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1.  Disease Progression in Hemodynamically Stable Patients Presenting to the Emergency Department With Sepsis 
Aggressive diagnosis and treatment of patients presenting to the emergency department (ED) with septic shock has been shown to reduce mortality. To enhance the ability to intervene in patients with lesser illness severity, a better understanding of the natural history of the early progression from simple infection to more severe illness is needed.
The objectives were to 1) describe the clinical presentation of ED sepsis, including types of infection and causative microorganisms, and 2) determine the incidence, patient characteristics, and mortality associated with early progression to septic shock among ED patients with infection.
This was a multicenter study of adult ED patients with sepsis but no evidence of shock. Multivariable logistic regression was used to identify patient factors for early progression to shock and its association with 30-day mortality.
Of 472 patients not in shock at ED presentation (systolic blood pressure > 90 mm Hg and lactate < 4 mmol / L), 84 (17.8%) progressed to shock within 72 hours. Independent factors associated with early progression to shock included older age, female sex, hyperthermia, anemia, comorbid lung disease, and vascular access device infection. Early progression to shock (vs. no progression) was associated with higher 30-day mortality (13.1% vs. 3.1%, odds ratio [OR] = 4.72, 95% confidence interval [CI] = 2.01 to 11.1; p ≤ 0.001). Among 379 patients with uncomplicated sepsis (i.e., no evidence of shock or any end-organ dysfunction), 86 (22.7%) progressed to severe sepsis or shock within 72 hours of hospital admission.
A significant portion of ED patients with less severe sepsis progress to severe sepsis or shock within 72 hours. Additional diagnostic approaches are needed to risk stratify and more effectively treat ED patients with sepsis.
PMCID: PMC4283798  PMID: 20370777
sepsis; outcomes; septic shock; progression; biomarkers
2.  An integrated transcriptome and expressed variant analysis of sepsis survival and death 
Genome Medicine  2014;6(11):111.
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.
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.
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.
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 NCT00258869. Registered on 23 November 2005.
Electronic supplementary material
The online version of this article (doi:10.1186/s13073-014-0111-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4274761  PMID: 25538794
3.  An integrated clinico-metabolomic model improves prediction of death in sepsis 
Science translational medicine  2013;5(195):195ra95.
Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features, and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would die differed markedly from those who would survive. The different profiles of proteins and metabolites clustered into fatty acid transport and β-oxidation, gluconeogenesis and the citric acid cycle. They differed consistently among several sets of patients, and diverged more as death approached. In contrast, the metabolomes and proteomes of surviving patients with mild sepsis did not differ from survivors with severe sepsis or septic shock. An algorithm derived from clinical features together with measurements of seven metabolites predicted patient survival. This algorithm may help to guide the treatment of individual patients with sepsis.
PMCID: PMC3924586  PMID: 23884467
4.  Metabolomic Derangements Are Associated with Mortality in Critically Ill Adult Patients 
PLoS ONE  2014;9(1):e87538.
To identify metabolomic biomarkers predictive of Intensive Care Unit (ICU) mortality in adults.
Comprehensive metabolomic profiling of plasma at ICU admission to identify biomarkers associated with mortality has recently become feasible.
We performed metabolomic profiling of plasma from 90 ICU subjects enrolled in the BWH Registry of Critical Illness (RoCI). We tested individual metabolites and a Bayesian Network of metabolites for association with 28-day mortality, using logistic regression in R, and the CGBayesNets Package in MATLAB. Both individual metabolites and the network were tested for replication in an independent cohort of 149 adults enrolled in the Community Acquired Pneumonia and Sepsis Outcome Diagnostics (CAPSOD) study.
We tested variable metabolites for association with 28-day mortality. In RoCI, nearly one third of metabolites differed among ICU survivors versus those who died by day 28 (N = 57 metabolites, p<.05). Associations with 28-day mortality replicated for 31 of these metabolites (with p<.05) in the CAPSOD population. Replicating metabolites included lipids (N = 14), amino acids or amino acid breakdown products (N = 12), carbohydrates (N = 1), nucleotides (N = 3), and 1 peptide. Among 31 replicated metabolites, 25 were higher in subjects who progressed to die; all 6 metabolites that are lower in those who die are lipids. We used Bayesian modeling to form a metabolomic network of 7 metabolites associated with death (gamma-glutamylphenylalanine, gamma-glutamyltyrosine, 1-arachidonoylGPC(20:4), taurochenodeoxycholate, 3-(4-hydroxyphenyl) lactate, sucrose, kynurenine). This network achieved a 91% AUC predicting 28-day mortality in RoCI, and 74% of the AUC in CAPSOD (p<.001 in both populations).
Both individual metabolites and a metabolomic network were associated with 28-day mortality in two independent cohorts. Metabolomic profiling represents a valuable new approach for identifying novel biomarkers in critically ill patients.
PMCID: PMC3907548  PMID: 24498130
5.  Gene Expression-Based Classifiers Identify Staphylococcus aureus Infection in Mice and Humans 
PLoS ONE  2013;8(1):e48979.
