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An integrated transcriptome and expressed variant analysis of sepsis survival and death.

Tsalik EL, Langley RJ, Dinwiddie DL, Miller NA, Yoo B, van Velkinburgh JC, Smith LD, Thiffault I, Jaehne AK, Valente AM, Henao R, Yuan X, Glickman SW, Rice BJ, McClain MT, Carin L, Corey GR, Ginsburg GS, Cairns CB, Otero RM, Fowler VG, Rivers EP, Woods CW, Kingsmore SF - Genome Med (2014)

Bottom Line: Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality.Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes.The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology.

View Article: PubMed Central - PubMed

Affiliation: Emergency Medicine Service, Durham Veterans Affairs Medical Center, Durham, North Carolina 27705 USA ; Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA.

ABSTRACT

Background: Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality.

Methods: The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (SIRS due to infection), including 78 sepsis survivors and 28 sepsis non-survivors who had previously undergone plasma proteomic and metabolomic profiling. Gene expression differences were identified between sepsis survivors, sepsis non-survivors, and SIRS followed by gene enrichment pathway analysis. Expressed sequence variants were identified followed by testing for association with sepsis outcomes.

Results: The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflecting immune activation in sepsis. Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease-rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors. The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology.

Conclusions: The activation of immune response-related genes seen in sepsis survivors was muted in sepsis non-survivors. The association of sepsis survival with a robust immune response and the presence of missense variants in VPS9D1 warrants replication and further functional studies.

Trial registration: ClinicalTrials.gov NCT00258869. Registered on 23 November 2005.

No MeSH data available.


Related in: MedlinePlus

A systems survey of sepsis survival. (A) Schematic representing the different trajectories enrolled subjects might take. X-axis represents time (not to scale), emphasizing the illness progresses from local to systemic infection prior to clinical presentation (t0). The green line is flat only to distinguish subjects without infection, although these individuals could also have the full spectrum of clinical illness severity. Blue lines represent subjects with sepsis of different severities, all of whom survive at 28 days. This is in contrast to subjects with sepsis who die within 28 days, independent of initial sepsis severity. (B) Analytical plan for the CAPSOD cohort including previously published metabolome and proteome [11]. Metabolomic and proteomic analyses were performed on samples obtained at t0 and 24 h later. Transcriptomic analysis was performed on samples obtained at t0.
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Fig1: A systems survey of sepsis survival. (A) Schematic representing the different trajectories enrolled subjects might take. X-axis represents time (not to scale), emphasizing the illness progresses from local to systemic infection prior to clinical presentation (t0). The green line is flat only to distinguish subjects without infection, although these individuals could also have the full spectrum of clinical illness severity. Blue lines represent subjects with sepsis of different severities, all of whom survive at 28 days. This is in contrast to subjects with sepsis who die within 28 days, independent of initial sepsis severity. (B) Analytical plan for the CAPSOD cohort including previously published metabolome and proteome [11]. Metabolomic and proteomic analyses were performed on samples obtained at t0 and 24 h later. Transcriptomic analysis was performed on samples obtained at t0.

Mentions: The Community Acquired Pneumonia and Sepsis Outcome Diagnostics (CAPSOD) study was an observational trial enrolling subjects with community-acquired sepsis or pneumonia (ClinicalTrials.gov NCT00258869) (Figure 1A). Its focus was to define sepsis biology and to identify diagnostic and prognostic biomarkers in sepsis utilizing comprehensive clinical information and bioinformatic, metabolomic, proteomic, and mRNA sequencing technologies (Figure 1B). Subjects with suspected sepsis were enrolled in the emergency departments of Henry Ford Health System (Detroit, MI, USA), Duke University Medical Center (Durham, NC, USA), and the Durham Veterans Affairs Medical Center (Durham, NC, USA) from 2005 to 2009 by which time 1,152 subjects were enrolled [10-13] (Figure 2). Some enrolled subjects were later determined not to have sepsis, but rather a non-infectious systemic inflammatory response syndrome (SIRS). Infection status and 28-day mortality were independently adjudicated by a board-certified clinician followed by a second, confirmatory adjudication of 10% of cases (κ = 0.82) as previously described [10,12,13]. An indeterminate infection status in 259 subjects led to their exclusion (Figure 2). Twenty-eight day mortality in the remaining population of 893 was low (5.9%). Five subgroups were selected for mRNA sequencing: (1) Uncomplicated sepsis (n = 24); (2) Progression to severe sepsis within 3 days (n = 21); (3) Progression to septic shock within 3 days (n = 33); (4) Sepsis non-survivors at 28 days (n = 28); and (5) Patients with SIRS (n = 23). Subjects for each group were chosen to match non-survivors based on age, gender, race, enrollment site, and microbiological etiology (Table 1). As CAPSOD was an observational study, clinical care was not standardized and was determined by individual providers. Moreover, treatment administered to patients prior to enrollment (for example, self-administered, prescribed by outpatient providers, given by emergency medical services, or given in the ED) were not recorded and therefore were not controlled for in subsequent analyses.Figure 1


An integrated transcriptome and expressed variant analysis of sepsis survival and death.

