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Tuberculous Meningitis in Children: Reducing the Burden of Death and Disability.

ABSTRACT: Tuberculous meningitis disproportionately affects young children. As the most devastating form of tuberculosis, it is associated with unacceptably high rates of mortality and morbidity even if treated. Challenging to diagnose and treat, tuberculous meningitis commonly causes long-term neurodisability in those who do survive. There remains an urgent need for strengthened surveillance, improved rapid diagnostics technology, optimised anti-tuberculosis drug therapy, investigation of new host-directed therapy, and further research on long-term functional and neurodevelopmental outcomes to allow targeted intervention. This review focuses on the neglected field of paediatric tuberculous meningitis and bridges current clinical gaps with research questions to improve outcomes from this crippling disease.

SUBMITTER: Huynh J

PROVIDER: S-EPMC8778027 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Tuberculous Meningitis in Children: Reducing the Burden of Death and Disability.

Huynh Julie J Abo Yara-Natalie YN du Preez Karen K Solomons Regan R Dooley Kelly E KE Seddon James A JA

Pathogens (Basel, Switzerland) 20211230 1

Tuberculous meningitis disproportionately affects young children. As the most devastating form of tuberculosis, it is associated with unacceptably high rates of mortality and morbidity even if treated. Challenging to diagnose and treat, tuberculous meningitis commonly causes long-term neurodisability in those who do survive. There remains an urgent need for strengthened surveillance, improved rapid diagnostics technology, optimised anti-tuberculosis drug therapy, investigation of new host-direct ...[more]

PMID: 35055986

Similar Datasets

Epidemiological Characteristics and Disease Burden of Tuberculous Meningitis in Hospitalized Children in China: A Nationwide Retrospective Study.

Project description:ObjectivesTo investigate the epidemiological profile and cost burden of pediatric inpatients with tuberculous meningitis (TBM) in China.MethodsWe conducted a descriptive multicenter study involving pediatric TBM inpatients from 9 provincial hospitals and 20 municipal hospitals across 24 provinces in China from January 2016 to December 2021. Sociodemographic and geographic variables, admission and discharge information were extracted from face sheets of discharge medical records to describe the epidemiological characteristics. Length of hospital stay (LOS) and hospitalization expenses were used to assess disease burden.ResultsTBM accounted for 0.01% (971/7,647,598) of total hospitalization cases and 15.82% (971/6,138) of TB cases. The proportion of TBM children aged 1-3 (39.13%, 380/971) years were the highest. TBM children aged < 1 year had longest LOS (12d) and highest total costs ($2447.55). Minority patients had a higher proportion of TBM hospitalizations (24.09% vs 13.79%), longer LOS (11d) and higher diagnostic costs ($745.95 vs $628.47) than Han people. The northwest region had the highest rate of TBM hospitalization (n = 272, 28.01%) and the longest LOS (8d). TBM + PTB group exhibited the highest rate of outpatient admission (78.51%,263/335), shortest LOS (5d) and lowest total cost ($1729.75) and diagnostic cost ($827.30). The most prevalent concomitant TB infection site was the lung (n = 494, 50.82%). TBM + PTB + other EPTB group had the longest LOS (14d) and highest total cost ($3380.54).ConclusionPediatric TBM poses substantial disease burden in China, especially in western regions and children under six years old. Early diagnosis and treatment for children with TBM should be suggested.

| S-EPMC11832963 | biostudies-literature

The global burden of tuberculous meningitis in adults: A modelling study.

