Lonneke A van Vught1, Peter M C Klein Klouwenberg2, Cristian Spitoni3, Brendon P Scicluna4, Maryse A Wiewel1, Janneke Horn5, Marcus J Schultz5, Peter Nürnberg6, Marc J M Bonten7, Olaf L Cremer8, Tom van der Poll1. 1. Center for Experimental and Molecular Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. 2. 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. 3. Department of Mathematics, Utrecht University, Utrecht, the Netherlands. 4. 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. 5. Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. 6. 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. 7. 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. 8. Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
Abstract
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.
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.
Authors: Arie J Hoogendijk; Lonneke A van Vught; Maryse A Wiewel; Gwenny M Fuhler; Hakima Belkasim-Bohoudi; Janneke Horn; Marcus J Schultz; Brendon P Scicluna; Maikel P Peppelenbosch; Cornelis van 't Veer; Alex F de Vos; Tom van der Poll Journal: Haematologica Date: 2018-12-04 Impact factor: 9.941
Authors: Kaori Oshima; Xiaorui Han; Yilan Ouyang; Rana El Masri; Yimu Yang; Sarah M Haeger; Sarah A McMurtry; Trevor C Lane; Pavel Davizon-Castillo; Fuming Zhang; Xinping Yue; Romain R Vivès; Robert J Linhardt; Eric P Schmidt Journal: Am J Physiol Lung Cell Mol Physiol Date: 2019-08-28 Impact factor: 5.464
Authors: Héctor Diez; Ma José Benitez; Silvia Fernandez; Ignacio Torres-Aleman; Juan José Garrido; Francisco Wandosell Journal: Biochim Biophys Acta Date: 2016-07-12
Authors: Fabienne D Simonis; Ary Serpa Neto; Jan M Binnekade; Annemarije Braber; Karina C M Bruin; Rogier M Determann; Geert-Jan Goekoop; Jeroen Heidt; Janneke Horn; Gerard Innemee; Evert de Jonge; Nicole P Juffermans; Peter E Spronk; Lotte M Steuten; Pieter Roel Tuinman; Rob B P de Wilde; Marijn Vriends; Marcelo Gama de Abreu; Paolo Pelosi; Marcus J Schultz Journal: JAMA Date: 2018-11-13 Impact factor: 56.272