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Plasticity of the systemic inflammatory response to acute infection during critical illness: development of the riboleukogram.

McDunn JE, Husain KD, Polpitiya AD, Burykin A, Ruan J, Li Q, Schierding W, Lin N, Dixon D, Zhang W, Coopersmith CM, Dunne WM, Colonna M, Ghosh BK, Cobb JP - PLoS ONE (2008)

Bottom Line: 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.Moreover, riboleukograms may help explain variance in the host response due to differences in ethnic background, gender, and pathogen.

View Article: PubMed Central - PubMed

Affiliation: Center for Critical Illness and Health Engineering, Department of Surgery, Washington University in St. Louis, St. Louis, Missouri, USA.

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.

Methodology/principal findings: 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/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. 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.

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Related in: MedlinePlus

Phase space analysis of the average ICU patient riboleukogram trajectories as they develop VAP, respond to antibiotics, and recover.(A) Decrease of variance and the convergence of individual trajectories to a common small region in the phase space (“immunological attractor”) associated with health. The green and red circles indicate where the patients entered and exited the study, respectively. (B) Decreases in variance (standard deviation, STD) over time for the phase space trajectory in panel A, consistent with the existence of an attractor. The diagnosis of VAP was made by the attending physician on Day 0.
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pone-0001564-g005: Phase space analysis of the average ICU patient riboleukogram trajectories as they develop VAP, respond to antibiotics, and recover.(A) Decrease of variance and the convergence of individual trajectories to a common small region in the phase space (“immunological attractor”) associated with health. The green and red circles indicate where the patients entered and exited the study, respectively. (B) Decreases in variance (standard deviation, STD) over time for the phase space trajectory in panel A, consistent with the existence of an attractor. The diagnosis of VAP was made by the attending physician on Day 0.

Mentions: Independent analysis of patient microarray data resulted in the identification of 85 probe sets whose abundance changed significantly during the course of VAP (Table 2). Of the 109 human orthologs that were used to calculate the trajectories shown in Figure 2A, 5 probe sets (4.6%) were present in the list of human probe sets (lactotransferrin, cathelicidin antimicrobial peptide, phospholipid scramblase 1, inhibin beta A, and hydroxyprostaglandin dehydrogenase 15-(NAD)). Network analysis found that the expression behavior of these 85 genes segregated into four clusters (Figure 3A). Transcript abundance in clusters 1 and 2 generally increased and transcript abundance in clusters 3 and 4 generally decreased around the time of VAP diagnosis.


Plasticity of the systemic inflammatory response to acute infection during critical illness: development of the riboleukogram.

McDunn JE, Husain KD, Polpitiya AD, Burykin A, Ruan J, Li Q, Schierding W, Lin N, Dixon D, Zhang W, Coopersmith CM, Dunne WM, Colonna M, Ghosh BK, Cobb JP - PLoS ONE (2008)

Phase space analysis of the average ICU patient riboleukogram trajectories as they develop VAP, respond to antibiotics, and recover.(A) Decrease of variance and the convergence of individual trajectories to a common small region in the phase space (“immunological attractor”) associated with health. The green and red circles indicate where the patients entered and exited the study, respectively. (B) Decreases in variance (standard deviation, STD) over time for the phase space trajectory in panel A, consistent with the existence of an attractor. The diagnosis of VAP was made by the attending physician on Day 0.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2215774&req=5

pone-0001564-g005: Phase space analysis of the average ICU patient riboleukogram trajectories as they develop VAP, respond to antibiotics, and recover.(A) Decrease of variance and the convergence of individual trajectories to a common small region in the phase space (“immunological attractor”) associated with health. The green and red circles indicate where the patients entered and exited the study, respectively. (B) Decreases in variance (standard deviation, STD) over time for the phase space trajectory in panel A, consistent with the existence of an attractor. The diagnosis of VAP was made by the attending physician on Day 0.
Mentions: Independent analysis of patient microarray data resulted in the identification of 85 probe sets whose abundance changed significantly during the course of VAP (Table 2). Of the 109 human orthologs that were used to calculate the trajectories shown in Figure 2A, 5 probe sets (4.6%) were present in the list of human probe sets (lactotransferrin, cathelicidin antimicrobial peptide, phospholipid scramblase 1, inhibin beta A, and hydroxyprostaglandin dehydrogenase 15-(NAD)). Network analysis found that the expression behavior of these 85 genes segregated into four clusters (Figure 3A). Transcript abundance in clusters 1 and 2 generally increased and transcript abundance in clusters 3 and 4 generally decreased around the time of VAP diagnosis.

Bottom Line: 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.Moreover, riboleukograms may help explain variance in the host response due to differences in ethnic background, gender, and pathogen.

View Article: PubMed Central - PubMed

Affiliation: Center for Critical Illness and Health Engineering, Department of Surgery, Washington University in St. Louis, St. Louis, Missouri, USA.

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.

Methodology/principal findings: 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/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. 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.

Show MeSH
Related in: MedlinePlus