Project description:Tuberculous meningitis (TBM) is the most lethal form of tuberculosis. The incidence and mortality of TBM is unknown due to diagnostic challenges and limited disaggregated reporting of treated TBM by existing surveillance systems. We aimed to estimate the incidence and mortality of TBM in adults (15+ years) globally. Using national surveillance data from Brazil, South Africa, the United Kingdom, the United States of America, and Vietnam, we estimated the fraction of reported tuberculosis that is TBM, and the case fatality ratios for treated TBM in each of these countries. We adjusted these estimates according to findings from a systematic review and meta-analysis and applied them to World Health Organization tuberculosis notifications and estimates to model the global TBM incidence and mortality. Assuming the case detection ratio (CDR) for TBM was the same as all TB, we estimated that in 2019, 164,000 (95% UI; 129,000-199,000) adults developed TBM globally; 23% were among people living with HIV. Almost 60% of incident TBM occurred in males and 20% were in adults 25-34 years old. 70% of global TBM incidence occurred in Southeast Asia and Africa. We estimated that 78,200 (95% UI; 52,300-104,000) adults died of TBM in 2019, representing 48% of incident TBM. TBM case fatality in those treated was on average 27%. Sensitivity analysis assuming improved detection of TBM compared to other forms of TB (CDR odds ratio of 2) reduced estimated global mortality to 54,900 (95% UI; 32,200-77,700); assuming instead worse detection for TBM (CDR odds ratio of 0.5) increased estimated mortality to 125,000 (95% UI; 88,800-161,000). Our results highlight the need for improved routine TBM monitoring, especially in high burden countries. Reducing TBM incidence and mortality will be necessary to achieve the End TB Strategy targets.

| S-EPMC10021871 | biostudies-literature

Tuberculous Meningitis in Pediatric Patients

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

Application of Cerebrospinal Fluid Host Protein Biosignatures in the Diagnosis of Tuberculous Meningitis in Children from a High Burden Setting.

Project description:BackgroundThe diagnosis of tuberculous meningitis (TBM) especially in children is challenging. New tests are urgently needed for the diagnosis of the disease, especially in resource-limited settings.MethodsWe collected cerebrospinal fluid (CSF) samples from children presenting with symptoms requiring investigation for meningitis at a tertiary hospital in Cape Town, South Africa. Children were later classified as TBM or no TBM using published case definitions. Using a multiplex platform, we investigated the concentrations of biomarkers comprising a previously established 3-marker biosignature (VEGF, IL-13, and LL-37) and other potentially useful host biomarkers as diagnostic candidates for TBM.FindingsOut of 47 children, age, 3 months to 13 years, 23 were diagnosed with TBM and six (16%) were HIV-infected. We validated the previously identified CSF biosignature (sensitivity of 95.7% (95% CI, 79.0-99.2%) and specificity of 37.5% (95% CI, 21.2-57.3%)). However, substitution of IL-13 and LL-37 with IFN-γ and MPO, respectively, resulted in improved accuracy (area under the ROC curve (AUC) = 0.97, 95% CI, 0.92-1.00, up to 91.3% (21/23) sensitivity and up to 100% (24/24) specificity). An alternative four-marker biosignature (sICAM-1, MPO, CXCL8, and IFN-γ) also showed potential, with an AUC of 0.97.ConclusionWe validated a previously identified CSF biosignature and showed that refinement of this biosignature by incorporation of other biomarkers diagnosed TBM with high accuracy. Incorporation of these biomarkers into a point-of-care or bedside diagnostic test platform may result in the improved management of TBM in children.

| S-EPMC6501148 | biostudies-literature

Gene Expression Profiling of Tuberculous Meningitis

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

Gene Expression Profiling of Tuberculous Meningitis

2011-07-01 | GSE23074 | GEO

Tuberculous Meningitis in Pediatric Patients [CSF]

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

Tuberculous Meningitis in Children and Adults: A 10-Year Retrospective Comparative Analysis.

