Predictors of Immunologic Failure in Older Adults

描述(由申请人提供)： 从历史上看，虚弱一词曾与共同发病、残疾和极端老年互换。在过去的十年里，老年病学研究人员开发、完善和验证了脆弱的概念。这是一种综合症，其核心是临床状态对应激源的脆弱性，人们认为这是由于“多系统失调”造成的。衡量脆弱指数的标准包括：无意中体重减轻、精疲力竭、力量丧失、步行速度慢和活动水平低。虚弱指数是一种经过验证的工具，它将老年人分为三个定义的类别：健壮(健康)、体弱前弱和虚弱。在美国和欧洲的几个民族中，虚弱、死亡率上升和其他表现指标的下降之间存在明显的联系。在社区居住的老年人中，虚弱是一种常见的情况，65岁老年人的患病率为7%-10%，80岁以上老年人的患病率为25%，长期护理机构中老年人的患病率甚至更高。先天脆弱是介于强健和脆弱之间的一个中间类别，它预示着向脆弱发展。先天虚弱的发生率甚至比虚弱更常见。目前对老年人免疫系统的了解几乎完全基于年龄。很少有免疫学研究探讨免疫功能障碍与虚弱之间的关系。老年人，特别是那些虚弱程度更高的人，在很大程度上被排除在临床试验之外，而且研究严重不足。现已证实，年龄增长既会导致免疫功能障碍，也会导致对疫苗的不良反应。认为虚弱和年龄可以预测老年人免疫和疫苗接种失败的总体假设。然而，与免疫和疫苗接种失败的年龄相比，虚弱将是一个更强的预测因子。这一假说的具体目的如下：目的1.确定老年人的虚弱与免疫功能障碍之间的关系。这个假设是，某些免疫缺陷与虚弱的关系比与年龄更密切。为了验证这一假设，将使用一组已建立的免疫学测试来衡量老年人中T细胞、抗原提呈细胞(APC)和B细胞的功能，这些细胞是健壮的(健康的)、前期虚弱的和脆弱的，通过脆弱指数来衡量。受试者将被登记在65-74岁、75-84岁和85岁以上的年龄组，以便直接比较虚弱和年龄之间免疫功能的特定方面。免疫学小组的研究将集中在T细胞、APC和B细胞的表型和功能上，这些表型和功能对疫苗的成功反应至关重要。我们预测，随着衰老和衰弱的增加，T细胞室将表现出最大的功能障碍。目的2.确定老年人的虚弱状况与流感疫苗反应差之间的关系。我们假设疫苗的失败与脆弱和年龄密切相关。为了验证这一假设，我们将在目标1中为同样虚弱和年龄匹配的受试者接种三价灭活流感疫苗，并在4-12周后测量抗体反应。目的3.确定哪种特异性免疫功能障碍(S)在流感疫苗弱反应和不良反应之间的关系中起中介作用。观察到的特定免疫缺陷(目标1)将在以年龄为协变量的脆弱组中确定，这些缺陷介导了疫苗接种(目标2)导致的流感特异性抗体滴度下降。考虑到虚弱和年龄的影响，我们将确定哪些免疫功能最有可能是疫苗反应差的机制(S)。目的4.建立一种基于脆弱程度和年龄的流感疫苗接种效果预测的临床算法。我们将使用3个脆弱类别和3个年龄组来开发一种临床上有用的算法来预测流感疫苗的成败。该工具可指导临床预防和替代保护策略的使用。 公共卫生相关性： 拟议的研究对退伍军人群体具有非常重要的意义。退伍军人超过900万人，占退伍军人制度患者的39%，年龄在65岁或以上。在美国，大约90%与流感相关的死亡发生在65岁的成年人中。尽管开展了积极的疫苗接种运动，但老年人死于流感的风险仍在增加。在有或没有虚弱的老年人中确定和验证保护性疫苗的特定生物标记物，以及估计保护效力的算法，可以帮助确定谁可能需要在流感暴发背景下采取额外的保护措施。需要开发新的疫苗和/或给药时间表，以适应老化的免疫系统的需要。为了实现这一目标，有必要对老年退伍军人的免疫功能障碍有更多的了解，以确定哪些具体缺陷必须克服。

DESCRIPTION (provided by applicant): Historically the term frailty has been interchanged with co-morbidity, disability, and extreme old age. In the last decade Geriatrics researchers have developed, refined, and validated a concept of frailty. It is a syndrome that at its core involves a clinical state of vulnerability to stressors thought to be due to "multisystem dysregulation". The criteria of measuring a Frailty Index include: unintentional weight loss, exhaustion, loss of strength, slow walking speed, and low level of activity. The Frailty Index is a validated instrument that classifies older adults into three defined categories: robust (healthy), pre-frail, and frail. There is a clear association between frailty, increased mortality, and declines in other performance measures in several ethnic populations in the U.S. and Europe. Frailty is a common condition in community dwelling elderly adults with a prevalence 7-10 % among those age 65, 25% in individuals over age 80, and even higher in individuals in long-term care facilities. Pre-frailty is an intermediate category between robust and frail, and predicts progress to frailty. The incidence of pre-frailty is even more common than frailty. The current level of understanding of the immune system in older individuals is based almost exclusively on age. There have been very few immunologic studies that have addressed any relationship between immunologic dysfunction and frailty. Older individuals, especially ones with greater debility and frailty, are largely excluded from clinical trials and are significantly understudied. It has been established that increasing age leads to both immunologic dysfunction and poor responses to vaccination. The overall hypothesis that frailty and age predict immunologic and vaccination