Pseudomonas aeruginosa (PA) is a common cause of respiratory infection and morbidity. Pseudomonas elastase is an important virulence factor regulated by the lasR gene. Whether PA elastase activity is associated with worse clinical outcomes in ICU patients is unknown.Is there an association between PA elastase activity and worse host outcomes in a cohort of ICU patients?PA respiratory isolates from 238 unique ICU patients from two tertiary-care centers within the University of Pittsburgh Medical Center health system were prospectively collected and screened for total protease and elastase activity, biofilm production, antimicrobial resistance, and polymicrobial status. The association between pathogen characteristics and 30-day and 90-day mortality were calculated using logistic regression. For subgroup analysis, the two patterns of early (< 72h) and late sample (>72h) collections from index ICU admission were distinguished using a Finite Mixture Model. Lung inflammation and injury was evaluated in a mouse model using a PA high elastase versus low elastase producer.PA elastase activity was common in ICU respiratory isolates representing 75% of samples and was associated with increased 30-day mortality [adjusted OR (95% CI): 1.39 (1.05-1.83)]. Subgroup analysis demonstrated that elastase activity is a risk factor for 30 and 90-day mortality in the early sample group while antimicrobial resistance was a risk factor for 90-day mortality in the late sample group. Whole genome sequencing of high and low elastase producers showed that predicted loss-of-function lasR genotypes were less common among high elastase producers. Mice infected with a high elastase producer showed increased lung bacterial burden and inflammatory profile compared to mice infected with a low elastase producer.Elastase activity is associated with 30-day ICU mortality. A high elastase producing clinical isolate confers increased lung tissue inflammation compared to a low elastase producer in vivo.
Jill Zupetic, Hernán F Peñaloza, William Bain, Mei Hulver, Roberta Mettus, Peter Jorth, Yohei Doi, Jennifer Bomberger, Joseph Pilewski, Mehdi Nouraie, Janet S Lee