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

 描述(申请人提供)：尿路感染(UTI)是老年人最常见的细菌感染。在美国，尿路感染每年导致10万人住院，费用超过35亿美元。老年人的尿路感染与高发病率和死亡率有关。老年人的诊断具有挑战性，因为没有典型的症状，不典型的表现很常见，诊断测试的准确性很差。我们将通过研究尿路的先天性免疫反应来改进老年人尿路感染的诊断和治疗。先天免疫系统是老年人对尿路感染易感性和反应性的关键介质。然而，随着年龄的增长，尿路天然免疫的具体变化还没有得到严格的研究。抗菌蛋白(肽)是尿液天然免疫的关键效应物。老年人的基线水平尚不清楚，但可能与年轻人不同。根据年龄确定基线尿AMP水平对于了解老年人对尿路感染的易感性和反应是必要的。初步数据表明，包括人中性粒细胞多肽1-3(HNP 1-3)、α-防御素5(HD5)、人β防御素-2(HBD-2)和长春新碱(LL-37)在内的几种尿液AMP可以识别老年人尿路感染。这可能会导致更准确的尿路感染诊断，并改善临床结果。作为新的生物标志物，AMP既需要作为UTI的独立预测因子进行研究，也需要与目前的测试相结合进行研究。为了应对老年人诊断困难的挑战，一种方法是创建一个诊断预测模型，将当前的测试和AMP结合起来，以提高对老年ED患者的准确诊断。对于老年人的尿路感染，目前还没有这样的模型。通过创建这样的模型，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，从而确定适用于这一人群的最准确的诊断方法。这项建议的长期目标是利用先天免疫系统，特别是AMP，来改进对患有尿路感染的老年人的识别、诊断和最终治疗。具体目标1：测量与年龄相关的基线尿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。具体目的2：探讨尿AMP水平在老年急诊科疑似尿路感染患者中鉴别急性尿路感染、ASB和无感染的诊断准确性，建立老年ED患者尿路感染的诊断预测模型。目标1将是一项横断面研究，测量没有急性疾病的成年人(50%≥，65岁)的AMP水平。目的2将登记65岁≥疑似尿路感染的ED患者的前瞻性队列，并确定AMP的诊断准确性。该提案将通过提高诊断准确性，促进老年人群对先天免疫的了解，并改善对老年人的护理。

 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.