Empiric antibiotic therapy in early periprosthetic joint infection: a retrospective cohort study.

PURPOSE: Periprosthetic joint infection (PJI) is a devastating complication following total knee or total hip arthroplasty (TKA/THA). Appropriate empiric antibiotic treatment, initiated directly after debridement and implant retention (DAIR), is suggested to contribute to treatment success. The aim of this study was to describe the microbiology and the antibiotic susceptibility in early PJI to guide future empiric treatment in a region with a low incidence of methicillin-resistant Staphylococcus aureus (MRSA). METHODS: Consecutive patients who underwent DAIR within 3 months after primary unilateral TKA or THA between January 2011 and December 2018 were retrospectively identified from the hospital electronic health records. Data on causative pathogens, antimicrobial susceptibility and the number of post-operative days until cultures demonstrated bacterial growth were collected. RESULTS: One hundred and eleven early PJIs were identified of which 65 (59%) were monomicrobial and 46 (41%) polymicrobial. Among all isolated pathogens, Staphylococcus aureus (n = 53; 29%) was the most commonly identified pathogen in early PJI without any involvement of MRSA. 72% of PJIs were susceptible to vancomycin which could be increased to around 90% by adding gram-negative coverage. On the 5th postoperative day, bacterial growth was observed in 98% of cases. All gram-negative bacteria demonstrated positive tissue cultures on the 4th postoperative day. CONCLUSION: Vancomycin combined with ciprofloxacin or a third generation cephalosporin provided the highest antimicrobial coverage of all responsible pathogens identified in early PJI. Empiric treatment of gram-negative treatment can be safely terminated in the absence of gram-negative pathogens after 4 days of culturing in cases without preoperative antibiotic treatment.

Correction to: Predicting the clinical trajectory in critically ill patients with sepsis: a cohort study.

In the publication of this article [1], there are 4 collaborating authors missing from the 'MARS consortium'. This has now been included in this correction article.

Predicting the clinical trajectory in critically ill patients with sepsis: a cohort study.

BACKGROUND: To develop a mathematical model to estimate daily evolution of disease severity using routinely available parameters in patients admitted to the intensive care unit (ICU). METHODS: Over a 3-year period, we prospectively enrolled consecutive adults with sepsis and categorized patients as (1) being at risk for developing (more severe) organ dysfunction, (2) having (potentially still reversible) limited organ failure, or (3) having multiple-organ failure. Daily probabilities for transitions between these disease states, and to death or discharge, during the first 2 weeks in ICU were calculated using a multi-state model that was updated every 2 days using both baseline and time-varying information. The model was validated in independent patients. RESULTS: We studied 1371 sepsis admissions in 1251 patients. Upon presentation, 53 (4%) were classed at risk, 1151 (84%) had limited organ failure, and 167 (12%) had multiple-organ failure. Among patients with limited organ failure, 197 (17%) evolved to multiple-organ failure or died and 809 (70%) improved or were discharged alive within 14 days. Among patients with multiple-organ failure, 67 (40%) died and 91 (54%) improved or were discharged. Treatment response could be predicted with reasonable accuracy (c-statistic ranging from 0.55 to 0.81 for individual disease states, and 0.67 overall). Model performance in the validation cohort was similar. CONCLUSIONS: This prediction model that estimates daily evolution of disease severity during sepsis may eventually support clinicians in making better informed treatment decisions and could be used to evaluate prognostic biomarkers or perform in silico modeling of novel sepsis therapies during trial design. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01905033.

Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients.

Preclinical studies have suggested that platelets influence the host response during sepsis. We sought to assess the association of admission thrombocytopenia with the presentation, outcome, and host response in patients with sepsis. Nine hundred thirty-one consecutive sepsis patients were stratified according to platelet counts (very low <50 × 10(9)/L, intermediate-low 50 × 10(9) to 99 × 10(9)/L, low 100 × 10(9) to 149 × 10(9)/L, or normal 150 × 10(9) to 399 × 10(9)/L) on admission to the intensive care unit. Sepsis patients with platelet counts <50 × 10(9)/L and 50 × 10(9) to 99 × 10(9)/L presented with higher Acute Physiology and Chronic Health Evaluation scores and more shock. Both levels of thrombocytopenia were independently associated with increased 30-day mortality (hazard ratios with 95% confidence intervals 2.00 [1.32-3.05] and 1.72 [1.22-2.44], respectively). To account for baseline differences besides platelet counts, propensity matching was performed, after which the association between thrombocytopenia and the host response was tested, as evaluated by measuring 17 plasma biomarkers indicative of activation and/or dysregulation of pathways implicated in sepsis pathogenesis and by whole genome blood leukocyte expression profiling. In the propensity matched cohort, platelet counts < 50 × 10(9)/L were associated with increased cytokine levels and enhanced endothelial cell activation. All thrombocytopenic groups showed evidence of impaired vascular integrity, whereas coagulation activation was similar between groups. Blood microarray analysis revealed a distinct gene expression pattern in sepsis patients with <50 × 10(9)/L platelets, showing reduced signaling in leukocyte adhesion and diapedesis and increased complement signaling. These data show that admission thrombocytopenia is associated with enhanced mortality and a more disturbed host response during sepsis independent of disease severity, thereby providing clinical validity to animal studies on the role of platelets in severe infection.

