Dataset Information

Pathophysiologic Signatures of Bloodstream Infection in Critically Ill Adults.

ABSTRACT: Objectives:Bloodstream infection is associated with high mortality rates in critically ill patients but is difficult to identify clinically. This results in frequent blood culture testing, exposing patients to additional costs as well as the potential harms of unnecessary antibiotics. The purpose of this study was to assess whether the analysis of bedside physiologic monitoring data could accurately describe a pathophysiologic signature of bloodstream infection in patients admitted to the ICU. Design:Development of a statistical model using physiologic data from a retrospective observational cohort. Setting:University of Virginia Medical Center (Charlottesville, VA), a tertiary-care academic medical center. Patients:Critically ill patients consecutively admitted to either the medical or surgical/trauma ICUs with available physiologic monitoring data between February 2011 and June 2015. Interventions:None. Measurements and Main Results:We analyzed 9,954 ICU admissions with 144 patient-years of vital sign and electrocardiography waveform data, totaling 1.3 million hourly measurements. There were 15,577 blood culture instances, with 1,184 instances of bloodstream infection (8%). The multivariate pathophysiologic signature of bloodstream infection was characterized by abnormalities in 15 different physiologic features. The cross-validated area under the receiver operating characteristic curve was 0.78 (95% CI, 0.69-0.85). We also identified distinct signatures of Gram-negative and fungal bloodstream infections, but not Gram-positive bloodstream infection. Conclusions:Signatures of bloodstream infection can be identified in the routine physiologic monitoring data of critically ill adults. This may assist in identifying infected patients, maximizing diagnostic stewardship, and measuring the effect of new therapeutic modalities for sepsis.

SUBMITTER: Zimmet AN

PROVIDER: S-EPMC7523775 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Pathophysiologic Signatures of Bloodstream Infection in Critically Ill Adults.

Zimmet Alex N AN Clark Matthew T MT Gadrey Shrirang M SM Bell Taison D TD Zimmet Amanda M AM Moorman J Randall JR Moore Christopher C CC

Critical care explorations 20200923 10

<h4>Objectives</h4>Bloodstream infection is associated with high mortality rates in critically ill patients but is difficult to identify clinically. This results in frequent blood culture testing, exposing patients to additional costs as well as the potential harms of unnecessary antibiotics. The purpose of this study was to assess whether the analysis of bedside physiologic monitoring data could accurately describe a pathophysiologic signature of bloodstream infection in patients admitted to th ...[more]

PMID: 33063017

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Project description:BackgroundThe gut microbiome is believed to contribute to bloodstream infection (BSI) via translocation of dominant gut bacteria in vulnerable patient populations. However, conclusively linking gut and blood organisms requires stringent approaches to establish strain-level identity.MethodsWe enrolled a convenience cohort of critically ill patients and investigated 86 bloodstream infection episodes that occurred in 57 patients. Shotgun metagenomic sequencing was used to define constituents of their gut microbiomes, and whole genome sequencing and assembly was done on 23 unique bloodstream isolates that were available from 21 patients. Whole genome sequences were downloaded from public databases and used to establish sequence-identity distribution and define thresholds for unrelated genomes of BSI species. Gut microbiome reads were then aligned to whole genome sequences of the cognate bloodstream isolate and unrelated database isolates to assess identity.ResultsGut microbiome constituents matching the bloodstream infection species were present in half of BSI episodes, and represented >30% relative abundance of gut sequences in 10% of episodes. Among the 23 unique bloodstream organisms that were available for whole genome sequencing, 14 were present in gut at the species level. Sequence alignment applying defined thresholds for identity revealed that 6 met criteria for identical strains in blood and gut, but 8 did not. Sequence identity between BSI isolates and gut microbiome reads was more likely when the species was present at higher relative abundance in gut.ConclusionIn assessing potential gut source for BSI, stringent sequence-based approaches are essential to determine if organisms responsible for BSI are identical to those in gut: of 14 evaluable patients in which the same species was present in both sites, they were identical in 6/14, but were non-identical in 8/14 and thus inconsistent with gut source. This report demonstrates application of sequencing as a key tool to investigate infection tracking within patients.

Project description:Background: Systemic inflammation is a whole body reaction that can have an infection-positive (i.e. sepsis) or infection-negative origin. It is important to distinguish between septic and non-septic presentations early and reliably, because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on a small number of RNAs expressed in peripheral blood could be discovered that would: 1) determine which patients with systemic inflammation had sepsis; 2) be robust across independent patient cohorts; 3) be insensitive to disease severity; and 4) provide diagnostic utility. The overall goal of this study was to identify and validate such a molecular classifier. Methods and Findings: We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICU). Biomarker discovery was conducted with an Australian cohort (n = 105) consisting of sepsis patients and post -surgical patients with infection-negative systemic inflammation. Using this cohort, a four-gene classifier consisting of a combination of CEACAM4, LAMP1, PLA2G7 and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyteÂ® Lab, was externally validated using RT-qPCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Cohort 1 (n=59) consisted of unambiguous septic cases and infection-negative systemic inflammation controls; SeptiCyteÂ® Lab gave an area under curve (AUC) of 0.96 (95% CI: 0.91-1.00). ROC analysis of a more heterogeneous group of patients (Cohorts 2-5; 249 patients after excluding 37 patients with infection likelihood possible) gave an AUC of 0.89 (95% CI: 0.85-0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or the Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility o f SeptiCyteÂ® Lab was evaluated by comparison to various clinical and laboratory parameters that would be available to a clinician within 24 hours of ICU admission. SeptiCyteÂ® Lab was significantly better at differentiating sepsis from infection-negative systemic inflammation than all tested parameters, both singly and in various logistic combinations. SeptiCyteÂ® Lab more than halved the diagnostic error rate compared to PCT in all tested cohorts or cohort combinations. Conclusions: SeptiCyteÂ® Lab is a rapid molecular assay that may be clinically useful in the management of ICU patients with systemic inflammation. SIRS and Sepsis ICU patients, admission samples Retrospective, mutli-site sutdy using retrospective physician adjudication as a comparator

