A new blood test has been found to predict more accurately the development of tuberculosis (TB) up to 2 years before its onset in people living with someone with active TB.1

Those living with someone with active TB are at highest risk for developing the disease, yet only 5% to 20% of people infected with tuberculosis actually develop TB. A blood test that predicts the development of TB in order to avoid unnecessarily putting large numbers of lower-risk people through preventive treatment is not currently available.

Researchers from an international research consortium have recently developed and validated a blood test that measures the expression levels of four genes that can more accurately predict the development of TB among high-risk patients in sub-Saharan Africa, up to 2 years before onset of the disease.

“We found that this prediction is possible through measurements of a combination of a four-gene signature in the blood,” says Gerhard Walzl, MMed, PhD, lead study author and leader of the immunology research group at Stellenbosch University. “This signature, known as ‘RISK4,’ was found to be present in all cohorts in the study from South Africa, Gambia, and Ethiopia.” RISK4 is a combination of four genes associated with inflammatory responses.

For quality control, the scientists used a training-test set approach: they separated out a number of samples to create a discovery (training) set on which the RISK4 signature was developed, and then tested the signature on the remainder of the samples (test set) in a blinded manner. Although blood samples from individuals in Uganda were initially included in the study design, they were not available in large enough quantities to be properly analyzed.

Focusing on people who lived with someone with active TB, the research team enrolled 4,466 HIV-negative, healthy study participants from the households of 1,098 index cases (people with active TB, who allowed the researchers to enroll members of their household who did not have TB in its active stage). Blood samples were taken from the 4,466 study participants, and stored.

At the end of the initial study period, when it was apparent who had progressed to TB, the researchers analyzed the blood samples of 79 individuals who had progressed to active TB between 3 and 24 months following exposure, and 328 who remained healthy during the 2 years of followup. The researchers measured a variety of biosignatures—combinations of gene or protein levels that together resulted in a test readout relating to an individual’s current or future risk of developing the condition. Due to the cost of the tests, the blood samples of other study participants were not tested.

“The individual components of this signature may not be sufficient to deliver an accurate diagnosis of prediction, but a combination of these markers improves its accuracy,” says Walzl.

A number of companies have the ability to develop tests that measure the presence of the four genes. “We are hoping that primary health clinics will be able to use such a test and the reagents would then be readily available in that format, similar to the tests that are currently used to diagnose TB.”

While there are currently tests on the market that may predict progression to TB, the test developed by Walzl and colleagues gives positive results for a smaller percentage of high-risk household contacts than the current tests. This translates to fewer people being treated unnecessarily in order to prevent TB.

“Preventative treatment is several weeks long and has potential side effects,” Walzl says. “One wants to limit the number of people who have to undergo such treatment to those most likely to be at risk for developing active TB.”

Caused by infection with Myobacterium tuberculosis, tuberculosis is the world’s leading cause of death brought on by a single pathogen. More than 10 million new cases of TB are diagnosed each year, and almost two million people die from the disease. Globally, 1.7 billion people are estimated to be infected with M. tuberculosis.

“This study is the first step, and now the impact of this test on prevention of TB will have to be tested in multicenter clinical trials,” Walzl says. “In addition, the validity of the prediction in high-risk individuals in Asia, South America, and other high-priority areas needs to be assessed.”


  1. Suliman S, Thompson E, Sutherland J, et al. Four-gene pan-African blood signature predicts progression to tuberculosis. Am J Respir Crit Care Med. Published online in advance, April 6, 2018; doi: 1164/rccm.201711-2340OC.