Effect of cytomegalovirus reactivation on the time course of systemic host response biomarkers in previously immunocompetent critically ill patients with sepsis: a matched cohort study.

BACKGROUND: Cytomegalovirus (CMV) reactivation in previously immunocompetent critically ill patients is associated with increased mortality, which has been hypothesized to result from virus-induced immunomodulation. Therefore, we studied the effects of CMV reactivation on the temporal course of host response biomarkers in patients with sepsis. METHODS: In this matched cohort study, each sepsis patient developing CMV reactivation between day 3 and 17 (CMV+) was compared with one CMV seropositive patient without reactivation (CMVs+) and one CMV seronegative patient (CMVs-). CMV serostatus and plasma loads were determined by enzyme-linked immunoassays and real-time polymerase chain reaction, respectively. Systemic interleukin-6 (IL-6), IL-8, IL-18, interferon-gamma-induced protein-10 (IP-10), neutrophilic elastase, IL-1 receptor antagonist (RA), and IL-10 were measured at five time points by multiplex immunoassay. The effects of CMV reactivation on sequential concentrations of these biomarkers were assessed in multivariable mixed models. RESULTS: Among 64 CMV+ patients, 45 could be matched to CMVs+ or CMVs- controls or both. The two baseline characteristics and host response biomarker levels at viremia onset were similar between groups. CMV+ patients had increased IP-10 on day 7 after viremia onset (symmetric percentage difference +44% versus -15% when compared with CMVs+ and +37% versus +4% when compared with CMVs-) and decreased IL-1RA (-41% versus 0% and -49% versus +10%, respectively). However, multivariable analyses did not show an independent association between CMV reactivation and time trends of IL-6, IP-10, IL-10, or IL-1RA. CONCLUSION: CMV reactivation was not independently associated with changes in the temporal trends of host response biomarkers in comparison with non-reactivating patients. Therefore, these markers should not be used as surrogate clinical endpoints for interventional studies evaluating anti-CMV therapy.

The Host Response in Patients with Sepsis Developing Intensive Care Unit-acquired Secondary Infections.

RATIONALE: Sepsis can be complicated by secondary infections. We explored the possibility that patients with sepsis developing a secondary infection while in the intensive care unit (ICU) display sustained inflammatory, vascular, and procoagulant responses. OBJECTIVES: To compare systemic proinflammatory host responses in patients with sepsis who acquire a new infection with those who do not. METHODS: Consecutive patients with sepsis with a length of ICU stay greater than 48 hours were prospectively analyzed for the development of ICU-acquired infections. Twenty host response biomarkers reflective of key pathways implicated in sepsis pathogenesis were measured during the first 4 days after ICU admission and at the day of an ICU-acquired infection or noninfectious complication. MEASUREMENTS AND MAIN RESULTS: Of 1,237 admissions for sepsis (1,089 patients), 178 (14.4%) admissions were complicated by ICU-acquired infections (at Day 10 [6-13], median with interquartile range). Patients who developed a secondary infection showed higher disease severity scores and higher mortality up to 1 year than those who did not. Analyses of biomarkers in patients who later went on to develop secondary infections revealed a more dysregulated host response during the first 4 days after admission, as reflected by enhanced inflammation, stronger endothelial cell activation, a more disturbed vascular integrity, and evidence for enhanced coagulation activation. Host response reactions were similar at the time of ICU-acquired infectious or noninfectious complications. CONCLUSIONS: Patients with sepsis who developed an ICU-acquired infection showed a more dysregulated proinflammatory and vascular host response during the first 4 days of ICU admission than those who did not develop a secondary infection.

