Novel approach identifies people at risk of developing TB
A novel approach to studying the progression of tuberculosis (TB) from infection to disease has identified and treated people at increased risk of developing the disease that current methods of testing would not.
Researchers at the National Institute for Health and Care Research (NIHR) Leicester Biomedical Research Centre (BRC) hope the findings of their study, published in the Lancet Microbe on 17 January, could help with global efforts to reduce the spread of the disease.
Dr Pranabashis Haldar, Clinical Senior Lecturer in Respiratory
Medicine at the University of Leicester and a Principal
Investigator at the NIHR Leicester BRC, where the research was
carried out, said: “Tuberculosis rates in the UK and
around the world are not declining despite global efforts.
“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 that 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.
“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.”
In
this study researchers 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.
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.
PET-CT
Dr Jee Whang Kim, a Clinical Research Fellow from the University
of Leicester, who conducted the study said: “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.
“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.
“In this case, we were looking
for evidence of metabolic activity associated with infection by
the TB bacteria that cannot be seen using a chest x-ray or
deduced by the blood tests used in routine clinical
practice.
“In keeping with what is
understood about the natural history of this infection, we found
that the radiotracer activity tended to be taken up around the
lungs, or in lymph nodes around the lungs. We then went on to
perform a second PET-CT scan after 3 months to find out whether
the infection was progressing or not. Where possible, we also
took samples from the active sites to test for presence of the
TB bacteria.”
Phage-based diagnostic
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 Dr Jee Whang Kim.
“Until now, studies have been limited by
challenges of detecting low bacterial numbers.”
In
this study the team used a novel bacteriophage-based assay
called Actiphage (developed by PBD Biotech).
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 the bacterial DNA that cannot otherwise be detected
using existing clinical tools.
“We
wanted to see whether this approach could identify metabolically
active and replicating M tuberculosis in the blood of
individuals who were otherwise completely well,” added Dr
Jee Whang Kim.
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.
Dr Haldar said: “Of the
20 contacts recruited to the study, one had a subtly abnormal
chest radiograph that was picked up retrospectively. Using
existing clinical tools and criteria, we can conclude that only
this person may have been identified at routine contact
screening to have—or be at higher risk of
developing—tuberculosis.
“But
using PET-CT we identified four people in whom the TB bacteria
could be isolated from either the lung airway or PET-positive
lymph nodes and two further people that had progressive changes
after the second PET-CT scan. All six individuals were given TB
treatment and in all of them, a further PET-CT scan 3 months
after completing treatment showed resolving or completely
resolved changes, further supporting our view that the PET-CT
changes were caused by metabolically active tuberculosis
infection.”
“We were also
encouraged by the result of the Actiphage test,” added Dr
Haldar.
“We 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%)
participants at baseline and positive in all six of the treated
PET-CT- positive participants.
“Our results
are exciting for two reasons. Firstly, they show that PET-CT
could be an effective tool for identifying people with higher
risk TB infection. This can help us to perform studies to
develop new tests and evaluate new treatments, including
vaccines more efficiently and at lower cost.
“Secondly,
our findings suggest that TB bacteria are found in blood more
often than has previously been thought and importantly, the
presence of the bacteria in blood may be an indicator of
uncontrolled or progressive TB infection.
“Based
on our findings we propose that blood biomarkers aimed at
detecting the bacteria, can complement existing biomarkers of
the host immune response to enable better stratification of TB
risk in those that have TB infection.”
For the full paper, please visit:
The NIHR Leicester BRC is part of the NIHR and hosted by the University Hospitals of Leicester NHS Trust in partnership with the University of Leicester, Loughborough University and the University Hospitals of Northamptonshire NHS Group.
