A new study conducted by researchers in Leicester and Nottingham has shown the potential for a new blood test to not only diagnose human tuberculosis (TB) but also identify those at most risk of developing the disease, according to findings published in medical journal Clinical Infectious Diseases.
Despite recent reductions, England still has one of the highest rates of TB in Western Europe . While TB cases have been declining overall in the UK, the rate of TB in some of the most deprived areas remains more than seven times higher than in the least deprived . TB is a serious bacterial infection, which can be life threatening if not properly treated with antibiotics. Pulmonary TB of the lungs or throat is contagious although TB can affect any part of the body.
The research, carried out at the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre (BRC) and the University of Nottingham's School of Biosciences, used new blood test called Actiphage to look for the presence of the bacteria that cause TB (Mycobacterium tuberculosis; MTB). The study involved 66 participants in four groups: those with active pulmonary TB, those with latent TB, a control group of patients referred for suspected TB but found not to have the disease, and a control group of healthy individuals.
The new blood test was used to test all of the patients twice, 12 months apart. Actiphage tested positive in 73 per cent of people that we subsequently diagnosed with TB - for an experimental study this was a much higher level than expected. None of the participants in the control groups tested positive with Actiphage and none of the patients with latent TB who tested negative with Actiphage went on to develop active TB.
Intriguingly, two of the three participants with latent TB infection who tested positive with Actiphage went on to develop the disease more than six months later, suggesting the test may have a predictive role in identifying people with the infection at risk of developing the disease.
Senior author of the paper, Dr Pranabashis Haldar, Clinical Senior Lecturer at the University of Leicester and Consultant in Respiratory Medicine at Leicester's Hospitals, said:
"TB is the leading cause of death from an infectious disease. It most commonly affects the lungs and from this site is transmitted to others by coughing and sneezing. As there is a lack of diagnostic tools for people unable to bring up sputum, diagnosis is delayed, increasing the likelihood that the disease is spread."
Around a quarter of the world's population carry the infection. In the vast majority, this is in the form of latent TB, which does not affect their health, but carries a risk of progressing to the active form of TB in around ten per cent of those infected. The mechanism for this is poorly understood.
Dr Haldar continued: "Our observations provide new insights into how human TB develops and support recent evidence of the existence of a transitional state of TB infection called incipient TB that does not produce symptoms but carries a high risk of progressing to active TB. There is potential for Actiphage to be developed, both as a mainstream blood test to diagnose TB and as a test used in screening programmes to help us identify and treat people with latent infection.
"As a blood test, it is particularly suitable for patients unable to produce sputum, including children, and may help support diagnosis in underserved groups that struggle to access freely available healthcare resources."
The new Actiphage test has been developed by the University of Nottingham in conjunction with the UK's Royal Veterinary College and commercialised by PBD Biotech for major diseases in livestock, primarily as a blood or milk test for bovine TB and Johne's disease. This is the first time the blood test has been trialled in humans.
Unlike many common bacterial infections, detection of the bacteria that cause TB is limited by the fact that Mycobacterium tuberculosis (MTB) is very slow growing, making traditional culture methods inefficient. More rapid molecular tests that detect MTB DNA are limited due to its tough cell wall that makes DNA extraction difficult. The new test uses a specific bacteriophage that infects live MTB and breaks open the cells to release DNA. The whole testing process can be completed in as little 6 hours.
Study co-author Dr Catherine Rees, Associate Professor in Microbiology at the University of Nottingham and Chief Scientific Officer at PBD Biotech, said:
"Actiphage is a novel blood test for mycobacteria that was developed to identify mycobacterial infections in farmed animals, helping farmers to control these difficult diseases.
"The data from our initial study in humans suggest that following infection, MTB is circulating in the blood at levels that were previously undetectable, and that the immune system may be failing to effectively contain the bacteria within the lungs.
"While we are cautious about generalising from a small sample size, we are optimistic that these initial findings indicate that Actiphage can be used as a tool to help us better understand the dynamics of the infection in humans.
"The new Actiphage blood test offers the potential to target those at risk of TB and allow treatment to start early. This is a very exciting development that invites further study."
The paper, 'A novel high-sensitivity bacteriophage-based assay identified low M. tuberculosis bacteraemia in immunocompetent patients with active and incipient TB', can be accessed at Clinical Infectious Diseases academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciz548/5522421?
