Predictors of Immunologic Failure in Older Adults

老年人免疫失败的预测因素

基本信息

批准号：
8195966
负责人：
DAVID H CANADAY
金额：
--
依托单位：
LOUIS STOKES CLEVELAND VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-10-01 至 2012-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8195966
关键词：
Accounting Address Adult Age Aged, 80 and over Aging Algorithms Antibodies Antibody Formation Antigen-Presenting Cells B-Lymphocytes Biological Markers Body Weight decreased Categories Cessation of life Clinical Clinical Trials Communities Comorbidity Country Data Set Defect Elderly Enrollment Europe Failure Functional disorder Geriatrics Immune Immune System Diseases Immune system Immunologic Tests Immunologics Incidence Individual Infection Influenza Influenza vaccination Long-Term Care Measures Mediating Modeling Morbidity - disease rate Mortality Decline Patients Performance Phenotype Pneumonia Population Prevalence Prophylactic treatment Research Personnel Risk Schedule Speed Syndrome System T-Lymphocyte Testing Vaccinated Vaccination Vaccines Validation Veterans Walking age group aged base disability exhaustion frailty immune function indexing influenza outbreak influenza virus vaccine instrument mortality novel vaccines protective efficacy public health relevance response stressor success tool

项目摘要

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.

描述（由申请人提供）：从历史上看，脆弱的一词与多人，残疾和极端年龄相互交换。在过去的十年中，老年研究人员已经开发，完善和验证了一个脆弱的概念。这是一种综合征，其核心涉及对压力源脆弱性的临床状态，认为这是由于“多系统失调”。测量脆弱指数的标准包括：无意的体重减轻，精疲力尽，强度损失，步行速度缓慢和活动水平较低。脆弱的指数是一种经过验证的工具，将老年人分为三个定义的类别：健壮（健康），预告和脆弱。在美国和欧洲，脆弱，死亡率增加和其他绩效措施的下降之间存在明显的联系。脆弱是在社区住宅的老年人中的常见状况，在65岁的年龄较高的人中为7-10％，在80岁以上的个人中25％，长期护理设施中的个体甚至更高。弗里尔蒂是健壮和虚弱之间的中间类别，并预测了脆弱的进步。弗雷尔蒂的发生率甚至比脆弱更为普遍。当前对老年人免疫系统的理解水平几乎完全基于年龄。很少有免疫学研究解决了免疫功能障碍与脆弱之间的任何关系。老年人，尤其是具有更大的虚弱性和脆弱性的年龄较大的人，在很大程度上被排除在临床试验之外，并且被大量研究了。已经确定，增加的年龄会导致免疫功能障碍和对疫苗接种的反应不佳。脆弱和年龄预测老年人的免疫学和疫苗接种失败的总体假设。但是，脆弱的预测因素将比免疫学和疫苗接种失败的年龄更强。该假设将以以下特定目的解决：目的1。确定老年人脆弱和免疫功能障碍之间的关系。假设是，某些免疫缺陷将与年龄更大的脆弱相关。为了检验这一假设，将使用一组已建立的免疫学检测，以测量具有脆弱指数衡量的强大（健康），预拖网和脆弱的老年人中T细胞的功能，抗原呈递细胞（APC）和B细胞的功能。受试者将在65-74、75-84岁和85年以上的年龄组中招募，以直接比较脆弱和年龄之间免疫功能的特定方面。免疫学面板中的研究将集中在T细胞，APC和B细胞表型和功能上，这对于成功的疫苗反应至关重要。我们预测，T细胞室将证明具有脆弱和年龄的最大功能障碍。目的2。确定老年人脆弱状态与流感疫苗不良反应之间的关系。我们假设疫苗衰竭与脆弱和年龄密切相关。为了检验这一假设，我们将在AIM 1中接种相同的脆弱和年龄匹配的受试者，并在4-12周后与三价灭活流感疫苗并测量抗体反应。目的3。确定哪种特定的免疫功能障碍介导了脆弱和不良流感疫苗反应之间的关系。观察到的特定免疫缺陷（AIM 1）将在疫苗接种导致的降低的流感特异性抗体滴度（AIM 2）中确定，将在年龄的脆弱组中确定。考虑到脆弱和年龄的影响，我们将确定哪些免疫功能最有可能是疫苗反应不良的机制。目的4。开发一种临床算法，以根据脆弱和年龄类别来预测流感疫苗接种的功效。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，以预测流感疫苗的成功和失败。该工具可以在临床上指导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人口非常重要。 VA系统中有39％的患者占39％的退伍军人超过65岁以上。在联合国> 65岁的成年人中，大约90％的与流感相关的死亡发生。尽管有激进的疫苗接种运动，但老年人的流感死亡风险仍增加。在有或没有脆弱的老年人中，对保护性疫苗接种的特定生物标志物的鉴定和验证以及保护效力估计的算法可以帮助确定谁在疫苗暴发的情况下可能需要采取其他保护措施。需要开发新的疫苗和/或管理时间表来量身定制衰老免疫系统的需求。为了实现这一目标，有必要增加对老年退伍军人的免疫功能障碍的了解，以确定必须克服哪些特定缺陷。