Correlates of risk in children exposed to multidrug-resistant tuberculosis

每年约有1000万人患结核病，其中许多人与孩子住在一所房子里。如果儿童吸入结核菌，他们就有可能感染结核病。这意味着结核病细菌生活在他们的体内，但不会引起任何问题。全球约有6000万儿童感染结核病。每年大约有100万名儿童的结核病细菌战胜了免疫系统，导致儿童患病。这就是所谓的结核病。在患结核病的儿童中，四分之一死亡。这使得结核病成为全世界儿童死亡的最大原因之一。如果你给感染结核病的儿童服用药物，就会减少他们患结核病的机会。然而，你必须治疗大量的儿童，以防止每一个结核病病例。在世界上大多数地方，即使提供这种预防药物是政策，也没有提供。如果有可能确定哪些儿童在家中暴露于结核病后患结核病的风险最高，那么你就可以更有选择性地给他们药物。了解儿童在接受结核感染治疗时免疫系统发生了什么变化也是有用的，因为这可能有助于做出有关临床护理的决定以及新治疗方法的研究。最后，我们知道一种叫做巨细胞病毒（CMV）的病毒会打开儿童免疫系统的某些部分。这些部分与结核病的发展有关。巨细胞病毒是一种非常常见的病毒，因此，了解巨细胞病毒是否会增加患结核病的风险非常重要。有没有可能从接触过结核病患者的儿童的血液样本中预测他们自己是否有患结核病的高风险？2.是否有可能通过血液检测来确定结核病感染儿童在接受治疗时免疫系统的变化？3. CMV感染是否会开启与结核病发展相关的免疫系统部分？4. CMV感染是否会增加您接触结核病患者后感染结核病的风险？建议的研究虽然我们知道如何治疗结核病感染的儿童，如果他们已经暴露于正常的结核病，我们不知道该怎么办，如果他们已经暴露于耐药结核病。已经资助了一项临床试验（称为TB-CHAMP），计划回答这个问题。TB-CHAMP将从南非的四个地点招募1500名儿童，这些儿童曾接触过耐药结核病，并将他们随机分配到每天接受一种名为左氧氟沙星的抗生素，为期六个月，或安慰剂（非活性的模拟药物）。这项试验提供了一个惊人的和独特的机会，研究发生在儿童暴露后，谁没有得到治疗。由于我们知道如何治疗接触正常结核病的儿童，因此在没有治疗的情况下仔细监测其中一组儿童是不合适的。作为试验的一部分，所有儿童都将定期进行血液检查。在这次奖学金中，我计划通过实验室和数据分析来使用这些血液样本来回答上述问题。谁参与了这项研究大部分工作将由我在南非完成，并得到斯泰伦博斯大学南非专家的定期支持和合作。然而，我也将受益于与伦敦的临床和基础科学家的合作，他们将提供建议，投入和培训。潜在的好处如果有可能通过血液检测来确定哪些儿童在接触结核病患者后患病的风险最大，这可能会极大地改变我们管理接触结核病的儿童的方式，并可能减少因结核病而不适的人数。

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.