Evaluation of New Biomarker-based Approaches for Improving the Diagnosis of Childhood Tuberculous Meningitis

NCT04308928 | Completed DMC

• 1 other identifier: UStellenboschTBM
• Study Type: observational
• Target: 332
• Locations: 1 country
• Sites: 1

Brief Summary

The rapid diagnosis of tuberculosis (TB) in children remains a serious challenge owing to limitations in the existing diagnostic tests. TB meningitis (TBM), an extrapulmonary form of TB, is the most severe manifestation of paediatric TB. TBM results in high morbidity and mortality in children, despite the availability of chemotherapy, mainly due to diagnostic delay. Most tests required for proper TBM diagnosis including analysis of cerebrospinal fluid (CSF) and brain imaging are not available in resource-limited settings e.g., in most of Africa including South Africa. New tests for TBM are urgently needed. The main goal of this proposal is to develop a point-of-care (POC) diagnostic test for TBM, based on CSF and bloodbiomarkers. Aim 1: Evaluate the diagnostic potentials of 51 host inflammatory biomarkers that the investigators recently identified in CSF and blood samples from children with suspected meningitis in a repository of 100 stored CSF and serum samples using a multiplex platform. After statistical analysis including multi-marker modelling by linear discriminant analysis, random forest, and other modelling techniques, the investigators will select the best combination of up to four biomarkers for incorporation into the prototype diagnostic test (Aim 2). Aim 2: Incorporate the best performing CSF and serum biomarkers into a novel, patented biosensor-based POC diagnostic test. The investigators will develop a multi-biomarker prototype test for detecting up to 4 biomarkers in serum or CSF. Aim 3: Evaluate the newly developed POC test on 300 children prospectively. This will be done at the Tygerberg Academic Hospital. The diagnostic yield of the POC test will be compared to the routine diagnostic tests.

Conditions

Tuberculous Meningitis

Keywords

Tuberculosis; meningitis; childhood tuberculous meningitis

Outcome Measures

Primary Outcomes (3)

• Identify CSF or blood-based biosignatures for the diagnosis of TBM in children

  We have identified a total of 51 inflammatory biomarkers in CSF and/or serum samples in children with suspected TBM. 47 of these host markers (including 10 of the 14 that showed potential in serum either as individual markers or as part of 3-marker signatures) were detected in CSF samples, with only four of these proteins (CCL2, IL-4, adipsin and Ab42) showing potential only in serum samples. Using a repository of 100 CSF and serum samples, currently available in our biobank, from children with suspected TBM, n=50 with TBM, we will look for correlated markers that can be substituted to identify the best performing biomarker set for the POC device (Aim 2).

  2019-2021

• Develop a prototype POC diagnostic test platform based on the biosignatures.

  The validated, best performing CSF and serum biomarkers (sub aims 1a and b) will be incorporated into our POC diagnostic platform, at the Engineering Faculty, SU. The first prototype of the biosensor-based assay was shown to quantify antibodies in bodily fluids in the range of 50 ng/ml - 1 µg/ml (22). We will develop a multibiomarker prototype test for 4 biomarkers in CSF or serum. The prototype multi-biomarker test will undergo prospective evaluation in the field (Aim 3), in years 4 and 5. Assay development will be led by Distinguished Professor Willem Perold, a co-investigator on the project, who will be the lead supervisor of one MSc.Engineering student, with Dr. Chegou as co-supervisor.

  2020-2022

• Evaluate the newly developed test in a new patient cohort.

  We will evaluate the newly developed test prospectively in a new cohort of children with suspected TBM. Clinical study design Recruitment of study participants will follow a longitudinal cohort design. Children suspected of having meningitis will be recruited and assessed for TBM at Tygerberg Academic Hospital, a tertiary level referral hospital and a teaching hospital for SU. It is the second-largest hospital in South Africa. These children will later be classified as having "definite", "probable", "possible" and "no TBM" based on international, standardized criteria (26).