Incidence, Predictors, and Outcomes of New-Onset Atrial Fibrillation in Critically Ill Patients with Sepsis. A Cohort Study.

RATIONALE: Patients admitted to intensive care units with sepsis are prone to developing cardiac dysrhythmias, most commonly atrial fibrillation. OBJECTIVES: To determine the incidence, risk factors, and outcomes of atrial fibrillation in a cohort of critically ill patients with sepsis. METHODS: We assessed the association between atrial fibrillation and mortality using time-dependent competing risks survival analysis. Subsequently, for development of a risk score estimating the probability of a first occurrence of atrial fibrillation within the following 24 hours, we performed logistic regression analysis. MEASUREMENTS AND MAIN RESULTS: Among 1,782 patients with sepsis admitted to two tertiary intensive care units in the Netherlands between January 2011 and June 2013, a total of 1,087 episodes of atrial fibrillation occurred in 418 (23%) individuals. The cumulative risk of new-onset atrial fibrillation was 10% (95% confidence interval [CI], 8-12), 22% (95% CI, 18-25), and 40% (95% CI, 36-44) in patients with sepsis, severe sepsis, and septic shock, respectively. New-onset atrial fibrillation was associated with a longer stay (hazard ratio [HR], 0.55; 95% CI, 0.48-0.64), an increased death rate (HR, 1.52; 95% CI, 1.16-2.00), and an overall increased mortality risk (subdistribution HR, 2.10; 95% CI, 1.61-2.73) when considering discharge as a competing event. A simple risk score for daily prediction of atrial fibrillation occurrence yielded good discrimination (C statistic, 0.81; 95% CI, 0.79-0.84) and calibration (chi-square, 9.38; P = 0.31), with similar performance in an independent validation cohort (C statistic, 0.80; 95% CI, 0.76-0.85). CONCLUSIONS: Atrial fibrillation is a common complication of sepsis and independently associated with excess mortality. A simple risk score may identify patients at high risk of this complication. Clinical trial registered with www.clinicaltrials.gov (NCT 01905033).

Short-Course Adjunctive Gentamicin as Empirical Therapy in Patients With Severe Sepsis and Septic Shock: A Prospective Observational Cohort Study.

BACKGROUND.: Metaanalyses failed to demonstrate clinical benefits of beta lactam plus aminoglycoside combination therapy compared to beta lactam monotherapy in patients with sepsis. However, few data exist on the effects of short-course adjunctive aminoglycoside therapy in sepsis patients with organ failure or shock. METHODS.: We prospectively enrolled consecutive patients with severe sepsis or septic shock in 2 intensive care units in the Netherlands from 2011 to 2015. Local antibiotic protocols recommended empirical gentamicin add-on therapy in only 1 of the units. We used logistic regression analyses to determine the association between gentamicin use and the number of days alive and free of renal failure, shock, and death, all on day 14. RESULTS.: Of 648 patients enrolled, 245 received gentamicin (222 of 309 [72%] in hospital A and 23 of 339 [7%] in hospital B) for a median duration of 2 days (interquartile range, 1-3). The adjusted odds ratios associated with gentamicin use were 1.39 (95% confidence interval [CI], 1.00-1.94) for renal failure, 1.34 (95% CI, 0.96-1.86) for shock duration, and 1.41 (95% CI, 0.94-2.12) for day-14 mortality. Based on in vitro susceptibilities, inappropriate (initial) gram-negative coverage was given in 9 of 245 (4%) and 18 of 403 (4%) patients treated and not treated with gentamicin, respectively (P = .62). CONCLUSIONS.: Short-course empirical gentamicin use in patients with sepsis was associated with an increased incidence of renal failure but not with faster reversal of shock or improved survival in a setting with low prevalence of antimicrobial resistance.

Epidemiology of Multiple Herpes Viremia in Previously Immunocompetent Patients With Septic Shock.

