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

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 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.