Researchers from the South African Tuberculosis Vaccine Initiative (SATVI) at the University of Cape Town (UCT), the Center for Global Infectious Disease Research - Seattle in the United States, and a large consortium of collaborators have developed a validated a new, simple blood-based test that has the potential to serve multiple functions in the fight against TB.
The test, called RISK6, can identify healthy individuals who are at risk of developing tuberculosis (TB) disease, identify people with subclinical or clinical disease and contribute to understanding how well a patient would respond to treatment. And it has now been validated in seven cohorts across two continents.
The researchers also showed that RISK6, which can be applied to capillary blood collected by finger prick, could be developed into a rapid, fingerprick blood-based test device for use at points of care.
This advance, published in the journal Scientific Reports today, paves the way for studies to evaluate and implement the test in community and primary care settings.
"Finding everyone with TB, so that they can receive antibiotic treatment to get better and so that they do not infect others, is critically important," says Professor Thomas Scriba, deputy director of immunology at SATVI.
"Most people with TB are identified too late, when they have already passed the bacterium to family and friends."
Why do we need a new TB test?
It is estimated that more than 1.7 billion people are infected with the bacterium Mycobacterium tuberculosis globally, of which 10 million developed TB disease and more than 1.4 million died in 2018 (according to the World Health Organization [WHO] Global TB Report 2019).
"Finding everyone with TB, so that they can receive antibiotic treatment to get better and so that they do not infect others, is critically important."
Current diagnostic tools for TB rely on detecting the bacterium in sputum (phlegm). This makes it possible to administer these tests only to people with advanced TB and who can produce sputum samples.
There is currently no effective test that can detect the bacterium or the disease in people who are not symptomatic. And there is no test that can predict which healthy individuals infected with M. tuberculosis (latent TB) will progress to developing TB disease. Effective tools to monitor people's response to treatment are also lacking.
Yet, at the same time, the scientific community is increasingly realising that if we are to reduce the transmission of TB and curb the infection rate, we will need to find and treat individuals with TB disease much earlier during their disease - ideally before they develop symptoms.
A test that can identify healthy individuals who are at high risk of developing the disease would allow a physician to prescribe preventive treatment before they can spread the bacteria to anyone.
"This study is an important step forward because a new diagnostic test that is not based on sputum and that can identify people with TB disease and those who are at high risk of developing TB in the future could potentially transform how we manage this devastating infectious disease," says Scriba.
In South Africa, it is estimated that a person with TB can infect up to 10 people before being diagnosed and receiving treatment. And, as in many developing countries, 60-80% of the population is infected with M. tuberculosis, making the treatment of such vast numbers unfeasible. As such, latent or asymptomatic TB is not treated as part of standard of care.
One test, multiple applications
In this study, the investigators show that the ability of the new RISK6 test to predict outcomes of people with latent TB significantly exceeds that of previous candidate tests. RISK6 performance for diagnosing subclinical and clinical disease in people with and without HIV also met or approached the WHO benchmarks for other non-sputum tests.
"The next step is to develop a hand-held device that can perform this test immediately after blood is collected by finger prick."
In addition, the results from RISK6 for treatment response agreed with results from a standard method of assessing degree of lung immunopathology (positron emission tomography) and tracked the TB treatment response of the individual.
RISK6 also allowed identification of patients with who failed TB treatment before it was initiated, demonstrating that a blood test could be used to guide or adjust TB treatment to achieve better efficacy. The study also showed that performance of the test was similar when using capillary blood and venous blood.
RISK6 has the potential to fill a critical gap in non-sputum screening of communities to identify those with the greatest need for treatment and to monitor treatment response.
"The next step is to develop a hand-held device that can perform this test immediately after blood is collected by finger prick," continue Scriba. "And the test needs to give a quick result - ideally in less than 30 minutes - so that the person who is being tested knows if they can go home, or if a visit to a clinic or hospital is necessary.
"We have identified industry partners to pursue these next steps."
Penn-Nicholson et al. (2020) RISK6, a 6-gene transcriptomic signature of TB disease risk, diagnosis and treatment response. Scientific Reports. DOI: 10.1038/s41598-020-65043-8
Collaborating across the world
A strength of this research is the extensive validation of the RISK6 test in seven human cohorts assembled by clinical collaborators from Brazil, Ethiopia, South Africa, Peru and The Gambia.
The large consortium of researchers involved includes researchers in South Africa at Stellenbosch University, the Desmond Tutu HIV Centre, the UCT Institute of Infectious Disease and Molecular Medicine, the Centre for the AIDS Programme of Research in Africa and the South African Medical Research Council; the Medical Research Council of The Gambia; the Max Planck Institute for Infection Biology in Germany; Harvard Medical School, the Hagler Institute for Advanced Study at Texas A&M University, Vanderbilt University School of Medicine and the Catalysis Foundation for Health in the United States; and in Brazil, the Oswaldo Cruz Foundation (Fundação Oswaldo Cruz).