Background: Systemic reactivations of herpesviruses may occur in intensive care unit (ICU) patients, even in those without prior immune deficiency. However, the clinical relevance of these events is uncertain. Methods: In this study we selected patients admitted with septic shock and treated for more than 4 days from a prospectively enrolled cohort of consecutive adults in the mixed ICUs of 2 tertiary care hospitals in the Netherlands. We excluded patients who had received antiviral treatment in the week before ICU admission and those with known immunodeficiency. We studied viremia episodes with cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), and varicella zoster virus (VZV) by weekly polymerase chain reaction in plasma. Results: Among 329 patients, we observed 399 viremia episodes in 223 (68%) patients. Viremia with CMV, EBV, HHV-6, HSV-1, HSV-2, and VZV was detected in 60 (18%), 157 (48%), 80 (24%), 87 (26%), 13 (4%), and 2 (0.6%) patients, respectively; 112 (34%) patients had multiple concurrent viremia events. Crude mortality in the ICU was 36% in this latter group compared to 19% in remaining patients (P < .01). After adjustment for potential confounders, time-dependent bias, and competing risks, only concurrent CMV and EBV reactivations remained independently associated with increased mortality (adjusted subdistribution hazard ratio, 3.17; 95% confidence interval, 1.41-7.13). Conclusions: Herpesvirus reactivations were documented in 68% of septic shock patients without prior immunodeficiency and frequently occurred simultaneously. Concurrent reactivations could be independently associated with mortality. Clinical Trials Registration: NCT01905033.

An Unbalanced Inflammatory Cytokine Response Is Not Associated With Mortality Following Sepsis: A Prospective Cohort Study.

OBJECTIVE: The prevailing theory of host response during sepsis states that an excessive production of pro-inflammatory mediators causes early deaths, whereas a predominantly anti-inflammatory response may lead to immunosuppression, secondary infection, and late deaths. We assessed inflammatory (im)balance by measuring pro-inflammatory interleukin-6 and anti-inflammatory interleukin-10 during three distinct time periods after sepsis, and assessed its association with mortality. DESIGN: Prospective observational cohort. SETTING: Two tertiary mixed ICUs in The Netherlands. PATIENTS: Consecutive patients presenting with severe sepsis or septic shock from 2011 to 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We repeatedly measured plasma interleukin-6 and interleukin-10 concentrations using cytometric bead array. Poisson regression was used to analyze the relation between inflammatory markers measured on 1) ICU admission and day 4 mortality, 2) day 4 and day 28 mortality, and 3) ICU discharge and 1-year mortality. Secondary outcome was development of ICU-acquired infections. Among 708 patients, 86 (12%) died within 4 days, 140 (20%) died between days 4 and 28, and an additional 155 (22%) died before 1 year. Interleukin-6 and interleukin-10 levels were both independently associated with mortality, but the balance of this response as modelled by an interleukin-6 and interleukin-10 interaction term was not (relative risk, 0.99; 95% CI, 0.95-1.04 on admission; relative risk, 1.02; 95% CI, 0.98-1.06 on day 4; and relative risk, 1.12; 95% CI, 0.98-1.29 at ICU discharge). However, inflammatory imbalance on day 4 was associated with development of ICU-acquired infections (subdistribution hazard ratio, 0.87; 95% CI, 0.77-0.98). CONCLUSIONS: Although both interleukin-6 and interleukin-10 productions are associated with death, the balance of these inflammatory mediators does not seem to impact either early, intermediate, or late mortality in patients presenting to the ICU with sepsis.

Association of Gender With Outcome and Host Response in Critically Ill Sepsis Patients.

OBJECTIVE: To determine the association of gender with the presentation, outcome, and host response in critically ill patients with sepsis. DESIGN AND SETTING: A prospective observational cohort study in the ICU of two tertiary hospitals between January 2011 and January 2014. PATIENTS: All consecutive critically ill patients admitted with sepsis, involving 1,815 admissions (1,533 patients). INTERVENTIONS: The host response was evaluated on ICU admission by measuring 19 plasma biomarkers reflecting organ systems implicated in sepsis pathogenesis (1,205 admissions) and by applying genome-wide blood gene expression profiling (582 admissions). MEASUREMENTS AND MAIN RESULTS: Sepsis patients admitted to the ICU were more frequently males (61.0%; p < 0.0001 vs females). Baseline characteristics were not different between genders. Urosepsis was more common in females; endocarditis and mediastinitis in men. Disease severity was similar throughout ICU stay. Mortality was similar up to 1 year after ICU admission, and gender was not associated with 90-day mortality in multivariate analyses in a variety of subgroups. Although plasma proteome analyses (including systemic inflammatory and cytokine responses, and activation of coagulation) were largely similar between genders, females showed enhanced endothelial cell activation; this difference was virtually absent in patients more than 55 years old. More than 80% of the leukocyte blood gene expression response was similar in male and female patients. CONCLUSIONS: The host response and outcome in male and female sepsis patients requiring ICU admission are largely similar.

Comparative Analysis of the Host Response to Community-acquired and Hospital-acquired Pneumonia in Critically Ill Patients.

