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SURE+DP: improving Diagnosis and Prognosis for paediatric tuberculous meningitis through the SURE treatment trial - NU/LSHTM project

Title of PhD project / theme

SURE+DP: improving Diagnosis and Prognosis for paediatric tuberculous meningitis through the SURE treatment trial

Supervisory team

LSHTM supervisor (lead):

Dr Robin BASU ROY (robin.basu-roy@lshtm.ac.uk)

Nagasaki University supervisor:

Professor Koya Ariyoshi  (kari@nagasaki-u.ac.jp)

UK PhD co-supervisor:

Professor Di Gibb, MRC Clinical Trials Unit, UCL, (diana.gibb@ucl.ac.uk)

Brief description of project / theme

Background: Young children are at high risk of developing tuberculous meningitis (TBM), which has high morbidity and mortality.1 Confirming the diagnosis is difficult in children and microbiological confirmation is rare.2 Beyond clinical parameters, there are limited data on prognostic markers at presentation.

Foundations: The Short Intensive Treatment for Children with Tuberculous Meningitis (SURE) randomised controlled trial of treatment strategies for TBM in children (ISRCTN40829906) is the largest ever RCT of antimicrobial treatment strategies for TBM in children. It will assess whether a short, 6-month intensified anti-TB treatment regimen is non-inferior to the current 12-month standard WHO-recommended treatment regimen with all-cause mortality as the primary endpoint. In an additional factorial placebo-controlled randomisation with a superiority design, the efficacy of aspirin on neurodevelopmental outcome at 48 weeks will be evaluated. The trial is taking place in Zambia, Zimbabwe, Uganda, India and Vietnam and is co-ordinated and led by the MRC Clinical Trials Unit at UCL, where Dr Basu Roy holds an honorary clinical lecturer position and is part of the SURE team.

PhD Proposal: There is the possibility to build PhD projects in parallel to the SURE study as sub-studies. It is particularly suitable for diagnostic studies as described below, although alternative sub-studies could focus on neuroradiology or child development and growth for example.  

Example Project:

Aim 1: To prospectively recruit a cohort of children in Uganda, Zambia & Zimbabwe who are presenting with symptoms of central nervous system infection but do not have TBM to act as non-TBM controls for the TBM diagnostic sub-study.

Aim 2: To evaluate the performance of novel diagnostics in paediatric TBM cases and controls using whole blood, serum, urine, and cerebrospinal fluid (CSF) samples.

Aim 3: Using whole blood gene expression and CSF metabonomic data from paediatric TBM cases, to identify biomarkers at presentation that are linked to outcome and treatment response.

Laboratory methodologies: Include i) validation of existing 3-gene RT-PCR whole blood signature for paediatric pulmonary TB in TBM3; ii) RNA sequencing of whole blood to identify TBM-specific gene expression profiles and pathophysiology through pathway analysis; and iii) untargeted metabonomic mass spectrometry of CSF and serum, iv) detection of urinary mycobacterial lipoarabinomannan,4 and v) targeted amino acid and oxylipin mass spectrometry assays on CSF.5

References:

1  Chiang SS, Khan FA, Milstein MB, et al. Treatment outcomes of childhood tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2014; 14: 947–57.

2  Bahr NC, Marais S, Caws M, et al. GeneXpert MTB/Rif to Diagnose Tuberculous Meningitis: Perhaps the First Test but not the Last. Clin Infect Dis 2016; 62: 1133–5.

3  Gliddon HD, Kaforou M, Alikian M, et al. Identification of reduced host transcriptomic signatures for tuberculosis and digital PCR-based validation and quantification. bioRxiv 2019; : 583674.

4  Broger T, Nicol MP, Sigal GB, et al. Diagnostic accuracy of 3 urine lipoarabinomannan tuberculosis assays in HIV-negative outpatients. J Clin Invest 2020; published online Sept 28. DOI:10.1172/jci140461.

5  Van Laarhoven A, Dian S, Aguirre-Gamboa R, et al. Cerebral tryptophan metabolism and outcome of tuberculous meningitis: an observational cohort study. Lancet Infect Dis 2018; 18: 526–35.

The role of LSHTM and NU in this collaborative project

This project builds upon both LSHTM’s and NU’s commitment to improve global health through excellence in research. It would provide the PhD candidate with the opportunity to lead a large prospective paediatric TBM sub-study in high incidence TB settings, whilst also developing their project-specific and data analysis skills. With knowledge of the research networks at both LSHTM and NU, the project supervisors will be able to facilitate connections and collaborations with relevant Faculty.  

Professor Di Gibb of MRC Clinical Trials Unit at UCL is the Principal Investigator of the parent SURE study and will co-supervise the PhD.  

Particular prior educational requirements for a student undertaking this project

  • Medically qualified.
  • Clinical experience in the fields of paediatrics, infectious diseases, neurology or radiology is desirable.
  • Evidence of prior commitment to research desirable.

Skills we expect a student to develop/acquire whilst pursuing this project

  • Co-ordinating recruitment and overseeing logistics of a sub-study to a multicentre international RCT
  • Laboratory skills (project-dependent)
  • Data analysis skills
  • Academic writing for publication and PhD thesis.
  • Transferable skills in keeping with the Vitae Researcher Development Framework.