Correlates of risk in children exposed to multidrug-resistant tuberculosis

背景每年大约有1000万人患结核病，其中许多人与孩子住在一起。如果儿童吸入结核细菌，他们就有可能患上结核感染。这意味着结核杆菌生活在他们的体内，但不会造成任何问题。全球大约有6000万儿童感染了结核病。每年，在大约100万这些儿童中，结核病细菌会战胜免疫系统，导致儿童生病。这被称为结核病。在感染结核病的儿童中，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。如果你给患有结核病的儿童服用药物，就会降低他们患结核病的几率。然而，你必须治疗大量的儿童来预防每一个结核病病例。在世界上大多数地方，尽管政策规定提供这种预防药物，但却没有提供。如果有可能确定哪些儿童在家里接触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只给他们用药。发现儿童在接受结核病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关于临床护理的决定，也有助于研究新的治疗方法。最后，我们知道一种叫做巨细胞病毒（或CMV）的病毒，会开启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，弄清楚患有巨细胞病毒是否会增加患结核病感染和疾病的风险是很重要的。研究QUESTIONS1。是否有可能从儿童接触结核病患者后不久采集的血液样本中预测他们自己是否有患结核病的高风险？2. 是否有可能通过验血来确定结核感染儿童在接受治疗时免疫系统的变化？巨细胞病毒感染是否开启了与结核病发展相关的免疫系统部分？4. 与结核病患者接触后，巨细胞病毒感染是否会增加结核病感染和疾病的风险？拟议的研究尽管我们知道如何治疗感染结核病的儿童，如果他们暴露于正常的结核病，我们不知道如果他们暴露于耐药结核病该怎么办。一项名为TB-CHAMP的临床试验已经得到资助，计划回答这个问题。TB- champ将从南非的四个地点招募1500名接触过耐药结核病的儿童，并随机分配他们接受一种名为左氧氟沙星的抗生素，每天服用6个月，或者服用安慰剂（无活性的假药）。这项试验提供了一个惊人而独特的机会来研究暴露后没有接受治疗的儿童会发生什么。由于我们知道如何治疗暴露于正常结核病的儿童，因此不适当地对其中一组儿童进行仔细监测而不进行治疗。作为试验的一部分，所有儿童将定期接受血液检查。在这个项目中，我打算利用这些血液样本，通过实验室和数据分析来回答上述问题。世卫组织参与研究大部分工作将由我在南非完成，并得到南非斯坦伦博斯大学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查确定哪些儿童在接触过结核病患者后患病风险最大，这可能会极大地改变我们对接触过结核病的儿童的管理方式，并可能减少因结核病而患病的人数。

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.