Abstract
BackgroundSepsis, 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.MethodsThe 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.ResultsThe 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.ConclusionsThe 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 registrationClinicalTrials.gov NCT00258869. Registered on 23 November 2005.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-014-0111-5) contains supplementary material, which is available to authorized users.
Highlights
Sepsis, a leading cause of morbidity and mortality, is not a homogeneous disease but rather a syndrome encompassing many heterogeneous pathophysiologies
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 [10,11,12,13] (Figure 2)
We identified a more robust immune response in sepsis as compared to systemic inflammatory response syndrome (SIRS) which was muted in sepsis non-survivors, even when considering a 28-day mortality endpoint
Summary
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. Sepsis is a heterogeneous syndrome that leads to significant morbidity and mortality. Despite the availability of potent antibiotics and intensive care, mortality remains at. The majority of in-hospital sepsis deaths occur in patients with mild clinical disease that would not warrant early goal-directed therapy [4]. That mild initial clinical illness progresses to severe sepsis and death despite appropriate clinical care highlights host responses to sepsis that differ between survivors and nonsurvivors. There remains a high rate of morbidity and mortality after hospital discharge identifying another unmet prognostic need [5]
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