Determinants of long-term outcomes and heterogeneity in Gram-negative community-acquired pneumonia

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PROJECT SUMMARY Research: Lower respiratory infections such as community-acquired pneumonia (CAP) are the leading cause of infection-related deaths worldwide. Emerging evidence suggests that adverse long-term health outcomes are more common in CAP survivors compared with patients hospitalized for other reasons, challenging the concept of CAP as solely an acute disease. The mechanisms underlying adverse long-term CAP sequelae are unknown, although dysregulation of the host immune response during acute infection has been postulated to be a contributing factor. Moreover, the clinical and biological heterogeneity of CAP serves as a major barrier to identification of individualized and targeted therapies, which may impede prevention of adverse long-term outcomes. In Thailand, the burden of CAP is high and in the northeastern region of the country the Gram- negative bacterium Burkholderia pseudomallei is the most common and deadly etiology. Studying CAP due to this single pathogen (Bp-CAP) may help to disentangle CAP heterogeneity and host-mediated determinants of long-term outcomes. Utilizing a uniquely large multicenter prospective cohort of patients hospitalized with Bp- CAP in Northeast Thailand, Dr. Coston will address the following Aims: (1) Determine if admission CAP severity is associated with adverse outcomes after discharge; (2) Identify pro-inflammatory cytokines associated with adverse outcomes after discharge; (3) Identify novel subgroups of Bp-CAP by applying clustering strategies to routinely collected clinical and laboratory data. The proposed work will yield insight into determinants of long-term outcomes and heterogeneity in Bp-CAP, which could facilitate identification of modifiable factors and host-focused tailored therapeutics in the future. Such findings may be generalizable to other CAP etiologies and are an important area of future study. Candidate/Environment: The candidate, Dr. Coston, is a promising junior investigator who is beginning his career as a clinical-translational physician-scientist focused on the global threats pneumonia and severe infections. He has assembled a team of accomplished faculty to provide him with mentorship and training throughout the award. He will avail of the University of Washington’s rich academic environment, pulmonary and global health expertise, and track record of training successful physician-scientists in pulmonary and critical care medicine. Through the proposed research, he will develop fundamental skills for analysis of longitudinal cohort data, cluster analysis, study of biomarkers in the host response to infection, and ethical conduct of research in global settings. The research and training proposed in this project will further Dr. Coston’s development as a physician-scientist and will prepare him to compete successfully for a K23 career development award.