Gut barrier dysfunction and the risk of ICU-acquired bacteremia- a case-control study.

BACKGROUND: Impaired intestinal barrier function can enable passage of enteric microorganisms into the bloodstream and lead to nosocomial bloodstream infections during critical illness. We aimed to determine the relative importance of gut translocation as a source for ICU-acquired enterococcal bacteremia of unknown origin. METHODS: We conducted a nested case-control study in two mixed medical-surgical tertiary ICUs in the Netherlands among patients enrolled between 2011 and 2018. We selected 72 cases with ICU-acquired bacteremia due to enterococci (which are known gastrointestinal tract commensals) and 137 matched controls with bacteremia due to coagulase-negative staphylococci (CoNS) (which are of non-intestinal origin). We measured intestinal fatty acid-binding protein, trefoil factor-3, and citrulline 48 h before bacteremia onset. A composite measure for Gut Barrier Injury (GBI) was calculated as the sum of standardized z-scores for each biomarker plus a clinical gastrointestinal failure score. RESULTS: No single biomarker yielded statistically significant differences between cases and controls. Median composite GBI was higher in cases than in controls (0.58, IQR - 0.36-1.69 vs. 0.32, IQR - 0.53-1.57, p = 0.33) and higher composite measures of GBI correlated with higher disease severity and ICU mortality (p < 0.001). In multivariable analysis, higher composite GBI was not significantly associated with increased occurrence of enterococcal bacteremia relative to CoNS bacteremia (adjusted OR 1.12 95% CI 0.93-1.34, p = 0.22). CONCLUSIONS: We could not demonstrate an association between biomarkers of gastrointestinal barrier dysfunction and an increased occurrence of bacteremia due to gut compared to skin flora during critical illness, suggesting against bacterial translocation as a major vector for acquisition of nosocomial bloodstream infections in the ICU.

The Diagnostic Yield of Routine Admission Blood Cultures in Critically Ill Patients.

OBJECTIVES: Although the Surviving Sepsis Campaign bundle recommends obtaining blood cultures within 1 hour of sepsis recognition, adherence is suboptimal in many settings. We, therefore, implemented routine blood culture collection for all nonelective ICU admissions (regardless of infection suspicion) and evaluated its diagnostic yield. DESIGN: A before-after analysis. SETTING: A mixed-ICU of a tertiary care hospital in the Netherlands. PATIENTS: Patients acutely admitted to the ICU between January 2015 and December 2018. MEASUREMENTS AND MAIN RESULTS: Automatic orders for collecting a single set of blood cultures immediately upon ICU admission were implemented on January 1, 2017. Blood culture results and the impact of contaminated blood cultures were compared for 2015-2016 (before period) and 2017-2018 (after period). Positive blood cultures were categorized as bloodstream infection or contamination. Blood cultures were obtained in 573 of 1,775 patients (32.3%) and in 1,582 of 1,871 patients (84.5%) in the before and after periods, respectively (p < 0.0001), and bloodstream infection was diagnosed in 95 patients (5.4%) and 154 patients (8.2%) in both study periods (relative risk 1.5; 95% CI 1.2-2.0; p = 0.0006). The estimated number needed to culture for one additional patient with bloodstream infection was 17. Blood culture contamination occurred in 40 patients (2.3%) and 180 patients (9.6%) in the before period and after period, respectively (relative risk 4.3; 95% CI 3.0-6.0; p < 0.0001). Rate of vancomycin use or presumed episodes of catheter-related bloodstream infections treated with antibiotics did not differ between both study periods. CONCLUSIONS: Implementation of routine blood cultures was associated with a 1.5-fold increase of detected bloodstream infection. The 4.3-fold increase in contaminated blood cultures was not associated with an increase in vancomycin use in the ICU.

Robustness of sepsis-3 criteria in critically ill patients.

BACKGROUND: Early recognition of sepsis is challenging, and diagnostic criteria have changed repeatedly. We assessed the robustness of sepsis-3 criteria in intensive care unit (ICU) patients. METHODS: We studied the apparent incidence and associated mortality of sepsis-3 among patients who were prospectively enrolled in the Molecular Diagnosis and Risk Stratification of Sepsis (MARS) cohort in the Netherlands, and explored the effects of minor variations in the precise definition and timing of diagnostic criteria for organ failure. RESULTS: Among 1081 patients with suspected infection upon ICU admission, 648 (60%) were considered to have sepsis according to prospective adjudication in the MARS study, whereas 976 (90%) met sepsis-3 criteria, yielding only 64% agreement at the individual patient level. Among 501 subjects developing ICU-acquired infection, these rates were 270 (54%) and 260 (52%), respectively (yielding 58% agreement). Hospital mortality was 234 (36%) vs 277 (28%) for those meeting MARS-sepsis or sepsis-3 criteria upon presentation (p < 0.001), and 121 (45%) vs 103 (40%) for those having sepsis onset in the ICU (p < 0.001). Minor variations in timing and interpretation of organ failure criteria had a considerable effect on the apparent prevalence of sepsis-3, which ranged from 68 to 96% among those with infection at admission, and from 22 to 99% among ICU-acquired cases. CONCLUSION: The sepsis-3 definition lacks robustness as well as discriminatory ability, since nearly all patients presenting to ICU with suspected infection fulfill its criteria. These should therefore be specified in greater detail, and applied more consistently, during future sepsis studies. TRIAL REGISTRATION: The MARS study is registered at ClinicalTrials.gov (identifier NCT01905033).

A pilot study of a novel molecular host response assay to diagnose infection in patients after high-risk gastro-intestinal surgery.

PURPOSE: SeptiCyte LAB measures the expression of four host-response RNAs in peripheral blood to distinguish sepsis from sterile inflammation. This study evaluates whether sequential monitoring of this assay has diagnostic utility in patients after esophageal surgery. MATERIALS AND METHODS: Patients who developed a complication within 30 days following esophageal surgery and a random sample of 100 patients having an uncomplicated course. SeptiCyte LAB scores (ranging 0-10 reflecting increasing likelihood of infection) were compared to post-hoc physician adjudication of infection likelihood. RESULTS: Among 370 esophagectomy patients, 120 (32%) subjects developed a complication requiring ICU (re)admission, 63 (53%) of whom could be analyzed. Immediate postoperative SeptiCyte LAB scores were highly variable, yet similar for patients having a complicated and uncomplicated postoperative course (median score of 2.4 (IQR 1.6-3.3) versus 2.2 (IQR 1.3-3), respectively). In a direct comparison of patients developing a confirmed infectious (n = 34) and non-infectious complication (n = 12), addition of SeptiCyte LAB to CRP improved diagnostic discrimination of infectious complications (AUC 0.88 (95%CI 0.77-0.99)) compared to CRP alone (AUC 0.76 (95%CI 0.61-0.91); p = .04). CONCLUSIONS: Sequential measurement of SeptiCyte LAB may have diagnostic value in the monitoring of surgical patients at high risk of postoperative infection, but its clinical performance in this setting needs to be validated.

Epidemiology and outcomes of source control procedures in critically ill patients with intra-abdominal infection.

PURPOSE: To describe the characteristics and procedural outcomes of source control interventions among Intensive Care Unit (ICU) patients with severe intra-abdominal-infection (IAI). MATERIAL AND METHODS: We identified consecutive patients with suspected IAI in whom a source control intervention had been performed in two tertiary ICUs in the Netherlands, and performed retrospective in-depth case reviews to evaluate procedure type, diagnostic yield, and adequacy of source control after 14 days. RESULTS: A total of 785 procedures were observed among 353 patients, with initial interventions involving 266 (75%) surgical versus 87 (25%) percutaneous approaches. Surgical index procedures typically involved IAI of (presumed) gastrointestinal origin (72%), whereas percutaneous index procedures were mostly performed for infections of the biliary tract/pancreas (50%) or peritoneal cavity (33%). Overall, 178 (50%) patients required multiple interventions (median 3 (IQR 2-4)). In a subgroup of 236 patients having their first procedure upon ICU admission, effective source control was ultimately achieved for 159 (67%) subjects. Persistence of organ failure was associated with inadequacy of source control at day 14, whereas trends in inflammatory markers were non-predictive. CONCLUSIONS: Approximately half of ICU patients with IAI require more than one intervention, yet successful source control is eventually achieved in a majority of cases.