  2023-2024

Study Arms (2)

Children with suspected meningitis

Patients must have a clinical diagnosis of meningitis including one or more of the following symptoms: headache, irritability, vomiting, fever and neck stiffness (Table 1). The diagnosis of probable or possible TBM is based on 1) clinical findings 2) CSF results 3) neuroimaging findings 4) evidence for TB outside the central nervous system and 5) additional laboratory criteria. A scoring system then determines whether a patient falls in the probable or possible TBM category. Points are allocated for a positive finding in each of the categories, with a maximum score for each category. A total score of at least 10 is compatible with probable TBM, while a total score of at least 6 equates with a possible TBM diagnosis.

Children with definite tuberculous meningitis

Definite TBM requires demonstration of acid- fast bacilli in the CSF, Mycobacterium tuberculosis culture from CSF, a positive nucleic acid amplification test (PCR) of CSF or histopathological evidence of Mycobacterium tuberculosis from a central nervous system site.

Eligibility Criteria

• Age: 3 Months - 13 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

The study will be conducted at Tygerberg Children's Hospital, Parow Valley, Cape Town. The hospital is the tertiary academic hospital of the Faculty of Medicine and Health Sciences, University of Stellenbosch. Children with tuberculous meningitis are referred from primary care day hospitals, district and secondary level hospitals from our drainage area. Children with suspected TBM are referred to our institution to establish the diagnosis of TBM and to treat the complications associated with advanced disease (stage 2 and 3 TBM, e.g. hydrocephalus). Research samples collected for the purposes of the current study shall be processed at the Stellenbosch University Immunology Research Group (SUN-IRG) laboratory, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences.

You may qualify if:

• Children between the ages of 3 months and 13 years with suspected meningitis, and who require CSF examination for routine diagnostic purposes at Tygerberg Children's Hospital.
• If possible, assent will be obtained in those children older than 7 years who have a normal level of consciousness, i.e. a Glasgow Coma Score (GCS) of 15/15.

You may not qualify if:

• Children 13 years and older will be excluded from the study.
• Failure to obtain written consent will also exclude children from the study.

Sponsors & Collaborators

• European and Developing Countries Clinical Trials Partnership (EDCTP): collaborator
• Medical Research Council, South Africa: collaborator
• University of Stellenbosch: lead

Study Sites (1)

Stellenbosch University Immunology Research Group

Cape Town, Western Cape, 7505, South Africa

Location

Related Publications (2)

• Kim D, Perold WJ, Chegou NN. Development of a Biosensor for the Early Detection of Tuberculous Meningitis in Infants. Engineering Proceedings. 2025; 109(1):12. https://doi.org/10.3390/engproc2025109012

  RESULT

• Manyelo CM, Solomons RS, Snyders CI, Kidd M, Kooblal Y, Leukes VN, Claassen C, Roos K, Stanley K, Walzl G, Chegou NN; TBMBIOMARKERS study group. Validation of host cerebrospinal fluid protein biomarkers for early diagnosis of tuberculous meningitis in children: a replication and new biosignature discovery study. Biomarkers. 2022 Sep;27(6):549-561. doi: 10.1080/1354750X.2022.2071991. Epub 2022 May 12.

  PMID: 35506251 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

Cerebrospinal fluid, serum, urine

MeSH Terms

Conditions

Tuberculosis, Meningeal; Tuberculosis; Meningitis

Condition Hierarchy (Ancestors)

Meningitis, Bacterial; Central Nervous System Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Tuberculosis, Central Nervous System; Tuberculosis, Extrapulmonary; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Central Nervous System Infections; Central Nervous System Diseases; Nervous System Diseases; Neuroinflammatory Diseases

Study Officials

• Novel Chegou, Prof

  University of Stellenbosch

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 11, 2020
• First Posted: March 16, 2020
• Study Start: April 1, 2020
• Primary Completion: October 31, 2024
• Study Completion: July 31, 2025
• Last Updated: December 16, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (1)