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

1)结核病（TB）每年导致150万人死亡。印度是世界上结核病病例最多的国家，仅2011年就有220万例。世界卫生组织的目标是到2050年消除结核病。结核病通常是在结核病细菌的潜伏感染（称为“潜伏结核病感染”）变得活跃时出现的。LTBI通常在儿童时期吸入感染性活动性结核病患者咳出的结核菌后获得。当他们成年时，大约80%的印度人将获得LTBI。在这些人中，10-20%的LTBI将在其一生中重新激活，导致活动性结核病。因此，首先防止人们-特别是儿童-获得LTBI可以大大减少继续发展为活动性结核病的人数。然而，目前控制结核病的传统方法侧重于发现和治疗感染性活动性结核病患者，以打破传播周期。这一战略不会在结核病非常普遍的国家消除结核病，因为新的活动性结核病病例将继续从许多LTBI患者中出现。现有的结核病疫苗BCG不能预防LTBI，最近一项新疫苗的试验结果令人失望。因此，如果要实现2050年消除目标，就需要采取新的战略来保护儿童免受LTBI的影响。我们建议补充维生素D -阳光维生素-可以提高对结核菌的免疫力，从而预防暴露于传染性结核病的儿童的LTBI。长期以来，维生素D被认为可以增强对结核菌的免疫力。在发现抗生素之前，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有助于白色血细胞杀死结核菌。对患者的研究表明，维生素D水平较低的患者在接触传染性结核病病例后更容易获得LTBI。此外，最近在蒙古的120名学童中进行的一项临床试验表明，补充维生素D可将获得LTBI的风险降低59%。虽然有希望，这项研究是小的，和一个更大的试验之前，维生素D可以被推荐用于结核病预防。2）目的和目标这项研究的主要目的是确定是否每月口服维生素D补充剂，3年，可以降低结核病非常常见的地区的学童获得LTBI的风险。我们将通过在新德里的6,750名小学生中进行临床试验来实现这一目标。尽管阳光充足，但新德里85%的学童缺乏维生素D，这可能是空气污染阻挡阳光的结果。参与者将在基线时进行LTBI的血液测试：测试阴性的人将被随机分配接受36个月剂量的维生素D或安慰剂（具有相同味道和外观的模拟药物）。研究工作人员将在3年内每月访问儿童，给予研究药物剂量并检查结核病症状。在研究结束时，将比较接受维生素D与安慰剂的儿童的LTBI发生率。3）潜在的应用和益处如果结果是积极的，维生素D可以用来预防儿童的LTBI。维生素D缺乏症影响着全球10亿人，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。维生素D缺乏的人在结核病的风险将受益于发现一种廉价，安全的方法，以减少他们的结核病风险。结核病控制界将从发现结核病控制的新工具中受益。结核病研究人员将受益于对维生素D影响的新科学见解。研究参与者将受益，因为他们将接受结核病筛查，否则他们不会有。

1) Context of the researchTuberculosis (TB) kills 1.5 million people each year. India has the highest number of TB cases in the world - some 2.2 million in 2011 alone. 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 India 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 dramatically 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, does not prevent LTBI, 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 monthly 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 6,750 primary schoolchildren in New Delhi. Despite plentiful sunshine, vitamin D deficiency is present in 85% of schoolchildren in New Delhi, possibly as a result of air pollution which blocks out sunshine. Participants will have a blood test for LTBI at baseline: those who test negative will be allocated to receive 36 monthly doses of vitamin D or placebo (dummy medication with identical taste and appearance) at random. Study staff will visit children monthly 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.