Microbiome-host interplay in viral respiratory infections: A tracheostomy cohort

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PROJECT SUMMARY / ABSTRACT Children with tracheostomy and home ventilation have an annual mortality rate of 5%, and have the highest healthcare utilization and costs of all U.S. children, with annual hospital charges that exceed $2.5 billion. ARIs are the #1 cause of death and hospitalization in this very high-risk population of healthcare superutilizers. Yet, little is known about the pathophysiology of these ARIs, the mechanisms underlying their severity, and no treatment pathways exist. Our long term goal is to refine the “one pathogen-one disease” ARI paradigm to a more ecosystem-wide approach to ARI pathobiology in order to develop more precise ARI treatment strategies for this population. The overall objective of this study is to determine the interplay within the ecosystem (i.e., between airway microbiome and host response) in the severity of viral ARI. The rationale is that while most ARIs are viral, viruses infect airways colonized with functional bacteria. In a previous tracheostomy study we found blooms (i.e., increased relative abundance) of a colonizing bacterium during a viral ARI. However, it remains unclear if these blooms represent infections requiring antibiotics or are associated with ARI severity. Our cross-sectional results and those of others show children with dominance of specific microbiota compositions are associated with increased viral ARI severity. We will now extend this work by applying metatranscriptomic (microbial function) and transcriptomic (host response) approaches to tracheal aspirates collected longitudinally over an 18 month period from children with tracheostomy and home ventilation. To conduct this study, we propose a 10-center, prospective cohort of 300 children with a tracheostomy and home ventilation, which would be the largest and most comprehensive study in this population to date. We will conduct this study with the expertise of the Emergency Medicine Network (EMNet) and the support of the Pediatric Acute Lung Injury & Sepsis Investigators (PALISI) network. Using tracheal aspirates collected ~1 week before and at the onset (i.e., day 1) of ARI, we plan to complete 3 Specific Aims. In Aim 1 we will determine if specific bacterial blooms are related to higher viral ARI severity. In Aim 2 we will determine the mechanisms underlying colonizing bacteria becoming pathogenic and how bacterial blooms contribute to viral ARI severity. In Aim 3 we will determine if bacterial blooms are related to the airway host response and viral ARI severity. Our pilot data demonstrate compelling support for our hypotheses. This study has >80% power for all aims, validates the results in a generalizable independent cohort, and creates a robust biorepository from multiple ecological environments for testing future hypotheses. Results from this study will provide fundamental insights into ARI pathophysiology and the mechanisms underlying ARI severity including how the airway microbiome relates to bacterial blooms and host responses in this very high-risk population. Ultimately, these results will inform ARI treatment strategies, including antibiotic use. This R01 has short- and long-term objectives to comprehensively understand ARIs in this high-risk, growing population.