title: Plasticity of the systemic inflammatory response to acute infection during critical illness: development of the riboleukogram.
abstract: BACKGROUND
  Diagnosis 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.
  
  
  RESULTS
  A 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
  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. 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.
authors.affiliation: Center for Critical Illness and Health Engineering, Department of Surgery, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: McDunn
authors.forename: Kareem D
authors.initials: KD
authors.lastname: Husain
authors.forename: Ashoka D
authors.initials: AD
authors.lastname: Polpitiya
authors.forename: Anton
authors.initials: A
authors.lastname: Burykin
authors.forename: Jianhua
authors.initials: J
authors.lastname: Ruan
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: William
authors.initials: W
authors.lastname: Schierding
authors.forename: Nan
authors.initials: N
authors.lastname: Lin
authors.forename: David
authors.initials: D
authors.lastname: Dixon
authors.forename: Weixiong
authors.initials: W
authors.lastname: Zhang
authors.forename: Craig M
authors.initials: CM
authors.lastname: Coopersmith
authors.forename: W Michael
authors.initials: WM
authors.lastname: Dunne
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Bijoy K
authors.initials: BK
authors.lastname: Ghosh
authors.forename: J Perren
authors.initials: JP
authors.lastname: Cobb
mesh_terms: D000208:Acute Disease; D000818:Animals; D016638:Critical Illness; D003948:Diagnostic Techniques, Respiratory System; D020869:Gene Expression Profiling; D006801:Humans; D007962:Leukocytes; D008722:Methods; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011014:Pneumonia / Q000175:diagnosis*; D053717:Pneumonia, Ventilator-Associated; D018746:Systemic Inflammatory Response Syndrome / Q000175:diagnosis*; D014158:Transcription, Genetic