Optimizing Antimicrobial and Host-Directed Therapies to Improve Clinical Outcomes of Childhood Tuberculous Meningitis.
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ABSTRACT:
SUBMITTER: Gafar F
PROVIDER: S-EPMC9410716 | biostudies-literature | 2022 Aug
REPOSITORIES: biostudies-literature
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Optimizing Antimicrobial and Host-Directed Therapies to Improve Clinical Outcomes of Childhood Tuberculous Meningitis.
Gafar Fajri F Marais Ben J BJ Nataprawira Heda M HM Alffenaar Jan Willem C JWC
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20220801 2
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Project description:A dysregulated host immune response significantly contributes to morbidity and mortality in tuberculous meningitis (TBM). Effective host directed therapies (HDTs) are critical to improve survival and clinical outcomes. Currently only one HDT, dexamethasone, is proven to improve mortality. However, there is no evidence dexamethasone reduces morbidity, how it reduces mortality is uncertain, and it has no proven benefit in HIV co-infected individuals. Further research on these aspects of its use, as well as alternative HDTs such as aspirin, thalidomide and other immunomodulatory drugs is needed. Based on new knowledge from pathogenesis studies, repurposed therapeutics which act upon small molecule drug targets may also have a role in TBM. Here we review existing literature investigating HDTs in TBM, and propose new rationale for the use of novel and repurposed drugs. We also discuss host variable responses and evidence to support a personalised approach to HDTs in TBM.
| S-EPMC8792876 | biostudies-literature
Project description:We retrospectively evaluated clinical features and outcomes in children treated for tuberculous meningitis (TBM) at Hasan Sadikin Hospital, Bandung, Indonesia, during 2011-2020. Among 283 patients, 153 (54.1%) were <5 years of age, and 226 (79.9%) had stage II or III TBM. Predictors of in-hospital death (n = 44 [15.5%]) were stage III TBM, hydrocephalus, male sex, low-income parents, seizures at admission, and lack of bacillus Calmette-Guérin vaccination. Predictors of postdischarge death (n = 18 [6.4%]) were hydrocephalus, tuberculoma, and lack of bacillus Calmette-Guérin vaccination. At treatment completion, 91 (32.1%) patients were documented to have survived, of whom 33 (36.3%) had severe neurologic sequelae and 118 (41.7%) had unknown outcomes. Predictors of severe neurologic sequelae were baseline temperature >38°C, stage III TBM, and baseline motor deficit. Despite treatment, childhood TBM in Indonesia causes substantial neurologic sequelae and death, highlighting the importance of improved early diagnosis, better tuberculosis prevention, and optimized TBM management strategies.
| S-EPMC8888221 | biostudies-literature
Project description:Tuberculous meningitis (TBM) remains a serious disease for children and its risk factors of poor outcome remain unclear. Therefore, a retrospective study was conducted aiming to investigate the risk factors associated with poor outcome of childhood TBM. Between January 2006 and December 2019, consecutive children patients (≤ 15 years old) who had a diagnosis of TBM were included for the analysis. The demographic, clinical, laboratory, and radiographic data were collected from the electronic medical records retrospectively. Poor outcome was defined as death or transfer to a higher-level hospital. Patients were then divided into good and poor outcome groups. Subsequently, risk factors for poor outcome were estimated using univariate and multivariate logistic regression analysis. A total of 149 children with TBM was enrolled, twenty-two patients suffered poor outcome, including 16 transfers to a higher-level hospital and 6 deaths, and the remaining 127 patients were classified as good outcome group. Further multivariate analysis revealed that coma (age- and sex-adjusted OR = 6.425, 95% CI: 1.743, 23.676; P < 0.01) and cerebrospinal fluid (CSF) protein (> 1188.3 mg/L; age- and sex-adjusted OR = 4.680, 95% CI: 1.469, 14.902; P < 0.01) were associated with the poor outcome of childhood TBM. Childhood TBM remains to have a high mortality rate in China. High CSF protein and coma were identified as risk factors for poor outcome of childhood TBM. Hence, more attention is required to be paid to suspected patients with such characteristics, thus facilitating access to optimum treatment.
| S-EPMC8060316 | biostudies-literature
Project description:Whole blood transcriptional profiles in children with or without tuberculous meningitis (TBM) were compared using RNA-Seq and a biomarker signature driven by inflammasome activation and signaling was identified
2019-08-06 | GSE111459 | GEO
Project description: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.
