Tracheobronchitis in the Critically Ill

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Nearly 30% of people recovering from critical illness requiring tracheostomy placement experience respiratory infections - termed tracheostomy associated tracheobronchitis (TATB) for this proposal. Our understanding of TATB comes from those with acute critical illness, and does not extend to the recovery phase of critical illness. Poor understanding of TATB may contribute to antibiotic overuse and limits testing of interventions. Our objective is to define the natural history and outcomes of TATB, as well as to identify changes in the airway bacterial populations and host innate immune response that predispose to TATB. To accomplish this goal, we will assemble a longitudinal cohort of participants with tracheostomies within a Long-Term Acute Care Hospital (LTACH). In Aim 1 we will assemble a longitudinal registry cohort of people admitted with a tracheostomy to test the hypothesis that tracheobronchitis episodes in the LTACH have clinical impact on long term outcomes. Within the cohort, we will determine the event rate of TATB, measure the effect of diagnosis of TATB on outcomes, including respiratory recovery rate, mortality and healthcare utilization, and determine clinical predictors of being diagnosed with TATB. Although TATB is treated with antibiotics, we do not know how often episodes are caused by active bacterial infections. Alternative causes include viral infections and other reasons for increased respiratory secretions in a population that is colonized with at least one pathogenic organism. In Aim 2 we hypothesize that infectious TATB episodes are caused by a bloom of an existing pathogen with an acute inflammatory response. We will use shallow metagenomics (shotgun sequencing) to determine the bacterial kinetics of infection down to the strain level during episodes. Shallow metagenomics will allow us to distinguish episodes of new pathogen invasion vs a bloom or genetic change in the existing pathogens within the microbiome. We will determine which episodes of TATB are associated with either a local airway inflammatory response or a systemic inflammatory response. Alternatively, viral infections may trigger TATB or trigger pathogenic bacterial growth. We will conduct a nested case-control study to determine if infection with respiratory viruses is associated with TATB. Together, these data will determine clinical endotypes. In Aim 3, we will examine how inflammation promotes the growth of pathogenic bacteria through the release of micronutrients needed for bacteria growth. We will test the hypotheses that breaches in local mucosal immunity or local inflammatory response increase the odds of TATB diagnosis. The nutritional environment in the sputum will be assessed through measurement of bacterial nutrients such as metals and carbon sources, the nutritional environment will be correlated with odds of TATB diagnosis, and the local inflammatory state prior to diagnosis of TATB will be assessed through cytokine profiling. The results from these studies will allow us to target specific phenotypes of TATB in future intervention or scientific studies.