Multidimensional assessment of the host response in mechanically ventilated patients with suspected pneumonia

James M. Walter*, Ziyou Ren, Tyrone Yacoub, Paul A. Reyfman, Raj D. Shah, Hiam Abdala-Valencia, Kiwon Nam, Vince K. Morgan, Kishore R. Anekalla, Nikita Joshi, Alexandra C. McQuattie-Pimentel, Ching I. Chen, Monica Chi, Seung Hye Han, Francisco J. Gonzalez-Gonzalez, Saul Soberanes, Raul P. Aillon, Satoshi Watanabe, Kinola J.N. Williams, Ziyan LuJoseph Paonessa, Peter Hountras, Madonna Breganio, Nicole Borkowski, Helen K. Donnelly, Jonathan P. Allen, Luis A. Amaral, Ankit Bharat, Alexander V. Misharin, Neda Bagheri, Alan R. Hauser, G. R.Scott Budinger, Richard G. Wunderink

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Scopus citations

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 languageEnglish (US)
Pages (from-to)1225-1237
Number of pages13
JournalAmerican journal of respiratory and critical care medicine
Volume199
Issue number10
DOIs
StatePublished - May 15 2019

Keywords

  • Alveolar macrophages
  • Bacterial pneumonia
  • Host response
  • RNA-Seq

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Walter, J. M., Ren, Z., Yacoub, T., Reyfman, P. A., Shah, R. D., Abdala-Valencia, H., Nam, K., Morgan, V. K., Anekalla, K. R., Joshi, N., McQuattie-Pimentel, A. C., Chen, C. I., Chi, M., Han, S. H., Gonzalez-Gonzalez, F. J., Soberanes, S., Aillon, R. P., Watanabe, S., Williams, K. J. N., ... Wunderink, R. G. (2019). Multidimensional assessment of the host response in mechanically ventilated patients with suspected pneumonia. American journal of respiratory and critical care medicine, 199(10), 1225-1237. https://doi.org/10.1164/rccm.201804-0650OC