Abstract
BackgroundDiagnosis of acute infection in the critically ill remains a challenge. We hypothesized that circulating leukocyte transcriptional profiles can be used to monitor the host response to and recovery from infection complicating critical illness.Methodology/Principal FindingsA translational research approach was employed. Fifteen mice underwent intratracheal injections of live P. aeruginosa, P. aeruginosa endotoxin, live S. pneumoniae, or normal saline. At 24 hours after injury, GeneChip microarray analysis of circulating buffy coat RNA identified 219 genes that distinguished between the pulmonary insults and differences in 7-day mortality. Similarly, buffy coat microarray expression profiles were generated from 27 mechanically ventilated patients every two days for up to three weeks. Significant heterogeneity of VAP microarray profiles was observed secondary to patient ethnicity, age, and gender, yet 85 genes were identified with consistent changes in abundance during the seven days bracketing the diagnosis of VAP. Principal components analysis of these 85 genes appeared to differentiate between the responses of subjects who did versus those who did not develop VAP, as defined by a general trajectory (riboleukogram) for the onset and resolution of VAP. As patients recovered from critical illness complicated by acute infection, the riboleukograms converged, consistent with an immune attractor.Conclusions/SignificanceHere we present the culmination of a mouse pneumonia study, demonstrating for the first time that disease trajectories derived from microarray expression profiles can be used to quantitatively track the clinical course of acute disease and identify a state of immune recovery. These data suggest that the onset of an infection-specific transcriptional program may precede the clinical diagnosis of pneumonia in patients. Moreover, riboleukograms may help explain variance in the host response due to differences in ethnic background, gender, and pathogen. Prospective clinical trials are indicated to validate our results and test the clinical utility of riboleukograms.
Highlights
Critical illness is marked by organ dysfunction, the need for vital support, and a high risk of death, occurring against a backdrop of systemic immune activation
Conclusions/Significance: Here we present the culmination of a mouse pneumonia study, demonstrating for the first time that disease trajectories derived from microarray expression profiles can be used to quantitatively track the clinical course of acute disease and identify a state of immune recovery
Using a bench-to-bedside approach, we have implemented a mouse model of pneumonia and found that RNA abundance profiles obtained from blood samples taken prior to appreciable mortality were able to distinguish between the two variables tested in the assay: lethality of the insult and type of infectious agent
Summary
Critical illness is marked by organ dysfunction, the need for vital support, and a high risk of death, occurring against a backdrop of systemic immune activation. This immune activation may begin as an adaptive response to the initial injury, as the disease progresses, the immune response may become maladaptive or paralyzed [1,2]. Critical illness-associated immune dysregulation has been described as the interplay between pro- and antiinflammatory responses [3], recent evidence suggests a mixed inflammatory state is common [4,5]. We hypothesized that circulating leukocyte transcriptional profiles can be used to monitor the host response to and recovery from infection complicating critical illness
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