NOTES FOR EDITORS
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About the NIHR Leicester Biomedical Research Centre
The National Institute for Health Research (NIHR) Leicester Biomedical Research Centre (BRC) is a partnership between University Hospitals of Leicester NHS Trust, the University of Leicester and Loughborough University. It is funded by the National Institute for Health Research (NIHR).
The NIHR Leicester BRC undertakes translational clinical research in priority areas of high disease burden and clinical need. These include cardiovascular disease, respiratory disease, and lifestyle, obesity and physical activity. There is also a cross-cutting theme for precision medicine. The BRC harnesses the power of experimental science to explore and develop ways to help prevent and treat chronic disease. It brings together 70 highly skilled researchers, 30 of which are at the forefront of clinical services delivery. By having scientists working closely with clinicians, the BRC can deliver research that is relevant to patients and the professionals who treat them.
The National Institute for Health Research (NIHR) is the nation's largest funder of health and care research. The NIHR:
- Funds, supports and delivers high quality research that benefits the NHS, public health and social care
- Engages and involves patients, carers and the public in order to improve the reach, quality and impact of research
- Attracts, trains and supports the best researchers to tackle the complex health and care challenges of the future
- Invests in world-class infrastructure and a skilled delivery workforce to translate discoveries into improved treatments and services
- Partners with other public funders, charities and industry to maximise the value of research to patients and the economy
The NIHR was established in 2006 to improve the health and wealth of the nation through research, and is funded by the Department of Health and Social Care. In addition to its national role, the NIHR supports applied health research for the direct and primary benefit of people in low- and middle-income countries, using UK aid from the UK government.
This work uses data provided by patients and collected by the NHS as part of their care and support and would not have been possible without access to this data. The NIHR recognises and values the role of patient data, securely accessed and stored, both in underpinning and leading to improvements in research and care. http://www.nihr.ac.uk/patientdata
About the University of Nottingham
The University of Nottingham is a research-intensive university with a proud heritage, consistently ranked among the world's top 100. Studying at the University of Nottingham is a life-changing experience and we pride ourselves on unlocking the potential of our 44,000 students - Nottingham was named both Sports and International University of the Year in the 2019 Times and Sunday Times Good University Guide, was awarded gold in the TEF 2017 and features in the top 20 of all three major UK rankings. We have a pioneering spirit, expressed in the vision of our founder Sir Jesse Boot, which has seen us lead the way in establishing campuses in China and Malaysia - part of a globally connected network of education, research and industrial engagement. We are ranked eighth for research power in the UK according to REF 2014. We have six beacons of research excellence helping to transform lives and change the world; we are also a major employer and industry partner - locally and globally.
About the University of Leicester
The University of Leicester is led by discovery and innovation - an international centre for excellence renowned for research, teaching and broadening access to higher education. It is among the top 25 universities in the Times Higher Education REF Research Power rankings with 75% of research adjudged to be internationally excellent with wide-ranging impacts on society, health, culture, and the environment. The University is home to just over 20,000 students and approximately 3,000 staff.
On 11 November 2018 (Armistice Day), the University of Leicester marked 100 years since the end of the First World War. This date also marks the beginning of the story to create a university in Leicester as a living memorial to honour those who made sacrifices during the Great War. This is reflected in the University's motto Ut vitam habeant - 'so that they may have life'. The University was founded as Leicester, Leicestershire and Rutland University College in 1921. This short film tells the story of our founding.
Out of this World Research
Research scientists at the University of Leicester have a long and distinguished record of discovery in space science. Every single year since 1967 has seen a Leicester-built instrument operating in space. We hold, and have held, vital roles in many space missions for space agencies including the recent BepiColombo mission to Mercury. The University is a partner in Space Park Leicester - a new hub for the analysis and commercialisation of space-enabled data and space mission development.
PBD Biotech Limited specialises in the use of novel bacteriophage-based technology. The company has developed proprietary, patented technology that can be used to detect the presence of mycobacteria such as Mycobacterium bovis (bovine TB) and Mycobacterium avium subsp.paratuberculosis (MAP; Johne's Disease), which are significant causes of morbidity and loss of productivity in the agricultural industry. In addition, the technology has application as a screening tool for human TB.
Clinical Infectious Diseases