RATIONALE: Preclinical studies suggest that hospitalized patients are susceptible to infections caused by nosocomial respiratory pathogens at least in part because of immune suppression caused by the condition for which they were admitted. OBJECTIVES: We aimed to characterize the systemic host response in hospital-acquired pneumonia (HAP) when compared with community-acquired pneumonia (CAP). METHODS: We performed a prospective study in two intensive care units (ICUs) in 453 patients with HAP (n = 222) or CAP (n = 231). Immune responses were determined on ICU admission by measuring 19 plasma biomarkers reflecting organ systems implicated in infection pathogenesis (in 192 patients with HAP and 183 patients with CAP) and by applying genome-wide blood gene expression profiling (in 111 patients with HAP and 110 patients with CAP). MEASUREMENTS AND MAIN RESULTS: Patients with HAP and CAP presented with similar disease severities and mortality rates did not differ up to 1 year after admission. Plasma proteome analysis revealed largely similar responses, including systemic inflammatory and cytokine responses, and activation of coagulation and the vascular endothelium. The blood leukocyte genomic response was greater than 75% common in patients with HAP and CAP, comprising proinflammatory, antiinflammatory, T-cell signaling, and metabolic pathway gene sets. Patients with HAP showed overexpression of genes involved in cell-cell junction remodeling, adhesion, and diapedesis, which corresponded with lower plasma levels of matrix metalloproteinase-8 and soluble E-selectin. In addition, patients with HAP demonstrated underexpression of a type-I interferon signaling gene signature. CONCLUSIONS: Patients with HAP and CAP present with a largely similar host response at ICU admission.

Admission Hyperglycemia in Critically Ill Sepsis Patients: Association With Outcome and Host Response.

OBJECTIVES: To investigate whether admission hyperglycemia is associated with the presentation and/or outcome of sepsis, what the influence of hyperglycemia is on key host responses to sepsis, and whether hyperglycemia differentially affects patients with diabetes mellitus. DESIGN AND SETTING: A substudy of a prospective observational cohort study was conducted in the intensive care of two tertiary hospitals between January 2011 and July 2013. PATIENTS: Of all consecutive critically ill sepsis patients, admission glucose was used to stratify patients in euglycemia (71-140 mg/dL), mild hyperglycemia (141-199 mg/dL), and severe hyperglycemia (≥ 200 mg/dL), and patients with hypoglycemia were excluded. Fifteen plasma biomarkers providing insight in key host responses implicated in sepsis pathogenesis were measured on admission. MEASUREMENTS AND MAIN RESULTS: Of 987 sepsis patients with admission glucose levels greater than 70 mg/dL, 519 (52.6%) had normal glucose levels, 267 (27.1%) had mild, and 201 (20.4%) severe hyperglycemia. Admission hyperglycemia was accompanied by mitigated alterations in plasma host response biomarker levels indicative of activation of the cytokine network, the vascular endothelium, and the coagulation system in patients without a history of diabetes. Severe, but not mild, admission hyperglycemia was associated with increased 30-day mortality (adjusted hazard ratio, 1.66 [95% CI, 1.24-2.23]), in both patients without diabetes (adjusted hazard ratio, 1.65 [95% CI, 1.12-2.42]) and with diabetes (adjusted hazard ratio, 1.91 [95% CI, 1.01-3.62]). CONCLUSION: Admission hyperglycemia is associated with adverse outcome of sepsis irrespective of the presence or absence of preexisting diabetes by a mechanism unrelated to exaggerated inflammation or coagulation.

Association of diabetes and diabetes treatment with the host response in critically ill sepsis patients.

BACKGROUND: Diabetes is associated with chronic inflammation and activation of the vascular endothelium and the coagulation system, which in a more acute manner are also observed in sepsis. Insulin and metformin exert immune modulatory effects. In this study, we aimed to determine the association of diabetes and preadmission insulin and metformin use with sepsis outcome and host response. METHODS: We evaluated 1104 patients with sepsis, admitted to the intensive care unit and stratified according to the presence or absence of diabetes mellitus. The host response was examined by a targeted approach (by measuring 15 plasma biomarkers reflective of pathways implicated in sepsis pathogenesis) and an unbiased approach (by analyzing whole genome expression profiles in blood leukocytes). RESULTS: Diabetes mellitus was not associated with differences in sepsis presentation or mortality up to 90 days after admission. Plasma biomarker measurements revealed signs of systemic inflammation, and strong endothelial and coagulation activation in patients with sepsis, none of which were altered in those with diabetes. Patients with and without diabetes mellitus, who had sepsis demonstrated similar transcriptional alterations, comprising 74 % of the expressed gene content and involving over-expression of genes associated with pro-inflammatory, anti-inflammatory, Toll-like receptor and metabolic signaling pathways and under-expression of genes associated with T cell signaling pathways. Amongst patients with diabetes mellitus and sepsis, preadmission treatment with insulin or metformin was not associated with an altered sepsis outcome or host response. CONCLUSIONS: Neither diabetes mellitus nor preadmission insulin or metformin use are associated with altered disease presentation, outcome or host response in patients with sepsis requiring intensive care.

