TB Diagnostics

GeneXpert development

EDCTP has made considerable investment in research into TB diagnostics, through a diverse portfolio of research studies from early stage testing of biomarkers, evaluation of new and improved diagnostics through to implementation of diagnostics in a real-life setting.

A Senior Fellowship awarded to Professor Mark Nicol (University of Cape Town, South Africa) provided supporting data leading to the WHO endorsement of the Xpert MTB/RIF test (GeneXpert®) in December 2010. Following on from the WHO endorsement, a rapid roll-out of GeneXpert has occurred. The Evaluation of multiple novel and emerging technologies for TB diagnosis, in smear-negative and HIV-infected persons, in high burden countries (TB-NEAT) consortium, supported by EDCTP and led by Prof. Keertan Dheda (University of Cape Town, South Africa), has measured the clinical effect of GeneXpert, which is an expensive intervention, by looking at its performance in well-managed primary-care health care facilities in four countries. The EDCTP-funded TB-CHILD consortium, led by Dr Fred Lwilla (Ifakara Health Research and Development Centre, Tanzania) and Dr Klaus Reither (Swiss Tropical and Public Health Institute, Switzerland), has explored the performance of several diagnostic tests in children..

Diagnosis of TB in children is challenging because children tend to have lower levels of infectious bacteria and cannot produce sputum, making it harder to detect by microscopy and to grow in culture. Limited data exist on the performance of GeneXpert in diagnosing TB in children. The TB-CHILD consortium assessed the diagnostic accuracy of GeneXpert using culture-confirmed TB cases as the reference standard in a study of 451 children in Tanzania and Uganda. GeneXpert provided timely results with moderate sensitivity and excellent specificity, detecting 1.7 times more culture-confirmed cases than smear microscopy with a similar time to detection. However, low yields in children with highly probable and probable TB remain problematic, making the search for new sputum-independent diagnostics a priority.

The consortium developed a new immunodiagnostic tool, known as TAM-TB, which has the potential to improve the diagnosis of TB in children. The TAM-TB assay is the first immunodiagnostic tool which can detect active tuberculosis disease in children with sensitivity similar to culture and with excellent specificity in a tuberculosis-endemic setting.

In a publication in The Lancet Infectious Diseases (2014), the TB CHILD consortium reported the results of a sputum-independent assay developed in Tanzania that is able to diagnose active tuberculosis in children. The T cell activation (TAM-TB) assay is the first immunodiagnostic tool which can detect active tuberculosis disease in children with sensitivity similar to culture and with excellent specificity in a tuberculosis-endemic setting.

The assay measures the CD27 phenotype of CD4+ T cells producing IFNg in response to Mycobacterium tuberculosis antigens using a standard intracellular cytokine staining procedure for flow cytometry.

The TAM-TB assay was tested in a proof-of-concept study carried out between May 2011 and February 2013. A total of 290 children that presented with symptoms of tuberculosis, were recruited and followed up at the National Institute for Medical Research (NIMR)-Mbeya Medical Research Center in Mbeya and the Ifakara Health Institute in Bagamoyo, Tanzania. According to results published in The Lancet the assay enabled the detection of 15 of 18 culture-confirmed cases (sensitivity 83.3%, 95% CI, 58.6–96.3). Specificity was 96.8% (95% CI 89.0–99.6) in the cases that were classified as not tuberculosis (n=63), with little effect from latent tuberculosis infection. The TAM-TB assay identified five additional patients with highly probable or probable tuberculosis, in whom M. tuberculosis was not isolated.

TB-NEAT Consortium tested GeneXpert in a study entitled “Utility of intensified case finding combined with a package of novel TB diagnostics performed at community-based clinics in Africa: a multi-centric prospective cohort study (XACT study)” by Professor Keertan Dheda of University of Cape Town. The first part of the trial enrolled 1502 patients in South Africa, Zambia and Zimbabwe. The study was completed in 2013 and published in The Lancet. The study showed that Xpert MTB/RIF can be accurately administered by a nurse in primary-care clinics, resulting in more patients starting same-day treatment, more culture-positive patients starting therapy, and a shorter time to treatment. A paediatric component of the studies enrolled 384 children in Cape Town and found that Xpert accurately detected TB in children with TB signs. This study was published in the Lancet Global Health. The urine test studies for HIV infected TB patients involved looking for LAM in samples.

Project overview:

Official title: Evaluation of new and emerging diagnostics for childhood tuberculosis in high burden countries (TB CHILD)
Project Coordinator: Fred Lwilla, Ifakara Health Research and Development Centre, Tanzania

  • European and Developing Countries Clinical Trials Partnership
  • German Federal Ministry of Education and Research
  • Swiss National Science Foundation

Total budget: € 3,331,073
EDCTP budget: € 1,907,407