title: Cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome.
abstract: OBJECTIVE
  Cytomegalovirus (CMV) reactivation occurs frequently in patients with the acute respiratory distress syndrome (ARDS) and has been associated with increased mortality. However, it remains unknown whether this association represents an independent risk for poor outcome. We aimed to estimate the attributable effect of CMV reactivation on mortality in immunocompetent ARDS patients.
  
  
  METHODS
  We prospectively studied immunocompetent ARDS patients who tested seropositive for CMV and remained mechanically ventilated beyond day 4 in two tertiary intensive care units in the Netherlands from 2011 to 2013. CMV loads were determined in plasma weekly. Competing risks Cox regression was used with CMV reactivation status as a time-dependent exposure variable. Subsequently, in sensitivity analyses we adjusted for the evolution of disease severity until onset of reactivation using marginal structural modeling.
  
  
  RESULTS
  Of 399 ARDS patients, 271 (68%) were CMV seropositive and reactivation occurred in 74 (27%) of them. After adjustment for confounding and competing risks, CMV reactivation was associated with overall increased ICU mortality (adjusted subdistribution hazard ratio (SHR) 2.74, 95% CI 1.51-4.97), which resulted from the joint action of trends toward an increased mortality rate (direct effect; cause specific hazard ratio (HR) 1.58, 95% CI 0.86-2.90) and a reduced successful weaning rate (indirect effect; cause specific HR 0.83, 95% CI 0.58-1.18). These associations remained in sensitivity analyses. The population-attributable fraction of ICU mortality was 23% (95% CI 6-41) by day 30 (risk difference 4.4, 95% CI 1.1-7.9).
  
  
  CONCLUSIONS
  CMV reactivation is independently associated with increased case fatality in immunocompetent ARDS patients who are CMV seropositive.
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands. davidsyong@gmail.com.|Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. davidsyong@gmail.com.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. davidsyong@gmail.com.
authors.forename: David S Y
authors.initials: DSY
authors.lastname: Ong
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Mathematics, Utrecht University, Utrecht, The Netherlands.
authors.forename: Cristian
authors.initials: C
authors.lastname: Spitoni
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Peter M C
authors.initials: PMC
authors.lastname: Klein Klouwenberg
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Frans M
authors.initials: FM
authors.lastname: Verduyn Lunel
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jos F
authors.initials: JF
authors.lastname: Frencken
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: Center of Experimental and Molecular Medicine and Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jozef
authors.initials: J
authors.lastname: Kesecioglu
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marc J M
authors.initials: MJM
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
mesh_terms: D018806:APACHE; D000368:Aged; D003586:Cytomegalovirus Infections / Q000401:mortality*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D011446:Prospective Studies; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome / Q000401:mortality* / Q000821:virology*; D012307:Risk Factors
keywords: ARDS; Cytomegalovirus; Mortality; Reactivation; Viremia