17 Apr, 2018

The three finalists for the 2018 RePORT International Awards are: 

  1. Towards a global TB biomarker: Comparison of small transcriptomic signatures to predict, diagnose and monitor TB disease in Brazil and South Africa
  2. Host RNA expression for diagnosis and monitoring of pediatric TB in Africa and India
  3. Determination of Efficacy of Xpert PCR Ultra and Transcriptional Signatures in the Diagnosis of Pleural Tuberculosis

 

Towards a global TB biomarker: Comparison of small transcriptomic signatures to predict, diagnose and monitor TB disease in Brazil and South Africa

Principal Investigators:

  • Bruno Andrade; FIOCRUZ, Rio de Janeiro, Brazil
  • Adam Penn-Nicholson; South African Tuberculosis Vacinne Initiative, University of Cape Town, South Africa

Abstract:

Tuberculosis (TB) is the world’s leading cause of mortality by an infectious disease.  With nearly a quarter of the global population infected with Mycobacterium tuberculosis (M.tb), the causative agent of TB disease, there is an urgent need for earlier disease identification using novel non-sputum-based diagnostics, linked to more effective preventive and curative strategies. An ideal TB signature should have application as both a diagnostic and prognostic biomarker.  Importantly, such a signature must be robust and easily translatable to an affordable point-of-care device for use in the field. Several new TB signatures have been discovered and validated, with varying diagnostic and prognostic performance. Many of these have been discovered in African populations, but few have been tested in populations beyond the continent.  We have recently developed a 16-gene signature capable of predicting TB disease, a year before the onset of symptoms, and have recently reduced this signature to a PCR test comprising 6 genes. In this study, we aim to determine the prognostic and diagnostic performance of this 6-gene signature as well and five previously published small TB signatures in a Brazilian cohort of close contacts, which is part of the RePORT Brazil study, and monitor treatment response in a cohort of Brazilian adults with prevalent TB undergoing treatment. Validating this transcriptomic signature in the diverse Brazilian population (which includes African, European, and Asian ancestry) could transform global TB prevention efforts—by identifying those at increased risk of progression, for targeted preventive therapy. This study will provide a head-to-head comparison of the performance of a panel of small TB risk and disease signatures in Brazil and South Africa, with application towards development of a point-of-care device suitable for the global TB epidemic.


Host RNA expression for diagnosis and monitoring of pediatric TB in Africa and India

Principal Investigators:

  • Lesley Workman, Heather Zar, Mark Nicol; University of Cape Town, South Africa
  • Mandar Paradkar, John Hopkins Byramjee Jeejeebhoy Medical College (BJMC Clinical), Pune, India
  • Syed Hissar; National Institute of Research in Tuberculosis, Chennai, India
  • Aarti Kinikar; Byramjee Jeejeebhoy Medical College, Pune, India

Abstract:

Lack of accurate and rapid diagnostic tests for TB disease results in delayed treatment for many children, and conversely over-treatment of children who may not have TB. There is thus an urgent need for improved diagnostic tests for childhood TB.

A host RNA expression profile which accurately predicts TB disease status in African children has been identified. However, there are very limited data on whether this biomarker signature is generalizable to non-African populations, particularly in India, where the burden of disease is high. Further, there are not any data on the effect of TB treatment on this biomarker signature.

This study will involve two RePORT consortia, South Africa and India, both high burden TB and TB-HIV settings with well-established cohorts of children with TB disease. Using available samples and clinical data from 404 well characterised children with suspected TB disease, [200 from South Africa and 204 from India], both pulmonary and extrapulmonary, a RNA expression signature for the diagnosis of TB disease will be derived and validated. The biomarker signature will be derived by comparing RNA sequencing profiles from blood specimens at enrolment in children with microbiologically confirmed TB, those clinically diagnosed with TB and those with other respiratory diseases. Changes in RNA expression profile after 3 months of treatment will be evaluated in the South African cohort. The robust, standardised platform for data variables and methodologies developed by TB Report will be used for this study.


Determination of Efficacy of Xpert PCR Ultra and Transcriptional Signatures in the Diagnosis of Pleural Tuberculosis

Principal Investigators:

  • Christopher Devasahayam; Christian Medical College, Vellore, India
  • Keertan Dheda; University of Cape Town, South Africa

Abstract:

Extra-pulmonary TB (EPTB) accounts for ~20% of all TB cases and tuberculous pleural effusion is the often the most common site of EPTB. Diagnosis of pleural TB is challenging due to the paucibacillary nature of the disease. Traditionally, pleural fluid ADA, histopathology of pleural tissue and cultures of both tissue and pleural fluid have been used for its diagnosis.

More recently, Xpert MTB/RIF (Xpert) of pleural fluid and tissue have been added to the diagnostic

armamentarium with modest improvements. A limitation of the Xpert is its low yield in paucibacillary samples in the setting of EPTB. This may be overcome by the Xpert MTB/RIF Ultra (Ultra), developed with a goal to increase the sensitivity, which has not been studied in pleural TB. Another promising marker is unstimulated interferongamma, which has a high sensitivity and specificity for the diagnosis of pleural TB in endemic settings. The proposed study aims to compare Ultra and unstimulated gamma performed in pleural fluid against the prevailing gold standard (MGIT culture and histopathology) in pleural TB, and its suitability for use in a high prevalence

settings such as India and South Africa.

In addition, the investigators also propose to evaluate blood and pleural fluid transcriptional signatures, which have shown promise in pulmonary TB. This approach has not been investigated using samples from endemic countries, and could provide clues to promising pleural fluid biomarkers. Samples will also be bio-banked for future biomarker studies.

This proposal speaks to the objective of developing biomarkers for TB diagnosis, and disease progression and severity, thus facilitating, not only improved patient care, but the more efficient evaluation of future immunotherapeutic or pharmacological interventions. EPTB, and pleural TB is a neglected entity with respect to these objectives. From a capacity development perspective, this proposal will facilitate the establishment of a new inter-country collaborative link in the RePORT network, and will also facilitate student and health worker training, thus driving sustainable research.