Tsalik EL, Langley RJ, Dinwiddie DL, Miller NA, Yoo B, van Velkinburgh JC, Smith LD, Thiffault I, Jaehne AK, Valente AM, Henao R, Yuan X, Glickman SW, Rice BJ, McClain MT, Carin L, Corey GR, Ginsburg GS, Cairns CB, Otero RM, Fowler VG, Rivers EP, Woods CW, Kingsmore SF - Genome Med (2014)

A systems survey of sepsis survival. (A) Schematic representing the different trajectories enrolled subjects might take. X-axis represents time (not to scale), emphasizing the illness progresses from local to systemic infection prior to clinical presentation (t0). The green line is flat only to distinguish subjects without infection, although these individuals could also have the full spectrum of clinical illness severity. Blue lines represent subjects with sepsis of different severities, all of whom survive at 28 days. This is in contrast to subjects with sepsis who die within 28 days, independent of initial sepsis severity. (B) Analytical plan for the CAPSOD cohort including previously published metabolome and proteome [11]. Metabolomic and proteomic analyses were performed on samples obtained at t0 and 24 h later. Transcriptomic analysis was performed on samples obtained at t0.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4274761&req=5

Fig1: A systems survey of sepsis survival. (A) Schematic representing the different trajectories enrolled subjects might take. X-axis represents time (not to scale), emphasizing the illness progresses from local to systemic infection prior to clinical presentation (t0). The green line is flat only to distinguish subjects without infection, although these individuals could also have the full spectrum of clinical illness severity. Blue lines represent subjects with sepsis of different severities, all of whom survive at 28 days. This is in contrast to subjects with sepsis who die within 28 days, independent of initial sepsis severity. (B) Analytical plan for the CAPSOD cohort including previously published metabolome and proteome [11]. Metabolomic and proteomic analyses were performed on samples obtained at t0 and 24 h later. Transcriptomic analysis was performed on samples obtained at t0.
Mentions: The Community Acquired Pneumonia and Sepsis Outcome Diagnostics (CAPSOD) study was an observational trial enrolling subjects with community-acquired sepsis or pneumonia (ClinicalTrials.gov NCT00258869) (Figure 1A). Its focus was to define sepsis biology and to identify diagnostic and prognostic biomarkers in sepsis utilizing comprehensive clinical information and bioinformatic, metabolomic, proteomic, and mRNA sequencing technologies (Figure 1B). Subjects with suspected sepsis were enrolled in the emergency departments of Henry Ford Health System (Detroit, MI, USA), Duke University Medical Center (Durham, NC, USA), and the Durham Veterans Affairs Medical Center (Durham, NC, USA) from 2005 to 2009 by which time 1,152 subjects were enrolled [10-13] (Figure 2). Some enrolled subjects were later determined not to have sepsis, but rather a non-infectious systemic inflammatory response syndrome (SIRS). Infection status and 28-day mortality were independently adjudicated by a board-certified clinician followed by a second, confirmatory adjudication of 10% of cases (κ = 0.82) as previously described [10,12,13]. An indeterminate infection status in 259 subjects led to their exclusion (Figure 2). Twenty-eight day mortality in the remaining population of 893 was low (5.9%). Five subgroups were selected for mRNA sequencing: (1) Uncomplicated sepsis (n = 24); (2) Progression to severe sepsis within 3 days (n = 21); (3) Progression to septic shock within 3 days (n = 33); (4) Sepsis non-survivors at 28 days (n = 28); and (5) Patients with SIRS (n = 23). Subjects for each group were chosen to match non-survivors based on age, gender, race, enrollment site, and microbiological etiology (Table 1). As CAPSOD was an observational study, clinical care was not standardized and was determined by individual providers. Moreover, treatment administered to patients prior to enrollment (for example, self-administered, prescribed by outpatient providers, given by emergency medical services, or given in the ED) were not recorded and therefore were not controlled for in subsequent analyses.Figure 1

Bottom Line: Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality.Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes.The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology.

View Article: PubMed Central - PubMed

Affiliation: Emergency Medicine Service, Durham Veterans Affairs Medical Center, Durham, North Carolina 27705 USA ; Department of Medicine, Duke University Medical Center, Durham, NC 27710 USA.

ABSTRACT

Background: Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies. Patient factors including genetics predispose to poor outcomes, though current clinical characterizations fail to identify those at greatest risk of progression and mortality.

Methods: The Community Acquired Pneumonia and Sepsis Outcome Diagnostic study enrolled 1,152 subjects with suspected sepsis. We sequenced peripheral blood RNA of 129 representative subjects with systemic inflammatory response syndrome (SIRS) or sepsis (SIRS due to infection), including 78 sepsis survivors and 28 sepsis non-survivors who had previously undergone plasma proteomic and metabolomic profiling. Gene expression differences were identified between sepsis survivors, sepsis non-survivors, and SIRS followed by gene enrichment pathway analysis. Expressed sequence variants were identified followed by testing for association with sepsis outcomes.

Results: The expression of 338 genes differed between subjects with SIRS and those with sepsis, primarily reflecting immune activation in sepsis. Expression of 1,238 genes differed with sepsis outcome: non-survivors had lower expression of many immune function-related genes. Functional genetic variants associated with sepsis mortality were sought based on a common disease-rare variant hypothesis. VPS9D1, whose expression was increased in sepsis survivors, had a higher burden of missense variants in sepsis survivors. The presence of variants was associated with altered expression of 3,799 genes, primarily reflecting Golgi and endosome biology.

Conclusions: The activation of immune response-related genes seen in sepsis survivors was muted in sepsis non-survivors. The association of sepsis survival with a robust immune response and the presence of missense variants in VPS9D1 warrants replication and further functional studies.

Trial registration: ClinicalTrials.gov NCT00258869. Registered on 23 November 2005.

No MeSH data available.


Related in: MedlinePlus