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.