Evaluation of a novel microbiological diagnostic test for latent tuberculosis infection in Ethiopia (Micro-LTBI)

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Tuberculosis (TB) is a bacterial infectious disease. It causes 1.5 million deaths each year, 95% of which occur in low- and middle-income countries (LMICs). The disease particularly affects young adults, with adverse consequences for economic growth. In many LMICs, this problem is compounded by the problem of TB in cattle (bovine TB). This 'double-hit' is a particular problem in Ethiopia, which has the tenth highest burden of human TB in the world: bovine TB is widespread (prevalence 5-30%) and the country's economy is highly dependent on cattle farming. Improved TB control in humans and cattle would significantly enhance economic growth and welfare in Ethiopia and other similarly-burdened LMICs.Most TB cases in humans arise when a dormant TB infection re-activates to cause disease. Dormant TB infection is very common in LMICs and this pool of infection will need to be treated if TB is ever going to be eliminated. Antibiotic treatment for dormant TB infection is effective, but roll-out of this treatment is limited by the lack of an accurate 'gold standard' diagnostic test for the condition. Existing tests for dormant TB infection rely on detecting an immune response to the bacteria, rather than detecting the bacteria itself. However, less than 10% of those with a positive immune test ever go on to develop active TB. This makes it difficult to target antibiotic treatment for dormant TB infection at the people who will benefit from it.This situation could be about to change: very recently, a team of researchers in Germany (one of whom is a co-applicant on this grant) has reported that they have been able to detect TB bacteria in the blood of people with dormant TB infection. The number of bacteria is very small, and quite a large amount of blood (100 ml) is needed in order to detect them reliably. This remarkable finding has been made in just seven people living in Europe. The next step is to run the new test in a larger group of people who live in a country where TB is widespread. To take this idea forward, we have forged a new collaboration between Ethiopian and British scientists who together have the exact combination of clinical and technical skills needed to evaluate this new test.We will carry out the following studies. First, we will recruit 200 healthy people who have recently been in contact with an infectious case of TB ('TB contacts') - 100 urban residents of Addis Ababa who have been exposed to a person with infectious lung TB living in their home, and 100 rural cattle herders who have been exposed to a cow suffering from bovine TB. We will run the new blood test in these TB contacts, and, where we find dormant TB bacteria in the blood stream, we will do genetic fingerprinting to see if the dormant bacteria found in the bloodstream are identical to those isolated from the case of infectious TB (human or bovine) to which they were exposed. If the genetic fingerprints of the TB bacteria are the same, this will suggest that detection of TB bacteria in the blood of people with dormant TB infection is very unlikely to be a 'chance finding'.We will also recruit 40 people who are about to start antibiotic treatment for dormant TB infection, and run the new test before and after treatment. If we find that the antibiotic treatment clears dormant TB bacteria from the blood stream, this would suggest an additional potential application for the new test: monitoring response to antibiotic treatment of dormant TB infection. This is important, because existing tests cannot tell if antibiotic treatment for dormant TB infection has been effective or not.Taken together, these studies will give us a clear idea as to whether the findings of the German team can be reproduced in a LMIC setting. If so, then we will apply for further funding to optimise the test to use smaller blood volumes, and conduct definitive studies to evaluate whether it could be integrated into existing TB control programmes in LMICs.