Staphylococcus aureus causes a spectrum of human infection. Diagnostic delays and uncertainty lead to treatment delays and inappropriate antibiotic use. A growing literature suggests the host’s inflammatory response to the pathogen represents a potential tool to improve upon current diagnostics. The hypothesis of this study is that the host responds differently to S. aureus than to E. coli infection in a quantifiable way, providing a new diagnostic avenue. This study uses Bayesian sparse factor modeling and penalized binary regression to define peripheral blood gene-expression classifiers of murine and human S. aureus infection. The murine-derived classifier distinguished S. aureus infection from healthy controls and Escherichia coli-infected mice across a range of conditions (mouse and bacterial strain, time post infection) and was validated in outbred mice (AUC>0.97). A S. aureus classifier derived from a cohort of 94 human subjects distinguished S. aureus blood stream infection (BSI) from healthy subjects (AUC 0.99) and E. coli BSI (AUC 0.84). Murine and human responses to S. aureus infection share common biological pathways, allowing the murine model to classify S. aureus BSI in humans (AUC 0.84). Both murine and human S. aureus classifiers were validated in an independent human cohort (AUC 0.95 and 0.92, respectively). The approach described here lends insight into the conserved and disparate pathways utilized by mice and humans in response to these infections. Furthermore, this study advances our understanding of S. aureus infection; the host response to it; and identifies new diagnostic and therapeutic avenues.
PMCID: PMC3541361  PMID: 23326304
6.  Multiplex PCR To Diagnose Bloodstream Infections in Patients Admitted from the Emergency Department with Sepsis ▿  
Sepsis is caused by a heterogeneous group of infectious etiologies. Early diagnosis and the provision of appropriate antimicrobial therapy correlate with positive clinical outcomes. Current microbiological techniques are limited in their diagnostic capacities and timeliness. Multiplex PCR has the potential to rapidly identify bloodstream infections and fill this diagnostic gap. We identified patients from two large academic hospital emergency departments with suspected sepsis. The results of a multiplex PCR that could detect 25 bacterial and fungal pathogens were compared to those of blood culture. The results were analyzed with respect to the likelihood of infection, sepsis severity, the site of infection, and the effect of prior antibiotic therapy. We enrolled 306 subjects with suspected sepsis. Of these, 43 were later determined not to have infectious etiologies. Of the remaining 263 subjects, 70% had sepsis, 16% had severe sepsis, and 14% had septic shock. The majority had a definite infection (41.5%) or a probable infection (30.7%). Blood culture and PCR performed similarly with samples from patients with clinically defined infections (areas under the receiver operating characteristic curves, 0.64 and 0.60, respectively). However, blood culture identified more cases of septicemia than PCR among patients with an identified infectious etiology (66 and 46, respectively; P = 0.0004). The two tests performed similarly when the results were stratified by sepsis severity or infection site. Blood culture tended to detect infections more frequently among patients who had previously received antibiotics (P = 0.06). Conversely, PCR identified an additional 24 organisms that blood culture failed to detect. Real-time multiplex PCR has the potential to serve as an adjunct to conventional blood culture, adding diagnostic yield and shortening the time to pathogen identification.
PMCID: PMC2812289  PMID: 19846634
7.  Early lactate clearance is associated with biomarkers of inflammation, coagulation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock 
Lactate clearance, a surrogate for the magnitude and duration of global tissue hypoxia, is used diagnostically, therapeutically and prognostically. This study examined the association of early lactate clearance with selected inflammatory, coagulation, apoptosis response biomarkers and organ dysfunction scores in severe sepsis and septic shock.
Measurements of serum arterial lactate, biomarkers (interleukin-1 receptor antagonist, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-alpha, intercellular adhesion molecule-1, high mobility group box-1, D-Dimer and caspase-3), and organ dysfunction scores (Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II, Multiple Organ Dysfunction Score, and Sequential Organ Failure Assessment) were obtained in conjunction with a prospective, randomized study examining early goal-directed therapy in severe sepsis and septic shock patients presenting to the emergency department (ED). Lactate clearance was defined as the percent change in lactate levels after six hours from a baseline measurement in the ED.
Two-hundred and twenty patients, age 65.0 +/- 17.1 years, were examined, with an overall lactate clearance of 35.5 +/- 43.1% and in-hospital mortality rate of 35.0%. Patients were divided into four quartiles of lactate clearance, -24.3 +/- 42.3, 30.1 +/- 7.5, 53.4 +/- 6.6, and 75.1 +/- 7.1%, respectively (p < 0.01). The mean levels of all biomarkers and organ dysfunction scores over 72 hours were significantly lower with higher lactate clearance quartiles (p < 0.01). There was a significant decreased in-hospital, 28-day, and 60-day mortality in the higher lactate clearance quartiles (p < 0.01).
Early lactate clearance as a surrogate for the resolution of global tissue hypoxia is significantly associated with decreased levels of biomarkers, improvement in organ dysfunction and outcome in severe sepsis and septic shock.
PMCID: PMC2837000  PMID: 20181046

Results 1-7 (7)