Correlates of risk in children exposed to multidrug-resistant tuberculosis

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BACKGROUNDAbout ten million people become ill with TB each year and many of these people live in a house with children. If a child breathes in TB bacteria there is a chance that they will develop TB infection. This means that the TB bacteria are living in their body but not causing any problems. Roughly sixty million children globally have TB infection. Each year, in about a million of these children, the TB bacteria overcome the immune system and cause the child to become sick. This is then called TB disease. Of the children who get TB disease, a quarter die. This makes TB one of the greatest causes of death in children worldwide. If you give a medication to children who have TB infection it reduces their chance of developing TB disease. However, you would have to treat a large number of children to prevent each case of TB disease. In most places in the world, even though it is the policy to give this preventive medicine, it is not given. If it were possible to identify which children were at the highest risk of developing TB disease after being exposed to TB in their house, then you could be more selective and give the medications just to them. It would also be useful to find out what happened to the immune system of children when they are given TB infection treatment, as this might help both to make decisions about clinical care as well as for studies of new treatments. Finally, we know that a virus called cytomegalovirus (or CMV), switches on certain parts of the immune system in children. These parts have been associated with the development of TB disease. CMV is a very common virus and it will be important to find out whether having CMV increases the risk of developing TB infection and disease.RESEARCH QUESTIONS1. Is it possible to predict, from a blood sample taken from a child soon after they have been exposed to someone with TB, whether they are at high risk of developing TB disease themselves? 2. Is it possible to identify, from a blood test, a change in the immune system in children with TB infection when they are treated?3. Does CMV infection switch on parts of the immune system that are associated with the development of TB disease? 4. Does CMV infection increase the risk of getting TB infection and disease after you have been exposed to someone with TB disease?PROPOSED RESEARCHAlthough we know how to treat children with TB infection if they have been exposed to normal TB, we do not know what to do if they have been exposed to drug-resistant TB. A clinical trial has already been funded (called TB-CHAMP) that plans to answer this. TB-CHAMP will recruit 1500 children, from four sites in South Africa, who have been exposed to drug-resistant TB and randomise them to receive either an antibiotic called levofloxacin each day for six months or a placebo (inactive, dummy drug). This trial provides an amazing and unique opportunity to study what happens to children following exposure, who are not given treatment. As we know how to treat children exposed to normal TB, it would not be appropriate to monitor a group of them carefully without treatment. As part of the trial all children will have regular blood tests taken. In this Fellowship, I plan to use these blood samples to answer the questions above by doing laboratory and data analysis. WHO IS INVOLVED IN THE RESEARCHThe majority of the work will be done by myself in South Africa with regular support and collaboration from South African experts at Stellenbosch University. However, I will also benefit from collaborating with clinical and basic scientists in London who will provide advice, input and training. POTENTIAL BENEFITSIf it were possible from a blood test to identify which children were at the greatest risk of getting sick, after they have been exposed to someone with TB, this could dramatically change how we manage children who have been exposed to TB and might reduce the number who become unwell with TB disease.