Project description:Background: Systemic inflammation is a whole body reaction that can have an infection-positive (i.e. sepsis) or infection-negative origin. It is important to distinguish between septic and non-septic presentations early and reliably, because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on a small number of RNAs expressed in peripheral blood could be discovered that would: 1) determine which patients with systemic inflammation had sepsis; 2) be robust across independent patient cohorts; 3) be insensitive to disease severity; and 4) provide diagnostic utility. The overall goal of this study was to identify and validate such a molecular classifier. Methods and Findings: We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICU). Biomarker discovery was conducted with an Australian cohort (n = 105) consisting of sepsis patients and post -surgical patients with infection-negative systemic inflammation. Using this cohort, a four-gene classifier consisting of a combination of CEACAM4, LAMP1, PLA2G7 and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte® Lab, was externally validated using RT-qPCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Cohort 1 (n=59) consisted of unambiguous septic cases and infection-negative systemic inflammation controls; SeptiCyte® Lab gave an area under curve (AUC) of 0.96 (95% CI: 0.91-1.00). ROC analysis of a more heterogeneous group of patients (Cohorts 2-5; 249 patients after excluding 37 patients with infection likelihood possible) gave an AUC of 0.89 (95% CI: 0.85-0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or the Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility o f SeptiCyte® Lab was evaluated by comparison to various clinical and laboratory parameters that would be available to a clinician within 24 hours of ICU admission. SeptiCyte® Lab was significantly better at differentiating sepsis from infection-negative systemic inflammation than all tested parameters, both singly and in various logistic combinations. SeptiCyte® Lab more than halved the diagnostic error rate compared to PCT in all tested cohorts or cohort combinations. Conclusions: SeptiCyte® Lab is a rapid molecular assay that may be clinically useful in the management of ICU patients with systemic inflammation. SIRS and Sepsis ICU patients, admission samples

Project description:BackgroundShorter-duration antibiotic treatment is sufficient for a range of bacterial infections, but has not been adequately studied for bloodstream infections. Our systematic review, survey, and observational study indicated equipoise for a trial of 7 versus 14 days of antibiotic treatment for bloodstream infections; a pilot randomized clinical trial (RCT) was a necessary next step to assess feasibility of a larger trial.MethodsWe conducted an open, pilot RCT of antibiotic treatment duration among critically ill patients with bloodstream infection across 11 intensive care units (ICUs). Antibiotic selection, dosing and route were at the discretion of the treating team; patients were randomized 1:1 to intervention arms consisting of two fixed durations of treatment - 7 versus 14 days. We recruited adults with a positive blood culture yielding pathogenic bacteria identified while in ICU. We excluded patients with severe immunosuppression, foci of infection with an established requirement for prolonged treatment, single cultures with potential contaminants, or cultures yielding Staphylococcus aureus or fungi. The primary feasibility outcomes were recruitment rate and adherence to treatment duration protocol. Secondary outcomes included 90-day, ICU and hospital mortality, relapse of bacteremia, lengths of stay, mechanical ventilation and vasopressor duration, antibiotic-free days, Clostridium difficile, antibiotic adverse events, and secondary infection with antimicrobial-resistant organisms.ResultsWe successfully achieved our target sample size (n = 115) and average recruitment rate of 1 (interquartile range (IQR) 0.3-1.5) patient/ICU/month. Adherence to treatment duration was achieved in 89/115 (77%) patients. Adherence differed by underlying source of infection: 26/31 (84%) lung; 18/29 (62%) intra-abdominal; 20/26 (77%) urinary tract; 8/9 (89%) vascular-catheter; 4/4 (100%) skin/soft tissue; 2/4 (50%) other; and 11/12 (92%) unknown sources. Patients experienced a median (IQR) 14 (8-17) antibiotic-free days (of the 28 days after blood culture collection). Antimicrobial-related adverse events included hepatitis in 1 (1%) patient, Clostridium difficile infection in 4 (4%), and secondary infection with highly resistant microorganisms in 10 (9%). Ascertainment was complete for all study outcomes in ICU, in hospital and at 90 days.ConclusionIt is feasible to conduct a RCT to determine whether 7 versus 14 days of antibiotic treatment is associated with comparable 90-day survival.Trial registrationClinicalTrials.gov , identifier: NCT02261506 . Registered on 26 September 2014.

Dataset Information

Pathophysiologic Signatures of Bloodstream Infection in Critically Ill Adults.

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Pathophysiologic Signatures of Bloodstream Infection in Critically Ill Adults.

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