Urine antimicrobial proteins in older adults: aging, infection, & innate immunity

 描述（由申请人提供）：尿路感染（UTI）是老年人最常见的细菌感染。每年在美国，UTI负责100，000次住院治疗和超过35亿美元的费用。老年人的UTI与高发病率和死亡率相关。老年人的诊断是具有挑战性的，因为典型症状不存在，非典型表现常见，诊断测试准确性差。我们将通过研究泌尿道的先天免疫反应来提高老年人泌尿道感染的诊断和治疗。 先天免疫系统是老年人对UTI的易感性和应答的关键介质。然而，尿路先天免疫对衰老的反应的具体变化尚未得到严格的研究。抗菌蛋白（肽）（AMP）是尿天然免疫的关键效应物。老年人的基线水平未知，但可能与年轻人不同。按年龄确定基线尿AMP水平对于了解老年人对UTI的易感性和反应是必要的。 初步数据表明，几种尿AMP，包括人中性粒细胞肽1-3（HNP 1- 3），α-防御素5（HD 5），人β防御素-2（hBD-2）和凯萨林菌素（LL-37）可以识别老年人的UTI。这可能导致更准确的UTI诊断，改善临床结果。 作为新的生物标志物，AMP需要作为UTI的独立预测因子以及与当前测试结合进行研究。为了应对老年人诊断困难的挑战，一种方法是建立一个诊断预测模型，结合当前的测试和AMP，以提高老年艾德患者的准确诊断。目前，在老年人中还没有这样的UTI模型。通过创建这样一个模型，我们将确定AMP作为独立测试的准确性及其对更复杂模型的贡献，为该人群确定最准确的诊断方法。 该提案的长期目标是利用先天免疫系统，特别是AMP，来改善老年人UTI的识别，诊断和最终治疗。 具体目标1：测量与衰老相关的基线尿AMP水平的变化，并为未感染的老年队列创建AMP的正态分布参数。 具体目标二：确定尿AMP水平在区分急性UTI、ASB和无感染的老年急诊科疑似UTI患者中的诊断准确性，并建立老年艾德成人UTI的诊断预测模型。目标1是一项横断面研究，测量门诊就诊的无急性疾病的成人（50% ≥65岁）的AMP水平。目标2将招募年龄≥65岁的疑似UTI艾德患者的前瞻性队列，并确定AMP的诊断准确性。该提案将促进对老年人群先天免疫的理解，并通过提高诊断准确性来改善老年人的护理。

 DESCRIPTION (provided by applicant): Urinary tract infection (UTI) is the most common bacterial infection in older adults. Annually in the US, UTIs are responsible for 100,000 hospitalizations and costs of over $3.5 billion. UTI in older adults is associated with high rates f morbidity and mortality. Diagnosis in older adults is challenging as classic symptoms are absent, atypical presentations common, and diagnostic test accuracy poor. We will improve diagnosis and management of UTI in older adults by studying the innate immune response of the urinary tract. The innate immune system is a key mediator of both susceptibility to and response to UTI in older adults. However, specific changes in urinary tract innate immunity in response to aging have not been rigorously studied. Antimicrobial proteins (peptides) (AMPs) are key effectors of urinary innate immunity. Baseline levels in older adults are unknown, but likely differ from younger adults. Identifying baseline urinary AMP levels by age is necessary to understand susceptibility to and response to UTI in older adults. Preliminary data indicates that several urinary AMPs, including human neutrophil peptide 1-3 (HNP 1- 3), alpha-defensin 5 (HD5), human beta defensin-2 (hBD-2), and cathelicidin (LL-37) can identify UTI in older adults. This could lead to more accurate UTI diagnosis with improvements in clinical outcome. As new biomarkers, AMPs require study both as stand-alone predictors of UTI and in conjunction with current tests. To meet the challenge of diagnostic difficulties in older adults, one approach is creation of a diagnostic prediction model incorporating both current tests and AMPs to improve accurate diagnosis for older ED patients. No such model currently exists for UTI in older adults. With the creation of such a model, we will determine accuracy of AMPs as stand-alone tests and their contribution to more complex models, identifying the most accurate diagnostic approach for this population. The long-term goal of this proposal is to use the innate immune system, specifically AMPs, to improve the identification, diagnosis, and ultimately treatment of older adults with UTI. Specific Aim 1: To measure changes in baseline urinary AMP levels associated with aging and to create a normal distribution parameter of AMPs for an uninfected older cohort. Specific Aim 2: To determine the diagnostic accuracy of urinary AMP levels in differentiating acute UTI, ASB, and absence of infection in geriatric emergency department patients with suspected UTI and to create a diagnostic prediction model for UTI in older ED adults. Aim 1 will be a cross-sectional study measuring AMP levels in adults (50% ≥65) without acute illness presenting to outpatient clinics. Aim 2 will enroll a prospective cohort of ED patients ≥65 years with suspected UTI and determine diagnostic accuracy of AMPs. The proposal will advance understanding of innate immunity in the geriatric population and improve care of older adults through improved diagnostic accuracy.