Impact of HIV infection on the presentation, outcome and host response in patients admitted to the intensive care unit with sepsis; a case control study.

BACKGROUND: Sepsis is a prominent reason for intensive care unit (ICU) admission in patients with HIV. We aimed to investigate the impact of HIV infection on presentation, outcome and host response in sepsis. METHODS: We performed a prospective observational study in the ICUs of two tertiary hospitals. For the current analyses, we selected all patients diagnosed with sepsis within 24 hours after admission. Host response biomarkers were analyzed in a more homogeneous subgroup of admissions involving HIV-positive patients with pneumosepsis, matched to admissions of HIV-negative patients for age, gender and race. Matching was done by nearest neighbor matching with R package "MatchIt". RESULTS: We analyzed 2251 sepsis admissions including 41 (1.8 %) with HIV infection (32 unique patients). HIV-positive patients were younger and admission of HIV-positive patients more frequently involved pneumonia (73.2 % versus 48.8 % of admissions of HIV-negative patients, P = 0.004). Disease severity and mortality up to one year after admission did not differ according to HIV status. Furthermore, sequential plasma levels of host response biomarkers, providing insight into activation of the cytokine network, the vascular endothelium and the coagulation system, were largely similar in matched admissions of HIV-positive and HIV-negative patients with pneumosepsis. CONCLUSIONS: Sepsis is more often caused by pneumonia in HIV-positive patients. HIV infection has little impact on the disease severity, mortality and host response during sepsis.

A molecular biomarker to diagnose community-acquired pneumonia on intensive care unit admission.

RATIONALE: Community-acquired pneumonia (CAP) accounts for a major proportion of intensive care unit (ICU) admissions for respiratory failure and sepsis. Diagnostic uncertainty complicates case management, which may delay appropriate cause-specific treatment. OBJECTIVES: To characterize the blood genomic response in patients with suspected CAP and identify a candidate biomarker for the rapid diagnosis of CAP on ICU admission. METHODS: The study comprised two cohorts of consecutively enrolled patients treated for suspected CAP on ICU admission. Patients were designated CAP (cases) and no-CAP patients (control subjects) by post hoc assessment. The first (discovery) cohort (101 CAP and 33 no-CAP patients) was enrolled between January 2011 and July 2012; the second (validation) cohort (70 CAP and 30 no-CAP patients) between July 2012 and June 2013. Blood was collected within 24 hours of ICU admission. MEASUREMENTS AND MAIN RESULTS: Blood microarray analysis of CAP and no-CAP patients revealed shared and distinct gene expression patterns. A 78-gene signature was defined for CAP, from which a FAIM3:PLAC8 gene expression ratio was derived with area under curve of 0.845 (95% confidence interval, 0.764-0.917) and positive and negative predictive values of 83% and 81%, respectively. Robustness of the FAIM3:PLAC8 ratio was ascertained by quantitative polymerase chain reaction in the validation cohort. The FAIM3:PLAC8 ratio outperformed plasma procalcitonin and IL-8 and IL-6 in discriminating between CAP and no-CAP patients. CONCLUSIONS: CAP and no-CAP patients presented shared and distinct blood genomic responses. We propose the FAIM3:PLAC8 ratio as a candidate biomarker to assist in the rapid diagnosis of CAP on ICU admission. Clinical trial registered with www.clinicaltrials.gov (NCT 01905033).

Incidence, Risk Factors, and Attributable Mortality of Secondary Infections in the Intensive Care Unit After Admission for Sepsis.

IMPORTANCE: Sepsis is considered to induce immune suppression, leading to increased susceptibility to secondary infections with associated late mortality. OBJECTIVE: To determine the clinical and host genomic characteristics, incidence, and attributable mortality of intensive care unit (ICU)-acquired infections in patients admitted to the ICU with or without sepsis. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study comprising consecutive admissions of more than 48 hours in 2 ICUs in the Netherlands from January 2011 to July 2013 stratified according to admission diagnosis (sepsis or noninfectious). MAIN OUTCOMES AND MEASURES: The primary outcome was ICU-acquired infection (onset >48 hours). Attributable mortality risk (fraction of mortality that can be prevented by elimination of the risk factor, acquired infection) was determined using time-to-event models accounting for competing risk. In a subset of sepsis admissions (n = 461), blood gene expression (whole-genome transcriptome in leukocytes) was analyzed at baseline and at onset of ICU-acquired infectious (n = 19) and noninfectious (n = 9) events. RESULTS: The primary cohort included 1719 sepsis admissions (1504 patients; median age, 62 years; interquartile range [IQR], 51-71 years]; 924 men [61.4%]). A comparative cohort included 1921 admissions (1825 patients, median age, 62 years; IQR, 49-71 years; 1128 men [61.8%] in whom infection was not present in the first 48 hours. Intensive care unit-acquired infections occurred in 13.5% of sepsis ICU admissions (n = 232) and 15.1% of nonsepsis ICU admissions (n = 291). Patients with sepsis who developed an ICU-acquired infection had higher disease severity scores on admission than patients with sepsis who did not develop an ICU-acquired infection (Acute Physiology and Chronic Health Evaluation IV [APACHE IV] median score, 90 [IQR, 72-107] vs 79 [IQR, 62-98]; P < .001) and throughout their ICU stay but did not have differences in baseline gene expression. The population attributable mortality fraction of ICU-acquired infections in patients with sepsis was 10.9% (95% CI, 0.9%-20.6%) by day 60; the estimated difference between mortality in all patients with a sepsis admission diagnosis and mortality in those without ICU-acquired infection was 2.0% (95% CI, 0.2%-3.8%; P = .03) by day 60. Among nonsepsis ICU admissions, ICU-acquired infections had a population attributable mortality fraction of 21.1% (95% CI, 0.6%-41.7%) by day 60. Compared with baseline, blood gene expression at the onset of ICU-acquired infections showed reduced expression of genes involved in gluconeogenesis and glycolysis. CONCLUSIONS AND RELEVANCE: Intensive care unit-acquired infections occurred more commonly in patients with sepsis with higher disease severity, but such infections contributed only modestly to overall mortality. The genomic response of patients with sepsis was consistent with immune suppression at the onset of secondary infection.

Epidemiology, Management, and Risk-Adjusted Mortality of ICU-Acquired Enterococcal Bacteremia.

BACKGROUND: Enterococcal bacteremia has been associated with high case fatality, but it remains unknown to what extent death is caused by these infections. We therefore quantified attributable mortality of intensive care unit (ICU)-acquired bacteremia caused by enterococci. METHODS: From 2011 to 2013 we studied consecutive patients who stayed >48 hours in 2 tertiary ICUs in the Netherlands, using competing risk survival regression and marginal structural modeling to estimate ICU mortality caused by enterococcal bacteremia. RESULTS: Among 3080 admissions, 266 events of ICU-acquired bacteremia occurred in 218 (7.1%) patients, of which 76 were caused by enterococci (incidence rate, 3.0 per 1000 patient-days at risk; 95% confidence interval [CI], 2.3-3.7). A catheter-related bloodstream infection (CRBSI) was suspected in 44 (58%) of these, prompting removal of 68% of indwelling catheters and initiation of antibiotic treatment for a median duration of 3 (interquartile range 1-7) days. Enterococcal bacteremia was independently associated with an increased case fatality rate (adjusted subdistribution hazard ratio [SHR], 2.68; 95% CI, 1.44-4.98). However, for patients with CRBSI, case fatality was similar for infections caused by enterococci and coagulase-negative staphylococci (CoNS; adjusted SHR, 0.91; 95% CI, .50-1.67). Population-attributable fraction of mortality was 4.9% (95% CI, 2.9%-6.9%) by day 90, reflecting a population-attributable risk of 0.8% (95% CI, .4%-1.1%). CONCLUSIONS: ICU-acquired enterococcal bacteremia is associated with increased case fatality; however, the mortality attributable to these infections is low from a population perspective. The virulence of enterococci and CoNS in a setting of CRBSI seems comparable.

A Molecular Host Response Assay to Discriminate Between Sepsis and Infection-Negative Systemic Inflammation in Critically Ill Patients: Discovery and Validation in Independent Cohorts.