Project description:Tuberculous meningitis (TBM) is the most lethal form of Mycobacterium tuberculosis infection, which has a high rate of neurological complications and sequelae.Our study offers a real-world infectious disease clinic perspective, being thus representative for the clinical environment of developing countries.We performed a retrospective analysis of the 127 adult and 77 pediatric cases diagnosed with TBM in the Infectious Disease Hospital of the School of Medicine of Iasi, Romania between 2004-2013.Definite diagnosis of TBM was established in 31% of children but in only 20% of adults (p = 0.043). A contact with an individual with pulmonary tuberculosis was documented in 30% of children vs. 13% of adults (p = 0.0007). Coma occurred in 19% of patients (similar in children and adults); other consciousness abnormalities were seen in 27% of children and in 72% of adults (p = 0.000001). Cranial nerve palsies occurred prior to therapy in 9% of cases (12% vs 7% of children and adults, respectively, p>0.05), and developed 2-7 days after treatment initiation in 10% (12 vs 9%). CSF cultures were positive for M. tuberculosis in 24% of patients (31% vs. 20%, p>0.05). Overall mortality was 7.35%, similar for children and adults. Yet, permanent neurological sequelae, which were seen in 23% of patients occurred significantly more frequent in children vs. adults (36% vs. 14%, respectively, p = 0.0121). In conclusion, our retrospective analysis on a significant number of cases of TBM identified striking differences between children and adults: while children were in an earlier stage at the admission, they associated a higher frequency of neurological sequelae and miliary pattern, and they were more likely to have normal CSF protein levels and positive cultures of CSF.

| S-EPMC4506084 | biostudies-other

Tuberculous Meningitis in Children and Adults: New Insights for an Ancient Foe.

Project description:Purpose of reviewTuberculous meningitis is the most devastating manifestation of infection with Mycobacterium tuberculosis and represents a medical emergency. Approximately one half of tuberculous meningitis patients die or suffer severe neurologic disability. The goal of this review will be to review the pathogenic, clinical, and radiologic features of tuberculous meningitis and to highlight recent advancements in translational and clinical science.Recent findingsPharmacologic therapy includes combination anti-tuberculosis drug regimens and adjunctive corticosteroids. It is becoming clear that a successful treatment outcome depends on an immune response that is neither too weak nor overly robust, and genetic determinants of this immune response may identify which patients will benefit from adjunctive corticosteroids. Recent clinical trials of intensified anti-tuberculosis treatment regimens conducted in Indonesia and Vietnam, motivated by the pharmacologic challenges of treating M. tuberculosis infections of the central nervous system, have yielded conflicting results regarding the survival benefit of intensified treatment regimens. More consistent findings have been observed regarding the relationship between initial anti-tuberculosis drug resistance and mortality among tuberculous meningitis patients. Prompt initiation of anti-tuberculosis treatment for all suspected cases remains a key aspect of management. Priorities for research include the improvement of diagnostic testing strategies and the optimization of host-directed and anti-tuberculosis therapies.

| S-EPMC5729589 | biostudies-literature

Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis.

Project description:Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and is currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampin, pyrazinamide, and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. A total of 100 Vietnamese children with TBM were treated with an 8-month antituberculosis regimen. Nonlinear mixed-effects modeling was used to evaluate the pharmacokinetic properties of the four drugs and to simulate different dosing strategies. The pharmacokinetic properties of rifampin and pyrazinamide in plasma were described successfully by one-compartment disposition models, while those of isoniazid and ethambutol in plasma were described by two-compartment disposition models. All drug models included allometric scaling of body weight and enzyme maturation during the first years of life. Cerebrospinal fluid (CSF) penetration of rifampin was relatively poor and increased with increasing protein levels in CSF, a marker of CSF inflammation. Isoniazid and pyrazinamide showed good CSF penetration. Currently recommended doses of isoniazid and pyrazinamide, but not ethambutol and rifampin, were sufficient to achieve target exposures. The ethambutol dose cannot be increased because of ocular toxicity. Simulation results suggested that rifampin dosing at 50 mg/kg of body weight/day would be required to achieve the target exposure. Moreover, low rifampin plasma exposure was associated with an increased risk of neurological disability. Therefore, higher doses of rifampin could be considered, but further studies are needed to establish the safety and efficacy of increased dosing.

| S-EPMC7927832 | biostudies-literature

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