Early PREdiction of sepsis using leukocyte surface biomarkers: the ExPRES-sepsis cohort study.

PURPOSE: Reliable biomarkers for predicting subsequent sepsis among patients with suspected acute infection are lacking. In patients presenting to emergency departments (EDs) with suspected acute infection, we aimed to evaluate the reliability and discriminant ability of 47 leukocyte biomarkers as predictors of sepsis (Sequential Organ Failure Assessment score ≥ 2 at 24 h and/or 72 h following ED presentation). METHODS: In a multi-centre cohort study in four EDs and intensive care units (ICUs), we standardised flow-cytometric leukocyte biomarker measurement and compared patients with suspected acute infection (cohort-1) with two comparator cohorts: ICU patients with established sepsis (cohort-2), and ED patients without infection or systemic inflammation but requiring hospitalization (cohort-3). RESULTS: Between January 2014 and February 2016, we recruited 272, 59 and 75 patients to cohorts 1, 2, and 3, respectively. Of 47 leukocyte biomarkers, 14 were non-reliable, and 17 did not discriminate between the three cohorts. Discriminant analyses for predicting sepsis within cohort-1 were undertaken for eight neutrophil (cluster of differentiation antigens (CD) CD15; CD24; CD35; CD64; CD312; CD11b; CD274; CD279), seven monocyte (CD35; CD64; CD312; CD11b; HLA-DR; CD274; CD279) and a CD8 T-lymphocyte biomarker (CD279). Individually, only higher neutrophil CD279 [OR 1.78 (95% CI 1.23-2.57); P = 0.002], higher monocyte CD279 [1.32 (1.03-1.70); P = 0.03], and lower monocyte HLA-DR [0.73 (0.55-0.97); P = 0.03] expression were associated with subsequent sepsis. With logistic regression the optimum biomarker combination was increased neutrophil CD24 and neutrophil CD279, and reduced monocyte HLA-DR expression, but no combination had clinically relevant predictive validity. CONCLUSIONS: From a large panel of leukocyte biomarkers, immunosuppression biomarkers were associated with subsequent sepsis in ED patients with suspected acute infection. CLINICAL TRIAL REGISTRATION: NCT02188992.

Cell-surface signatures of immune dysfunction risk-stratify critically ill patients: INFECT study.

PURPOSE: Cellular immune dysfunctions, which are common in intensive care patients, predict a number of significant complications. In order to effectively target treatments, clinically applicable measures need to be developed to detect dysfunction. The objective was to confirm the ability of cellular markers associated with immune dysfunction to stratify risk of secondary infection in critically ill patients. METHODS: Multi-centre, prospective observational cohort study of critically ill patients in four UK intensive care units. Serial blood samples were taken, and three cell surface markers associated with immune cell dysfunction [neutrophil CD88, monocyte human leucocyte antigen-DR (HLA-DR) and percentage of regulatory T cells (Tregs)] were assayed on-site using standardized flow cytometric measures. Patients were followed up for the development of secondary infections. RESULTS: A total of 148 patients were recruited, with data available from 138. Reduced neutrophil CD88, reduced monocyte HLA-DR and elevated proportions of Tregs were all associated with subsequent development of infection with odds ratios (95% CI) of 2.18 (1.00-4.74), 3.44 (1.58-7.47) and 2.41 (1.14-5.11), respectively. Burden of immune dysfunction predicted a progressive increase in risk of infection, from 14% for patients with no dysfunction to 59% for patients with dysfunction of all three markers. The tests failed to risk stratify patients shortly after ICU admission but were effective between days 3 and 9. CONCLUSIONS: This study confirms our previous findings that three cell surface markers can predict risk of subsequent secondary infection, demonstrates the feasibility of standardized multisite flow cytometry and presents a tool which can be used to target future immunomodulatory therapies. TRIAL REGISTRATION: The study was registered with clinicaltrials.gov (NCT02186522).

Lactate - Arterial and Venous Agreement in Sepsis: a prospective observational study.

BACKGROUND: Sepsis is a common condition in the emergency department (ED). Lactate measurement is an important part of management: arterial lactate (A-LACT) measurement is the gold standard. There is increasing use of peripheral venous lactate (PV-LACT); however, there is little research supporting the interchangeability of the two measures.If PV-LACT has good agreement with A-LACT, it would significantly reduce patient discomfort and the risks of arterial sampling for a large group of acutely unwell patients, while allowing faster and wider screening, with potential reduced costs to the healthcare system. OBJECTIVE: The aim of this study is to determine the agreement between PV-LACT and A-LACT in septic patients attending the ED. METHODS: We carried out a prospective observational cohort study of 304 consented patients presenting with sepsis to a single UK NHS ED (110 000 adult attendances annually) taking paired PV-LACT and A-LACT. Bland-Altman analysis was carried out to determine agreement. Receiver operating characteristic curves and 2×2 tables were constructed to explore the predictive value of PV-LACT for A-LACT. RESULTS: The mean difference (PV-LACT-A-LACT) is 0.4 mmol/l [95% confidence interval (CI): 0.37-0.45], with 95% limits of agreement from -0.4 (95% CI: -0.45 to -0.32) to 1.2 (95% CI: 1.14-1.27). A PV-LACT of at least 2 mmol/l predicts an A-LACT of at least 2 with 100% sensitivity (95% CI: 89-100%) and 83% specificity (95% CI: 77-87%). CONCLUSION: This study is the largest comparing the two measurements, and shows good clinical agreement. We recommend using PV-LACT in the routine screening of septic patients. A PV-LACT less than 2 mmol/l is predictive of an A-LACT less than 2 mmol/l.

