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Type III protein secretion is associated with poor clinical outcomes in patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa

Hauser, Alan R. MD, PhD; Cobb, Enesha BS; Bodí, Maria MD; Mariscal, Dolors MD; Vallés, Jordi MD, PhD; Engel, Joanne N. MD, PhD; Rello, Jordi MD, PhD

CLINICAL INVESTIGATIONS
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Objective  Pseudomonas aeruginosa is a frequent cause of ventilator-associated pneumonia. Recent evidence suggests that production of type III secretion proteins is correlated with increased pathogenicity in both cellular and animal models of infection. The objective of this study was to determine whether this system contributes to disease severity in humans with ventilator-associated pneumonia.

Design  Retrospective pilot cohort study.

Setting  University hospital.

Patients  Thirty-five mechanically ventilated patients with bronchoscopically confirmed ventilator-associated pneumonia caused by P. aeruginosa.

Measurements and Main Results  Ventilator-associated pneumonia was categorized as severe (patients died or had a recurrence of their pneumonia despite appropriate antibiotic therapy) or mild (patients uneventfully recovered from their pneumonia). The type III secretion genotypes and phenotypes of isolates cultured from the patients with ventilator-associated pneumonia were determined. Whereas every examined isolate harbored type III secretion genes, only 27 (77%) were capable of secreting detectable amounts of type III proteins in vitro. Twenty-two (81%) of the patients infected with these 27 isolates had severe disease. Of the eight isolates that did not secrete type III proteins, only three (38%) were cultured from patients with severe disease. Thus, infection with a type-III-secreting isolate correlated with severe disease (p < .05). In vitro assays indicated that ExoU, the type III effector protein most closely linked to mortality in animal models, was secreted in detectable amounts in vitro by 10 (29%) of the 35 examined isolates. Nine (90%) of these 10 isolates were cultured from patients with severe disease (p < .05 when compared with the nonsecreting isolates). In contrast, ExoS was secreted by 16 (46%) of the 35 examined isolates. Twelve (75%) of these 16 isolates were cultured from patients with severe disease (p = .14 when compared with the nonsecreting isolates).

Conclusions  In patients with ventilator-associated pneumonia, type-III-secreting isolates were associated with worse clinical outcomes, suggesting that this secretion system plays an important role in human disease. Our findings support the hypothesis that antibodies targeted against these proteins may be useful as adjunctive therapy in intubated patients with P. aeruginosa colonization or infection.

From the Departments of Microbiology/Immunology and Medicine, Northwestern University, Chicago, IL (ARH); the Departments of Microbiology and Immunology and Medicine, University of California, San Francisco, CA (JNE, EC); the Critical Care Department, Hospital Universitari Joan XXIII, Universitat Rovira i Virgili, Tarragona, Spain (JR, MB); and Hospital de Sabadell, Barcelona, Spain (DM, JV).

Supported, in part, by grants from CIRIT (SGR97/443,99/250 and 2000/128), FISS (96/27), FISS (99/32-01) and Distincio a la Recerca Universitaria (JR) and from the University Wide AIDS Research Program (JNE), the National Institutes of Health (JNE [R01 AI42806] and ARH [K08 AI001524]), the American Lung Association (JNE), the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation Fellowship, the Schweppe Foundation, and the Northwestern Memorial Hospital Intramural Research Grants Program (ARH). JNE is a career investigator of the American Lung Association.

Presented, in part, at the Annual Meeting of the American College of Chest Physicians in Chicago in October 1999 and at the Pseudomonas: Biotechnology and Pathogenesis International Meeting, Maui, September 1999.

The results of this study are consistent with the Pseudomonas aeruginosa type III secretion system being of major importance in ventilator-associated pneumonia and indicate that it may be an attractive target for novel therapeutic interventions.

© 2002 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins