title: Incidence, Risk Factors, and Attributable Mortality of Secondary Infections in the Intensive Care Unit After Admission for Sepsis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  METHODS
  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
  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.
authors.affiliation: Center for Experimental and Molecular Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Lonneke A
authors.initials: LA
authors.lastname: van Vught
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands3Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands4Julius Center for Health Sciences and Primary Care, Universi.
authors.forename: Peter M C
authors.initials: PM
authors.lastname: Klein Klouwenberg
authors.affiliation: Department of Mathematics, Utrecht University, Utrecht, the Netherlands.
authors.forename: Cristian
authors.initials: C
authors.lastname: Spitoni
authors.affiliation: Center for Experimental and Molecular Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands6Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, U.
authors.forename: Brendon P
authors.initials: BP
authors.lastname: Scicluna
authors.affiliation: Center for Experimental and Molecular Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Maryse A
authors.initials: MA
authors.lastname: Wiewel
authors.affiliation: Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Janneke
authors.initials: J
authors.lastname: Horn
authors.affiliation: Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
authors.affiliation: Cologne Center for Genomics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands4Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Marc J M
authors.initials: MJ
authors.lastname: Bonten
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Olaf L
authors.initials: OL
authors.lastname: Cremer
authors.affiliation: Center for Experimental and Molecular Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D018806:APACHE; D000368:Aged; D055499:Catheter-Related Infections / Q000453:epidemiology; D003428:Cross Infection / Q000453:epidemiology* / Q000276:immunology / Q000401:mortality; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics; D017052:Hospital Mortality; D006801:Humans; D015994:Incidence; D007362:Intensive Care Units / Q000706:statistics & numerical data; D007902:Length of Stay / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D063305:Organ Dysfunction Scores; D011446:Prospective Studies; D012307:Risk Factors; D018805:Sepsis / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000401:mortality; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000150:complications / Q000401:mortality; D016019:Survival Analysis