Capillary and Venous Lactate Agreement: a pilot prospective observational study.

BACKGROUND: Blood lactate is a marker of patient illness severity. Capillary lactate (CAP-LACT) measurement can potentially improve patient screening; however, it has poor evidence of clinical utility. AIM: We aimed to investigate agreement between CAP-LACT and peripheral venous lactate (PV-LACT). METHODS: We performed a prospective observational pilot study of 99 patients requiring lactate measurement. Paired CAP-LACT and PV-LACT was recorded. Agreement was determined by Bland-Altman analysis. RESULTS: Bias was 0.2 mmol/L, with 95% limits of agreement from -1.9 to 2.3. CONCLUSIONS: CAP-LACT has poor agreement with PV-LACT. Further research is needed to improve its potential clinical utility.

Early PREdiction of Severe Sepsis (ExPRES-Sepsis) study: protocol for an observational derivation study to discover potential leucocyte cell surface biomarkers.

INTRODUCTION: Sepsis is an acute illness resulting from infection and the host immune response. Early identification of individuals at risk of developing life-threatening severe sepsis could enable early triage and treatment, and improve outcomes. Currently available biomarkers have poor predictive value for predicting subsequent clinical course in patients with suspected infection. Circulating leucocytes provide readily accessible tissues that reflect many aspects of the complex immune responses described in sepsis. We hypothesise that measuring cellular markers of immune responses by flow cytometry will enable early identification of infected patients at risk of adverse outcomes. We aim to characterise leucocyte surface markers (biomarkers) and their abnormalities in a population of patients presenting to the hospital emergency department with suspected sepsis, and explore their ability to predict subsequent clinical course. METHODS AND ANALYSIS: We will conduct a prospective, multicentre, clinical, exploratory, cohort observational study. To answer our study question, 3 patient populations will be studied. First, patients with suspected sepsis from the emergency department (n=300). To assess performance characteristics of potential tests, critically ill patients with established sepsis, and age and gender matched patients without suspicion of infection requiring hospital admission (both n=100) will be recruited as comparator populations. In all 3 groups, we plan to assess circulating biomarker profiles using flow cytometry. We will select candidate biomarkers by cross-cohort comparison, and then explore their predictive value for clinical outcomes within the cohort with suspected sepsis. ETHICS AND DISSEMINATION: The study will be carried out based on the principles in the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice. Ethics approval has been granted from the Scotland A Research Ethics Committee (REC) and Oxford C REC. On conclusion of this study, the results will be disseminated via peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02188992; Pre-results.

Predictive value of cell-surface markers in infections in critically ill patients: protocol for an observational study (ImmuNe FailurE in Critical Therapy (INFECT) Study).

INTRODUCTION: Critically ill patients are at high risk of nosocomial infections, with between 20% and 40% of patients admitted to the intensive care unit (ICU) acquiring infections. These infections result in increased antibiotic use, and are associated with morbidity and mortality. Although critical illness is classically associated with hyperinflammation, the high rates of nosocomial infection argue for an importance of effect of impaired immunity. Our group recently demonstrated that a combination of 3 measures of immune cell function (namely neutrophil CD88, monocyte HLA-DR and % regulatory T cells) identified a patient population with a 2.4-5-fold greater risk for susceptibility to nosocomial infections. METHODS AND ANALYSIS: This is a prospective, observational study to determine whether previously identified markers of susceptibility to nosocomial infection can be validated in a multicentre population, as well as testing several novel markers which may improve the risk of nosocomial infection prediction. Blood samples from critically ill patients (those admitted to the ICU for at least 48 hours and requiring mechanical ventilation alone or support of 2 or more organ systems) are taken and undergo whole blood staining for a range of immune cell surface markers. These samples undergo analysis on a standardised flow cytometry platform. Patients are followed up to determine whether they develop nosocomial infection. Infections need to meet strict prespecified criteria based on international guidelines; where these criteria are not met, an adjudication panel of experienced intensivists is asked to rule on the presence of infection. Secondary outcomes will be death from severe infection (sepsis) and change in organ failure. ETHICS AND DISSEMINATION: Ethical approval including the involvement of adults lacking capacity has been obtained from respective English and Scottish Ethics Committees. Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02186522; Pre-results.

Arterial lactate levels in an emergency department are associated with mortality: a prospective observational cohort study.

