ABSTRACT A major driver of intensive care unit (ICU) hospital admissions is pneumonia. The immunocompromised patient group, which makes up 20% of ICU pneumonia admissions, is at increased risk for severe infection from common respiratory organisms as well as opportunistic pathogens that cannot be easily cultured or treated with standard empiric antibiotics. While standard practice for clinical identification of infection includes extensive culture and non-culture techniques, these tests often take many days to yield results and a definitive causative agent is identified in only 10%-40% of cases. As a result, patients often receive multiple courses of antibiotics without identification of a specific pathogen to guide therapy. The difficulty in determining the offending pathogens to guide proper treatment increases both costs and mortality for these patients; mortality is as high as 30%-50%. Current gold-standard diagnostics for infection rely on decades-old technology that can take weeks to complete, have limited sensitivity, and are limited in the type and number of microbes that can be screened by a single test. Thus, a critical gap exists due to the inability of current diagnostics to comprehensively screen and accurately detect microbial pathogens, which is a significant barrier to improved clinical outcomes for these patients. We have developed a comprehensive next generation sequencing (NGS) panel for detection and identification of microbes that also detects anti-microbial resistance (AMR) and host immune response features. Our previous studies have demonstrated the feasibility of our diagnostic tool for application to low-level respiratory infections in chronic disease and its superiority to both microbiological and molecular approaches to diagnosis. Our NGS diagnostics (Dx) panel is a significant technological innovation over current methodology; the Dx panel utilizes samples directly from the patient (rather than relying on cultures), provides greater sensitivity than qPCR or meta-genomic sequencing approaches and screens for the presence of tens of thousands of other microbes in a single assay. These features are possible due to our innovative design in addition to proprietary laboratory and analysis workflows. The long-term goal of this project is to provide a novel clinical tool for detection and characterization of infections in immunocompromised patients with infectious lung complications. In this Phase I, we will examine the feasibility of our assay for use in this acute clinical setting, evaluating for the first time the use of our AMR and host immune screening to provide supportive information for diagnosis and treatment guidance. Specifically, we will 1) estimate the rate at which our panel provides a definitive detection of one or more pathogens when clinical tests fail, 2) establish the feasibility of using our AMR profile to replace clinical culture isolate tests 3) determine the feasibility of immune profiling in this popula...