Adalimumab provides long-lasting clinical improvement in refractory mucocutaneous Behçet's disease without formation of antidrug antibodies.

OBJECTIVES: The TNF-blocker adalimumab can be effective in Behçet's disease (BD), a multisystem auto-inflammatory disorder. Unfortunately, the therapeutic efficacy of TNF-blockers can be hampered by the formation of anti-drug antibodies. We present an observational study of adalimumab in refractory BD with measurement of anti-drug antibodies. METHODS: The effect of fortnightly 40mg adalimumab in nine patients with therapy refractory mucocutaneous, non-ocular or organ threatening BD was studied up to 60 months. Primary endpoint was a decrease in disease activity, measured by the BD Current Activity Form (BDCAF) within 6 months. Secondary endpoints included serum cytokines and the long-term formation of anti-adalimumab antibodies. RESULTS: BDCAF improved significantly in all nine patients from 5.4 (SD=1.4) to 2.4 (SD=1.4) (p=0.007) within one month up to 6 months and after prolonged follow up of 5 years. All patients could either taper or stop concomitant therapy. Symptoms of mucocutaneous lesions, erythema nodosum and joint involvement decreased or disappeared. Serum TNF-alpha levels were elevates in five patients and decreased upon treatment (p=0.017). Adalimumab was save and none of the patients experienced therapy failure or antibodies against adalimumab. CONCLUSIONS: We present an observational study on patients with BD treated with adalimumab and provide a basis for long-term use in refractory mucocutaneous BD. These findings show that adalimumab can safely be administered yielding sustainable clinical effects in refractory BD patients with mucocutaneous disease without formation of anti-adalimumab antibodies, even after long follow up.

Validation of a Novel Molecular Host Response Assay to Diagnose Infection in Hospitalized Patients Admitted to the ICU With Acute Respiratory Failure.

OBJECTIVES: Discrimination between infectious and noninfectious causes of acute respiratory failure is difficult in patients admitted to the ICU after a period of hospitalization. Using a novel biomarker test (SeptiCyte LAB), we aimed to distinguish between infection and inflammation in this population. DESIGN: Nested cohort study. SETTING: Two tertiary mixed ICUs in the Netherlands. PATIENTS: Hospitalized patients with acute respiratory failure requiring mechanical ventilation upon ICU admission from 2011 to 2013. Patients having an established infection diagnosis or an evidently noninfectious reason for intubation were excluded. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Blood samples were collected upon ICU admission. Test results were categorized into four probability bands (higher bands indicating higher infection probability) and compared with the infection plausibility as rated by post hoc assessment using strict definitions. Of 467 included patients, 373 (80%) were treated for a suspected infection at admission. Infection plausibility was classified as ruled out, undetermined, or confirmed in 135 (29%), 135 (29%), and 197 (42%) patients, respectively. Test results correlated with infection plausibility (Spearman's rho 0.332; p < 0.001). After exclusion of undetermined cases, positive predictive values were 29%, 54%, and 76% for probability bands 2, 3, and 4, respectively, whereas the negative predictive value for band 1 was 76%. Diagnostic discrimination of SeptiCyte LAB and C-reactive protein was similar (p = 0.919). CONCLUSIONS: Among hospitalized patients admitted to the ICU with clinical uncertainty regarding the etiology of acute respiratory failure, the diagnostic value of SeptiCyte LAB was limited.