Trial of vitamin D supplementation to prevent acquisition of latent tuberculosis infection in schoolchildren

1)研究背景结核病每年夺去150万人的生命。南非是世界上结核病发病率最高的国家之一：每年有1%的人口患结核病。世界卫生组织的目标是到2050年消灭结核病。结核通常发生在结核细菌的休眠感染（称为“潜伏结核感染”）变得活跃时。LTBI通常在儿童时期由传染性活动性结核病患者咳嗽吸入结核细菌后获得。到他们成年时，大约80%的南非人将获得LTBI。在这些人中，10-20%的LTBI将在其一生中重新激活并引起活动性结核病。因此，首先防止人们——尤其是儿童——获得LTBI可以减少继续发展为活动性结核病的人数。然而，目前结核病控制的传统方法侧重于发现和治疗传染性活动性结核病患者，以打破传播循环。这一战略不会在结核病非常普遍的国家消除结核病，因为许多LTBI患者将继续出现新的活动性结核病病例。现有的结核病疫苗卡介苗已经被证明在非洲对结核病提供了非常有限的保护——如果有的话——而且最近对一种新疫苗的试验结果令人失望。因此，如果要实现2050年消除疟疾的目标，就需要采取新的战略来保护儿童免于罹患LTBI。我们提出补充维生素D——阳光维生素——可以增强对结核菌的免疫力，从而预防暴露于传染性结核病的儿童的LTBI。长期以来，人们一直认为维生素D可以增强对结核病细菌的免疫力。在发现抗生素之前，鳕鱼肝油（富含维生素D）和日光浴（提高维生素D水平）都被用来治疗结核病。实验室实验表明，维生素D有助于白细胞杀死结核细菌。对患者的研究表明，那些维生素D水平较低的人在接触传染性结核病病例后更容易获得LTBI。此外，最近在蒙古120名学童中进行的一项临床试验表明，补充维生素D可使LTBI的风险降低59%。虽然有希望，但这项研究规模很小，在维生素D被推荐用于预防结核病之前，还需要进行更大规模的试验。2)目的和目标本研究的主要目的是确定在结核病非常普遍的地区，每周口服维生素D补充剂3年是否可以降低学童获得LTBI的风险。我们将通过在开普敦周围乡镇的5400名小学生中进行临床试验来实现这一目标，我们之前已经表明，88%的人维生素D水平低。参与者将在基线时进行LTBI的血液测试：测试结果为阴性的人将被随机分配每周服用维生素D或安慰剂（具有相同味道和外观的虚拟药物）。研究人员将在3年内每周访问儿童，给予研究药物剂量并检查结核病症状。在研究结束时，将比较服用维生素D和安慰剂的儿童的LTBI率。3)潜在的应用和益处：如果结果是积极的，维生素D可用于预防儿童LTBI。全球有10亿人缺乏维生素D，估计有20亿人患有LTBI：因此，我们的研究结果可能具有全球重要性。有几个群体可以从这项研究中受益。面临结核病风险的维生素D缺乏症患者将受益于发现一种廉价、安全的降低结核病风险的方法。结核控制界将受益于结核控制新工具的发现。结核病研究人员将受益于关于维生素d作用的新的科学见解。研究参与者将受益，因为他们将得到本来不会得到的结核病筛查。

1) Context of the researchTuberculosis (TB) kills 1.5 million people each year. South Africa has one of the TB rates in the world: 1% of the population develops TB each year. The World Health Organisation aims to eliminate TB by 2050.TB usually arises when a dormant infection with TB bacteria, termed 'latent TB infection' (LTBI) becomes active. LTBI is usually acquired in childhood following inhalation of TB bacteria coughed up by a person with infectious active TB. By the time they reach adulthood, approximately 80% of people in South Africa will have acquired LTBI. In 10-20% of these people, LTBI will reactivate to cause active TB disease in their lifetime. Preventing people - especially children - from acquiring LTBI in the first place could therefore reduce the number of people who go on to develop active TB. Currently, however, conventional approaches to TB control focus instead on finding and treating people with infectious active TB in order to break the cycle of transmission. This strategy will not eliminate TB in countries where it is very common because new cases of active TB will continue to arise from the many people who have LTBI. The existing TB vaccine, BCG, has been shown to offer very limited protection against TB in Africa - if any - and a recent trial of a new vaccine had disappointing results. New strategies to protect children from acquiring LTBI will therefore be needed if the 2050 elimination target is to be met.We propose that supplementation with vitamin D - the sunshine vitamin - could boost immunity to TB bacteria, and thereby prevent LTBI in children exposed to infectious TB. Vitamin D has long been recognised to boost immunity to TB bacteria. Before the discovery of antibiotics, cod liver oil (rich in vitamin D) and sunbathing (which boosts vitamin D levels) were both used to treat TB. Laboratory experiments show that vitamin D helps white blood cells to kill TB bacteria. Studies in patients show that those with lower vitamin D levels are more susceptible to acquiring LTBI after exposure to an infectious TB case. Moreover, a recent clinical trial in 120 schoolchildren in Mongolia showed that vitamin D supplementation reduced risk of acquiring LTBI by 59%. Although promising, this study was small, and a much larger trial is needed before vitamin D can be recommended for TB prevention.2) Aims and objectivesThe primary aim of this research is to determine whether a weekly vitamin D supplement, taken by mouth for 3 years, can reduce the risk of acquiring LTBI among schoolchildren in an area where TB is very common. We will achieve this by conducting a clinical trial in 5,400 primary schoolchildren in townships around Cape Town, where we have previously shown that 88% of people have low vitamin D levels. Participants will have a blood test for LTBI at baseline: those who test negative will be allocated to receive weekly doses of vitamin D or placebo (dummy medication with identical taste and appearance) at random. Study staff will visit children weekly for 3 years to give doses of study medication and check for TB symptoms. At the end of the study, rates of LTBI will be compared between children who received vitamin D vs placebo.3) Potential applications and benefitsIf results are positive, vitamin D could be used to prevent LTBI in children. Vitamin D deficiency affects 1 billion people worldwide, and 2 billion are estimated to have LTBI: results of our study could therefore have global importance.Several groups could benefit from the study. Vitamin D deficient people at risk of TB would benefit from the discovery of a cheap, safe method of reducing their TB risk. The TB control community would benefit from the discovery of a new tool for TB control. TB researchers would benefit from new scientific insights into the effects of vitamin D. Study participants will benefit, as they will receive screening for TB which they would not otherwise have had.