failure in older adults. However, frailty will be a stronger predictor than age of immunologic and vaccination failure. This hypothesis will be addressed with the following specific Aims: Aim 1. To determine the relationship between frailty and immunologic dysfunction in older adults. The hypothesis is that certain immune defects will be more strongly associated with frailty than age. To test this hypothesis, a panel of established immunologic tests to measure the function of T cells, antigen presenting cells (APC), and B cells in older adults that are robust (healthy), pre-frail, and frail as measured by a Frailty Index will be used. Subjects will be enrolled in the age groups of 65-74, 75-84 and over 85 years to allow a direct comparison of specific aspects of immunologic function between frailty and age. The studies in the immunologic panel will focus on T cell, APC, and B cell phenotypes and functions that are critical for a successful vaccine response. We predict that the T cell compartment will demonstrate the greatest dysfunction with advancing frailty and age. Aim 2. To determine the relationship between frailty status and poor influenza vaccine response in older adults. We hypothesize that vaccine failure correlates closely with frailty as well as age. To test this hypothesis, we will vaccinate the same frailty and age matched subjects in Aim 1 with trivalent inactivated influenza vaccine and measure antibody responses after 4-12 weeks. Aim 3. To determine which specific immunologic dysfunction(s) mediate the relationship between frailty and poor influenza vaccine responses. The specific immune defects observed (Aim 1) that mediate the reduced influenza-specific antibody titers that result from vaccination (Aim 2) will be determined in the frailty groups with age as a covariable. Taking into account the influence of frailty and age, we will determine which immune functions most likely are the mechanism(s) of the poor vaccine response. Aim 4. To develop a clinical algorithm to predict the efficacy of influenza vaccination based on categories of frailty and age. We will use the 3 frailty categories and 3 age groups to develop a clinically useful algorithm to predict influenza vaccine success and failure. This tool could guide use of prophylaxis and alternative protective strategies clinically. PUBLIC HEALTH RELEVANCE: The proposed studies are highly significant to the Veteran population. Over 9 million veterans comprising of 39% of patients in the VA system are 65 or older. Around 90% of influenza-related deaths occurred among adults aged >65 years in the United Sates. The risk of mortality due to influenza is increased in older individuals in spite of an aggressive vaccination campaign. Identification and validation of specific biomarkers of protective vaccination in older adults with and without frailty and the algorithm of estimation of protective efficacy could help determine who might require additional protective measures in the setting of an influenza outbreak. New vaccines and/or administration schedules need to be developed to tailor to the needs of the aging immune system. In order to achieve this, it is necessary to have an increased understanding of the immune dysfunction in older veterans to identify what specific defects must be overcome.