Jill Zupetic1, Hernán F Peñaloza1, William Bain1, Mei Hulver1, Roberta Mettus2, Peter Jorth3, Yohei Doi2, Jennifer Bomberger2, Joseph Pilewski1, Mehdi Nouraie4, Janet S Lee5. 1. Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. 2. Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. 3. Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA. 4. Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA. 5. Acute Lung Injury Center of Excellence, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA. Electronic address: leejs3@upmc.edu.
Abstract
BACKGROUND: 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. RESEARCH QUESTION: Is there an association between PA elastase activity and worse host outcomes in a cohort of ICU patients? METHODS: 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 was calculated using logistic regression. For subgroup analysis, two patterns of early (≤72 h) and late sample (>72 h) collection from the 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 vs low elastase producer. RESULTS: 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 was a risk factor for 30- and 90-day mortality in the early sample group, whereas 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 with mice infected with a low elastase producer. INTERPRETATION: Elastase activity is associated with 30-day ICU mortality. A high elastase producing clinical isolate confers increased lung tissue inflammation compared with a low elastase producer in vivo.
BACKGROUND: 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. RESEARCH QUESTION: Is there an association between PA elastase activity and worse host outcomes in a cohort of ICU patients? METHODS: 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 was calculated using logistic regression. For subgroup analysis, two patterns of early (≤72 h) and late sample (>72 h) collection from the 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 vs low elastase producer. RESULTS: 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 was a risk factor for 30- and 90-day mortality in the early sample group, whereas 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 with mice infected with a low elastase producer. INTERPRETATION: Elastase activity is associated with 30-day ICU mortality. A high elastase producing clinical isolate confers increased lung tissue inflammation compared with a low elastase producer in vivo.
Authors: William Bain; Tolani Olonisakin; Minting Yu; Yanyan Qu; Mei Hulver; Zeyu Xiong; Huihua Li; Joseph Pilewski; Rama K Mallampalli; Mehdi Nouraie; Anuradha Ray; Prabir Ray; Zhenyu Cheng; Robert M Q Shanks; Claudette St Croix; Roy L Silverstein; Janet S Lee Journal: Blood Adv Date: 2019-02-12
Authors: Taylor E Woo; Jessica Duong; Nicole M Jervis; Harvey R Rabin; Michael D Parkins; Douglas G Storey Journal: Microbiology Date: 2016-12 Impact factor: 2.777
Authors: Shantelle L LaFayette; Daniel Houle; Trevor Beaudoin; Gabriella Wojewodka; Danuta Radzioch; Lucas R Hoffman; Jane L Burns; Ajai A Dandekar; Nicole E Smalley; Josephine R Chandler; James E Zlosnik; David P Speert; Joanie Bernier; Elias Matouk; Emmanuelle Brochiero; Simon Rousseau; Dao Nguyen Journal: Sci Adv Date: 2015-07-31 Impact factor: 14.136