Viral respiratory infections in a tracheostomy cohort: Microbiome-host interplay

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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 address these knowledge gaps by refining 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 objective of this study is to determine the dynamics – within the airway ecosystem – of the microbiome and host response during viral ARI and their contribution to ARI severity. 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., higher 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 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. In the first 6 months of our 1-year R56 AI163013 (Mansbach, PI) high- priority award, site teams at 11 U.S. hospitals will complete enrollment of 300 children with a tracheostomy and home ventilation. In late February 2022, these children will begin 6 months of specimen collection. With the expertise of the Emergency Medicine Network (EMNet) and the support of the Pediatric Acute Lung Injury & Sepsis Investigators (PALISI) network, we now seek to complete the remaining 4 years of work, including 12 more months of specimen collection. 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 body sites to test future hypotheses. Results from this study will provide fundamental insights into ARI pathophysiology and 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.