OBJECTIVES: Lactate measurements are routinely carried out in emergency departments and are associated with increased mortality in septic patients. However, no definitive research has been carried out into whether lactate measurements can be used as a prognostic marker in a clinically unwell population in the emergency department. METHODS: We carried out a prospective observational cohort study in consecutive patients whose arterial lactate concentration was measured in the emergency department of a tertiary referral hospital assessing 110,000 patients per year between 11th May and 11th August 2011. The main outcome measure was 30-day mortality. RESULTS: There were 120 deaths (16.1%) at 30 days postattendance in our cohort of 747 patients. Multivariate logistic regression revealed lower lactate levels were associated with 30-day survival: ORs for 30-day death compared with lactate ≥4 were 0.125 (95% CI 0.068 to 0.229) for lactate <2 and 0.273 (95% CI 0.140 to 0.533) for lactate 2-<4. Kaplan-Meier analysis showed a survival difference when dividing lactate concentrations into strata (p<0.0001). This survival difference was maintained when septic diagnoses were taken into account. CONCLUSIONS: A single arterial lactate measurement on presentation to the emergency department predicts 30-day mortality independent of other measures of illness severity.

Peripheral venous and arterial lactate agreement in septic patients in the emergency department: a pilot study.

Lactate measurements are routinely used in sepsis for prognostication and for guiding treatment. Although venous lactate measurements have widely been used, most studies have used arterial lactate (A-LACT). The interchangeability between the measurements is debatable. This pilot study aimed to investigate whether an agreement exists between peripheral venous lactate (PV-LACT) and A-LACT with respect to sepsis in the Emergency Department (ED). PV-LACT lactate and A-LACT measurements were taken from a convenience sample of 37 patients presenting to a tertiary hospital ED between November 2010 and August 2011. The agreement between the paired measurements was assessed using Bland-Altman analysis. The mean difference between the measurements (venous-arterial) was 0.54 mmol/l, with 95% limits of agreement of -0.11 to 1.18 mmol/l. This pilot study demonstrates the potential use of PV-LACT as a substitute for A-LACT measurement in septic ED patients. However, further definitive investigation is needed to support widespread clinical adoption of peripheral venous lactate.

Early lactate clearance in septic patients with elevated lactate levels admitted from the emergency department to intensive care: time to aim higher?

PURPOSE: Septic patients with hyperlactatemia have increased mortality rates, irrespective of hemodynamic and oxygen-derived variables. The aims of the study are the following: (1) to ascertain whether lactate clearance (LC) (percentage change in lactate over unit time) predicts mortality in septic patients admitted to intensive care directly from the emergency department and (2) to calculate the optimal "cut-off" value for mortality prediction. METHODS: Three-year retrospective observational study of consecutive patients with severe sepsis and septic shock admitted to intensive care from the emergency department of a tertiary UK hospital. We calculated 6-hour LC, performed receiver operating characteristic analyses to calculate optimal cut-off values for initial lactate and LC, dichotomized patients according to the LC cut-off, and calculated hazard ratios using a Cox proportional hazards model. RESULTS: One hundred six patients were identified; 78, after exclusions. Lactate clearance was independently associated with 30-day mortality (P<.04); optimal cut-off, 36%. Mortality rates were 61.1% and 10.7% for patients with 6-hour LC 36% or less and greater than 36%, respectively. Hazard ratio for death with LC 36% or less was 7.33 (95% confidence interval, 2.17-24.73; P<.001). CONCLUSIONS: Six-hour LC was independently associated with mortality, and the optimal cut-off value was 36%, significantly higher than previously reported. We would support further research investigating this higher LC as a distinct resuscitation end point in patients with severe sepsis and septic shock.

Inflammatory suppression rapidly attenuates microvascular dysfunction in rheumatoid arthritis.

Rheumatoid arthritis (RA) is associated with greater risk of cardiovascular morbidity and mortality, the inflammatory component of RA being strongly linked to this excess risk. Endothelial dysfunction is linked to atherosclerosis and has been demonstrated in larger vessels in RA. In this pilot study, we determined for the first time whether skin microvascular function was impaired in patients with active RA and also determined its response to anti-inflammatory treatment. This was assessed non-invasively using laser Doppler imaging combined with iontophoresis of the vasodilators acetylcholine (ACh, endothelium dependent) and sodium nitroprusside (SNP, endothelium independent) to the forearm. Eight RA patients admitted for acute flare-ups were assessed before and following anti-inflammatory treatment. Standard laboratory indices were obtained along with pain perception (VAS). A control group of eight subjects was included for baseline comparison. Compared to this group, vascular function was substantially and significantly (P<0.00001) lower in RA patients. Following treatment, as CRP and VAS decreased, vascular function improved for both ACh (P<0.00001) and SNP (P=0.001), this improvement being significantly greater for ACh (P<0.001). Vascular dysfunction is evident in RA patients, even at the level of the cutaneous microcirculation, but improves as inflammation regresses. Assessment of cutaneous vascular function may be a useful, non-invasive surrogate indicator of vascular risk in RA, inclusive of myocardial microvascular abnormalities.