Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1225-1237 |
| Number of pages | 13 |
| Journal | American journal of respiratory and critical care medicine |
| Volume | 199 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 15 2019 |
Funding
Supported by Northwestern University’s Lung Sciences Training Program grant 5T32HL076139-13 and a Dixon Translational Research Grant (J.M.W. and P.A.R.); Northwestern University’s Lung Sciences Training Program grant 1F32HL136111-01A1 (P.A.R.); NIH/National Institute of Allergy and Infectious Diseases (NIAID) grant 1 U19AI135964-01 (H.K.D., L.A.A., A.V.M., A.R.H., G.R.S.B., and R.G.W.); NIH grant HL125940 and matching funds from the Thoracic Surgery Foundation, a research grant from Society of University Surgeons, and a John H. Gibbon Jr. Research Scholarship from the American Association of Thoracic Surgery (A.B.); NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases grant AR061593, an ATS/Scleroderma Foundation Research Grant, NHLBI 1R56HL135124-01, Department of Defense grant PR141319, and a BD Bioscience Immunology Research Grant (A.V.M.); NIH grants ES013995, HL071643, AG049665, The Veterans Administration Grant BX000201, and Department of Defense grant PR141319, (G.R.S.B.); and the Office of the Assistant Secretary of Defense for Health Affairs, through the Peer Reviewed Medical Research Program under Award W81XWH-15-1-0215 (A.V.M. and G.R.S.B.). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. RNA-seq library preparation and sequencing were performed in the RNA-seq Center of the Division of Pulmonary and Critical Care Medicine at Northwestern. Flow Cytometry Cell Sorting was performed on a BD FACSAria SORP system, purchased through the support of NIH 1S10OD011996-01. This work was supported by the Northwestern University Pathology Core Facility and Cancer Center Support grant NCI CA060553.
Keywords
- Alveolar macrophages
- Bacterial pneumonia
- Host response
- RNA-Seq
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Critical Care and Intensive Care Medicine
