mg/dL) had significantly greater odds of TBM diagnosis (odds ratio, 2.2; 95% confidence interval, 1.0–4.5; p = 0.038). In the TBM group, patients with the lowest-quartile C3 level (<96.9 mg/dL) experienced a significantly higher 90-day mortality rate compared to other TBM patients (hazard ratio, 19.0; 95% confidence interval, 2.1–167.4.5; p = 0.008). Conclusion
Both serum C3 and C4 levels were significantly lower in the TBM group than in the VM group. TBM patients with lower serum C3 level had a significantly higher mortality rate than those with higher C3 level.
... We then assessed 65 full-text articles in detail (Fig 1). Ultimately, 20 articles were selected for characteristic collection and data analysis (Tables 1 and 2) [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47]. ...
... Four studies estimated unstimulated CSF IFN-γ levels with different methods (Luminex kits, ELISA, radioimmunoassay) and diagnostic thresholds (0.244-6.4 IU/mL) [30,37,42,47], and one study tested unstimulated blood IFN-γ levels using Luminex kits assay with a cutoff of 0.62 IU/mL [31]. Twentythree studies used IGRA (T-SPOT.TB and QFT-GIT) to estimate TBAg-stimulated IFN-γ levels using ELISPOT and ELISA methods, including eight studies that analyzed CSF samples and fifteen studies that analyzed blood samples. ...
Objective
Tuberculous meningitis (TBM) is one of the most devastating TB. Accurate identification of TBM is helpful to eliminate TB. Therefore, we assessed the performance of TBAg stimulated IFN-γ (IGRA) and unstimulated IFN-γ in blood and cerebrospinal fluid (CSF) for diagnosing TBM.
Methods
We searched Web of Science, PubMed, Embase and the Cochrane Library databases until March 2022. Bivariate and hierarchical summary receiver operating characteristic models were employed to compute summary estimates for diagnostic accuracy parameters of IGRA and unstimulated IFN-γ in blood and CSF for diagnosing TBM.
Results
28 studies including 1,978 participants and 2,641 samples met the inclusion criteria. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and area under the curve (AUROC) of blood IGRA were separately as 0.73, 0.83, 4.32, 0.33, 13.22 and 0.86, indicating a good diagnostic accuracy of blood IGRA for detecting TBM. The summary sensitivity, specificity, PLR, NLR, DOR and AUROC of CSF IGRA were separately as 0.77, 0.91, 8.82, 0.25, 34.59 and 0.93, indicating good diagnostic accuracy of CSF IGRA for detecting TBM. The summary sensitivity, specificity, PLR, NLR, DOR and AUROC of CSF IFN-γ were separately as 0.86, 0.92, 10.27, 0.16, 65.26 and 0.95, suggesting CSF IFN-γ provided excellent accuracy for diagnosing TBM.
Conclusions
For differentiating TBM from non-TBM individuals, blood and CSF IGRA are good assays and unstimulated CSF IFN-γ is an auxiliary excellent marker.