BACKGROUND: Systemic inflammation is a whole body reaction having an infection-positive (i.e., sepsis) or infection-negative origin. It is important to distinguish between these two etiologies early and accurately because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on peripheral blood RNAs 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 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 (ICUs). Biomarker discovery utilized an Australian cohort (n = 105) consisting of 74 cases (sepsis patients) and 31 controls (post-surgical patients with infection-negative systemic inflammation) recruited at five tertiary care settings in Brisbane, Australia, from June 3, 2008, to December 22, 2011. A four-gene classifier combining CEACAM4, LAMP1, PLA2G7, and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte Lab, was validated using reverse transcription quantitative PCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Patients for validation were selected from the Molecular Diagnosis and Risk Stratification of Sepsis study (ClinicalTrials.gov, NCT01905033), which recruited ICU patients from the Academic Medical Center in Amsterdam and the University Medical Center Utrecht. Patients recruited from November 30, 2012, to August 5, 2013, were eligible for inclusion in the present study. Validation cohort 1 (n = 59) consisted entirely of unambiguous cases and controls; SeptiCyte Lab gave an area under curve (AUC) of 0.95 (95% CI 0.91-1.00) in this cohort. ROC curve analysis of an independent, more heterogeneous group of patients (validation cohorts 2-5; 249 patients after excluding 37 patients with an infection likelihood of "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 Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility of SeptiCyte Lab was evaluated by comparison to various clinical and laboratory parameters available to a clinician within 24 h of ICU admission. SeptiCyte Lab was significantly better at differentiating cases from controls than all tested parameters, both singly and in various logistic combinations, and more than halved the diagnostic error rate compared to procalcitonin in all tested cohorts and cohort combinations. Limitations of this study relate to (1) cohort compositions that do not perfectly reflect the composition of the intended use population, (2) potential biases that could be introduced as a result of the current lack of a gold standard for diagnosing sepsis, and (3) lack of a complete, unbiased comparison to C-reactive protein. CONCLUSIONS: SeptiCyte Lab is a rapid molecular assay that may be clinically useful in managing ICU patients with systemic inflammation. Further study in population-based cohorts is needed to validate this assay for clinical use.

Cytomegalovirus seroprevalence as a risk factor for poor outcome in acute respiratory distress syndrome*.

OBJECTIVE: Cytomegalovirus reactivation may complicate critical illness in latent carriers of the virus, even in patients who were previously immunocompetent. Patients with acute respiratory distress syndrome are considered to be prone for reactivation. Prophylactic antiviral therapy in immunocompetent cytomegalovirus seropositive patients admitted to the ICU with acute respiratory distress syndrome has therefore been proposed. We assessed cytomegalovirus seroprevalence as a risk factor for morbidity and mortality in patients with acute respiratory distress syndrome. DESIGN: Prospective observational cohort study. We used the number of days alive and free of mechanical ventilation on day 28 as a composite outcome measure and used multivariable ordinal logistic regression analyses to adjust for potential confounders. SETTING: ICUs of two tertiary care hospitals in The Netherlands. PATIENTS: We included all newly admitted patients with acute respiratory distress syndrome who received mechanical ventilation for at least 4 days. Patients with known immunocompromise and those receiving antiviral treatment prior to ICU admission were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Over a 2-year period, 306 patients were included, 209 (68%) of whom were cytomegalovirus seropositive. Cytomegalovirus reactivation occurred in 53 of these cases (26%). One hundred patients (33%) died or continued to be mechanically ventilated by day 28. After adjustment for confounding, cytomegalovirus seroprevalence was not associated with the primary outcome (crude odds ratio, 1.09; 95% CI, 0.70-1.70; adjusted odds ratio, 1.01; 95% CI, 0.64-1.59). Seroprevalence was also not associated with poor outcome in any of the prespecified subgroup analyses. However, a significant association was found in a post hoc subgroup of patients who had developed acute respiratory distress syndrome in a setting of septic shock (adjusted odds ratio, 2.86; 95% CI, 1.32-6.23). The time course of pulmonary markers in survivors was comparable between the two serogroups. CONCLUSIONS: Cytomegalovirus seroprevalence is not associated with prolonged mechanical ventilation or increased mortality in critically ill patients with acute respiratory distress syndrome, with possible exception of patients presenting with septic shock. Therefore, a prevention strategy targeting an unselected cohort of seropositive patients with acute respiratory distress syndrome is unlikely to show any meaningful benefit.