Novel approach identifies people at risk of developing TB: Lancet study

A novel approach to studying the progression of tuberculosis (TB) from infection to disease can identify and treat people at increased risk of developing the disease that current methods of testing would not, according to a study published in The Lancet Microbe journal.

Researchers at the National Institute for Health and Care Research (NIHR) Leicester Biomedical Research Centre (BRC), UK, hope the findings could help with global efforts to reduce the spread of the disease.

TB is a bacterial disease that causes significant lung damage and can, without treatment, be fatal. It is spread in aerosol by inhaling droplets containing the bacteria.

 

Most people who become infected live with the infection and remain well. However, in a small proportion, the infection is not controlled and can progress to cause disease.

Current tests of TB infection use either a skin test or a blood test, called an interferon gamma release assay (IGRA) to detect an immune response to the infection. However, these tests cannot distinguish between those that are at high or low risk of developing TB, said Pranabashis Haldar from the University of Leicester and a Principal Investigator at the NIHR Leicester BRC, where the research was carried out.

An important research goal is to develop better tests that can identify the high-risk group so that we can provide more targeted treatment to prevent TB developing, Haldar said.

The latest study used PET-CT, a highly sensitive form of imaging, as a novel way of looking at how the infection progresses, and to identify people at greater risk of developing the disease.

This approach allowed the team to undertake a study evaluating a potential new blood test for identifying those at higher risk, without needing to recruit a large cohort, which can be challenging and very expensive.

Twenty adults traced back to households of people being treated for tuberculosis disease at University Hospitals of Leicester NHS Trust took part, the researchers said.

Participants underwent chest radiography and an IGRA to screen for TB infection. The research team then used two new methods of monitoring the progression of the disease over the following year: PET-CT imaging tools and a new blood test.

In PET-CT scans, patients are given fluorodeoxyglucose (FDG), a radiotracer which is similar to naturally occurring glucose (a type of sugar) that the body uses it in a similar way, Jee Whang Kim, a Clinical Research Fellow from the University of Leicester, who conducted the study said.

By analysing the areas where the radiotracer is taken up, it's possible to identify areas in the body where something might be going on, Kim added.

The researchers found that the radiotracer activity tended to be taken up around the lungs, or in lymph nodes around the lungs.

They then performed a second PET-CT scan after 3 months to find out whether the infection was progressing or not. Where possible, they also took samples from the active sites to test for presence of the TB bacteria.

The second novel test was looking for a new biomarker (a biological change) in the blood of patients with the infection.

There is evidence of bacterial escape from where the primary infection occurs (the lungs) during progressive infection, and that escape might occur into the bloodstream, added Kim.

In this study, the team used a novel bacteriophage-based assay called Actiphage.

Bacteriophages are viruses that infect bacterial cells and they are highly specific; with each phage preying on a single type of bacteria.

The Actiphage assay uses a bacteriophage that attacks live TB bacteria; releasing the bacterial DNA which can then be detected.

Using this approach, it is possible to detect very low levels of bacterial DNA that cannot otherwise be detected using existing clinical tools.

The 20 TB contacts were all asymptomatic with normal chest X-rays. They underwent a PET-CT baseline scan and, if it was positive and showed metabolic activity that could be sampled, they went on to have a bronchoscopy and sampling.

If the baseline PET-CT scan did not show anything that could be sampled or if the sampling was negative for TB, they were monitored with a second PET-CT after three to four months.

The researchers found a statistically significant association between a positive baseline Actiphage test and later being given treatment for high-risk features of TB infection.

Overall, Actiphage results were positive in 12 (60 per cent) participants at baseline and positive in all six of the treated PET-CT- positive participants, they found.