Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 199, Issue 10, Pages 1225-1237Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201804-0650OC
Keywords
bacterial pneumonia; host response; alveolar macrophages; RNA-Seq
Categories
Funding
- Northwestern University's Lung Sciences Training Program grant [5T32HL076139-13, 1F32HL136111-01A1]
- Dixon Translational Research Grant
- NIH/National Institute of Allergy and Infectious Diseases (NIAID) [1 U19AI135964-01]
- NIH [HL125940, ES013995, HL071643, AG049665, 1S10OD011996-01]
- Thoracic Surgery Foundation
- Society of University Surgeons
- John H. Gibbon Jr. Research Scholarship from the American Association of Thoracic Surgery
- NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases [AR061593]
- ATS/Scleroderma Foundation Research Grant
- NHLBI [1R56HL135124-01]
- Department of Defense [PR141319]
- BD Bioscience Immunology Research Grant
- Veterans Administration [BX000201]
- Office of the Assistant Secretary of Defense for Health Affairs, through the Peer Reviewed Medical Research Program [W81XWH-15-1-0215]
- Northwestern University Pathology Core Facility and Cancer Center Support grant [NCI CA060553]
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Rationale: The identification of informative elements of the host response to infection may improve the diagnosis and management of bacterial pneumonia. Objectives: To determine whether the absence of alveolar neutrophilia can exclude bacterial pneumonia in critically ill patients with suspected infection and to test whether signatures of bacterial pneumonia can be identified in the alveolar macrophage transcriptome. Methods: We determined the test characteristics of alveolar neutrophilia for the diagnosis of bacterial pneumonia in three cohorts of mechanically ventilated patients. In one cohort, we also isolated macrophages from alveolar lavage fluid and used the transcriptome to identify signatures of bacterial pneumonia. Finally, we developed a humanized mouse model of Pseudomonas aeruginosa pneumonia to determine if pathogen-specific signatures can be identified in human alveolar macrophages. Measurements and Main Results: An alveolar neutrophil percentage less than 50% had a negative predictive value of greater than 90% for bacterial pneumonia in both the retrospective (n = 851) and validation cohorts (n = 76 and n = 79). A transcriptional signature of bacterial pneumonia was present in both resident and recruited macrophages. Gene signatures from both cell types identified patients with bacterial pneumonia with test characteristics similar to alveolar neutrophilia. Conclusions: The absence of alveolar neutrophilia has a high negative predictive value for bacterial pneumonia in critically ill patients with suspected infection. Macrophages can be isolated from alveolar lavage fluid obtained during routine care and used for RNA-Seq analysis. This novel approach may facilitate a longitudinal and multidimensional assessment of the host response to bacterial pneumonia.
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