| S-EPMC10803428 | biostudies-literature
Project description:Background and purposeThe diagnosis of tuberculous meningitis (TBM) is difficult due to the lack of sensitive methods. Identification of TBM-specific biomarkers in the cerebrospinal fluid (CSF) may help diagnose and improve our understanding of TBM pathogenesis.Patients and methodsOf the 112 suspected patients with TBM prospectively enrolled in the study, 32 patients with inconclusive diagnosis, non-infectious meningitis, and long-term treatment with hormones and immunosuppressants were excluded. The expression of 8 proteins in the CSF was analyzed using ELISA in 22 patients with definite TBM, 18 patients with probable TBM, and 40 patients with non-TBM.ResultsSignificant differences in the expression of 7 proteins were detected between the TBM and non-TBM groups (P < 0.01). Unsupervised hierarchical clustering (UHC) analysis revealed a disease-specific profile consisting of 7 differentially expressed proteins for TBM diagnosis, with an accuracy of 82.5% (66/80). Logistic regression with forward stepwise analysis indicated that a combination of 3 biomarkers (APOE_APOAI_S100A8) showed a better ability to discriminate TBM from patients with non-TBM [area under the curve (AUC) = 0.916 (95%CI: 0.857-0.976)], with a sensitivity of 95.0% (95%CI: 83.1-99.4%) and a specificity of 77.5% (95%CI: 61.5-89.2%).ConclusionOur results confirmed the potential ability of CSF proteins to distinguish TBM from patients with non-TBM and provided a useful panel for the diagnosis of TBM.
| S-EPMC9393334 | biostudies-literature
Project description:Tuberculous meningitis is one of the fatal forms of extra pulmonary disease associated with high mortality and severe neurological defects in affected individuals. We have carried out transcriptome level analysis using whole human genome microarrays to identify differential expression of genes between tuberculous meningitis and normals. In our gene expression analysis, we found 2,434 genes that were differentially erexpressed with 2 or more than 2 fold changes between tuberculous meningitis compared to normal cases. Most of the genes encoded many of the proteins, which involves metabolism, energy pathways, cell growth and/or maintenance, transport and cell communication and signal transduction. We have performed immunohistochemistry for the validation of some of the novel candidates identified in our microarray studies.!Series_overall_design = Present study carried out mRNA expression profiling of five samples from patients diagnosed with tuberculous meningitis and four head injury cases were used as controls. We have used 4X44K arrays from agilent plaform. To validate our microarray results, we have done Immunohistochemistry on 15 TBM cases with control groups.
2011-07-01 | GSE23074 | GEO
Project description:Cerebrospinal fluid transcriptional profiles in children with tuberculous meningitis (TBM) or other infections were compared using RNA-Seq and a biomarker signature driven by NMDA-receptor activation was identified
2019-08-06 | GSE122377 | GEO
Project description:Tuberculous meningitis is one of the fatal forms of extra pulmonary disease associated with high mortality and severe neurological defects in affected individuals. We have carried out transcriptome level analysis using whole human genome microarrays to identify differential expression of genes between tuberculous meningitis and normals. In our gene expression analysis, we found 2,434 genes that were differentially erexpressed with 2 or more than 2 fold changes between tuberculous meningitis compared to normal cases. Most of the genes encoded many of the proteins, which involves metabolism, energy pathways, cell growth and/or maintenance, transport and cell communication and signal transduction. We have performed immunohistochemistry for the validation of some of the novel candidates identified in our microarray studies.!Series_overall_design = Present study carried out mRNA expression profiling of five samples from patients diagnosed with tuberculous meningitis and four head injury cases were used as controls. We have used 4X44K arrays from agilent plaform. To validate our microarray results, we have done Immunohistochemistry on 15 TBM cases with control groups. Present study carried out mRNA expression profiling of five samples from patients diagnosed with tuberculous meningitis and four head injury cases were used as controls. We have used 4X44K arrays from agilent plaform. To validate our microarray results, we have done Immunohistochemistry on 15 TBM cases with control groups.!Series_type = Expression profiling by array
2011-06-30 | E-GEOD-23074 | biostudies-arrayexpress
Project description:SETTING: National Center for Tuberculosis and Lung Diseases (NCTLD), Tbilisi, Georgia.OBJECTIVE: To determine clinical outcomes of patients with tuberculous meningitis (TBM) treated with an intensified regimen including a fluoroquinolone (FQ) and an injectable agent.DESIGN: Prospective cohort of patients aged ≥16 years initiating treatment for TBM at the NCTLD from January 2018 to December 2019. Treatment outcomes and neurologic disability at 1, 6 and 12 months after treatment initiation were assessed.RESULTS: Among 77 patients with median follow-up time of 363 days (IQR 269-374), 97% received a FQ, 62% an injectable agent, 44% linezolid and 39% a carbapenem. Fifty-seven patients (74%) successfully completed treatment, 2 (2.6%) had treatment failure, 6 (7.8%) died, and the remainder (12%) were lost to follow up. Among 11 patients treated for multidrug-resistant TBM, the median follow-up time was 467 days and one patient (8%) died. Regarding neurologic outcomes, 14/76 (18%) patients had Modified Rankin Scores of 0 at baseline, improving to 85% (56/66) and 94% (47/50) at 6 and 12 months, respectively.CONCLUSION: Intensified multidrug treatment regimens including a FQ and an injectable agent in all patients and newly implemented drugs in patients with multidrug-resistant TBM resulted in low mortality and favorable neurologic outcomes.
| S-EPMC8443977 | biostudies-literature