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Plasticity of the systemic inflammatory response to acute infection during critical illness

ABSTRACT: Diagnosis of acute infection in the critically ill remains a challenge. Changes in physiologic parameters and existing molecular diagnostics are not specific and microbiologic confirmation of infection can take days. As cellular first responders, preclinical studies indicate that circulating leukocytes are activated in response to bacterial infection, manifesting infection-specific transcriptional programs. We hypothesized that circulating leukocyte transcriptional profiles can be used to diagnose infection and monitor response to therapy in the critically ill. Keywords: ventilator associated pneumonia, predictor, microarray, timecourse, human, murine

ORGANISM(S): Homo sapiens

PROVIDER: GSE6377 | GEO | 2008/02/12

SECONDARY ACCESSION(S): PRJNA99603

REPOSITORIES: GEO

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Project description:Diagnosis of acute infection in the critically ill remains a challenge. Changes in physiologic parameters and existing molecular diagnostics are not specific and microbiologic confirmation of infection can take days. As cellular first responders, preclinical studies indicate that circulating leukocytes are activated in response to bacterial infection, manifesting infection-specific transcriptional programs. We hypothesized that circulating leukocyte transcriptional profiles can be used to diagnose infection and monitor response to therapy in the critically ill. Experiment Overall Design: A translational research approach was employed. Fifteen mice underwent intratracheal (i.t.) 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 20 mechanically ventilated patients every two days for up to three weeks; 11 of these patients developed pneumonia. Principal components analysis of the expression levels of the human orthologs for the mouse genes resulted in gene expression trajectories that describe the cohort of 11 patients as they develop, are treated for, and convalesce from ventilator-associated pneumonia (VAP). When the VAP microarray profiles were analyzed independently, 85 genes were identified with consistent changes in abundance during the seven days bracketing the diagnosis of VAP. The estimated prediction accuracy in this small patient cohort was 91%. The abundance of select transcripts was validated using real-time PCR. Principal components analysis of the average microarray-measured abundances of these genes defined a general trajectory (riboleukogram) for the onset of acute infection in this patient population. Individual riboleukograms demonstrated that the onset and course of infection are specific for each individual, but as patients recover from infection the riboleukograms converge. The gene ontologies of the co-expression networks indicate that leukocyte chemokines and granule maturation are especially informative for pneumonia diagnostics.

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Plasticity of the systemic inflammatory response to acute infection during critical illness

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