Effects of vitamin D and omega-3 fatty acids on infectious diseases and hCAP18

描述(由申请人提供)：感染是数百万美国老年人发病和死亡的主要原因。新出现的生物学和流行病学数据表明，维生素D补充剂有抗微生物的好处，可能还有海洋欧米茄-3脂肪酸(I-3FA)。然而，在普通人群中没有足够剂量的大型长期预防试验。国际移民组织最近呼吁对维生素D进行更多的研究。我们建议利用NIH资助的一项大型研究-维生素D和omega-3试验(VITAL)-来检查维生素D和I-3FA补充剂对感染的短期和长期影响。我们还将检查维生素D对血浆中人类抗菌素抗菌肽(HCAP18)水平的影响，这是维生素D假定的抗微生物益处的一个潜在机制。VITAL是一项随机、双盲、安慰剂对照的2x2因子试验，有20,000名参与者(男性年龄为60岁；女性为年龄为65岁)。从2011年4月开始，一直持续到2012年7月，受试者将接受为期3个月的磨合，在此期间他们将接受安慰剂。在磨合结束时，那些仍然愿意并符合条件的人，以及那些报告至少服用了三分之二药片的人，将被随机分配到四组中的一组，为期5年：维生素D3(2000IU/d)和鱼油(EPA+DHA，1g/d)；维生素D3和鱼油安慰剂；安慰剂维生素D3和鱼油；以及安慰剂维生素D3和安慰剂鱼油。每隔一年，参与者将收到一份新的药物供应和一份关于依从性、可能的副作用和终点发生率的后续问卷。这项辅助研究的主要目标是解决上呼吸道感染问题，并要求在2012年初及时建立一个亚队列(10%样本，n=2,000)。此URI分组将在2012年2月/3月(基线)、2012年10月/11月和2013年2月/3月(同一季节，一年后)收到特殊邮件。后一封邮件将收集有关最近URI的详细信息(例如，严重程度、病程、治疗)。我们将收集基线和一年后的血液样本，以检测25(OH)D、I-3和hCAP18水平的变化。这些数据将回答几个问题，包括维生素D是否增加hCAP18水平，以及这种变化是否调节了假设的URI减少。二级AIMS将检查几种其他类型的感染(肺炎和流感、尿路感染、皮肤、任何抗菌素治疗的感染、感染相关的住院/败血症)，我们将通过CMS联系进行确认。在每个结果的250个病例的子集中，我们将通过补充问卷进一步确认终点。长期的后续行动将使我们能够解决新出现的担忧，即在早期的有益效果之后，长期补充可能会削弱甚至逆转益处。本研究提出了一种高效和创新的策略来评估补充维生素D和I-3FA在短期和长期预防传染病方面的作用，并测试hCAP18作为一种潜在的机制。这一发现可能会对预防老年人感染产生直接的临床和公共卫生影响。

DESCRIPTION (provided by applicant): Infections are a leading cause of morbidity and mortality for millions of older Americans. Emerging biologic and epidemiologic data suggest antimicrobial benefits from vitamin D supplements, and possibly marine omega-3 fatty acids (I-3 FA). However, large, long-term prevention trials with adequate dosing in general populations are not available. The IOM recently called for more research on vitamin D. We propose to take advantage of a large NIH-funded study - the VITamin D and OmegA-3 TriaL (VITAL) - to examine the short- and long-term effects of vitamin D and I-3 FA supplements on infection. We also will examine the effect of vitamin D on plasma levels of human cathelicidin antimicrobial peptide (hCAP18), a potential mechanism for the hypothesized antimicrobial benefits of vitamin D. VITAL is a randomized, double-blind, placebo-controlled, 2x2 factorial trial with 20,000 participants (men age e60y; women e65y). Starting in April 2011 and continuing through July 2012, subjects will be enrolled in a 3-month run-in, during which they will receive placebos. At the end of the run-in, those who remain willing and eligible, and who report having taken at least two-thirds of pills, will be randomly assigned to one of four groups for 5 years: vitamin D3 (2000 IU/d) and fish oil (EPA+DHA, 1 g/d); vitamin D3 and fish oil placebo; placebo vitamin D3 and fish oil; and placebo vitamin D3 and placebo fish oil. At 1-year intervals, participants will receive a new supply of pills and a follow-up questionnaire on compliance, possible side effects, and incidence of endpoints. Primary aims of this ancillary study will address upper respiratory infections (URIs) and require the timely creation of a subcohort (10% sample, n=2,000) in early 2012. This URI subcohort will receive special mailings in Feb/Mar 2012 (baseline), Oct/Nov 2012, and Feb/Mar 2013 (same season, 1 year later). The latter mailings will collect details about recent URIs (e.g., severity, duration of illness, treatments). We will collect baseline and 1-year follow-up blood specimens to test for changes in 25(OH)D, I-3, and hCAP18 levels. These data will answer several questions, including whether vitamin D increases hCAP18 levels, and whether this change mediates the hypothesized reduction in URIs. Secondary aims will examine several other types of infections (pneumonia & influenza, urinary tract infections, skin, any antimicrobial-treated infection, infection-related hospitalizations/sepsis), which we will confirm by CMS linkage. In a subset of 250 cases of each outcome, we will further confirm endpoints by supplemental questionnaire. Long-term follow-up will allow us to address the emerging concern that an early beneficial effect could be followed by a weakening or even reversal of benefit with prolonged supplementation. The current study presents a highly efficient and innovative strategy to evaluate vitamin D and I-3 FA supplementation for short- and long-term prevention of infectious diseases, and to test hCAP18 as a potential mechanism. The findings may have direct clinical and public health impact for the prevention of infections in older adults.