Intensive Care Medicine

, Volume 42, Issue 3, pp 333–341 | Cite as

Cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome

  • David S. Y. OngEmail author
  • Cristian Spitoni
  • Peter M. C. Klein Klouwenberg
  • Frans M. Verduyn Lunel
  • Jos F. Frencken
  • Marcus J. Schultz
  • Tom van der Poll
  • Jozef Kesecioglu
  • Marc J. M. Bonten
  • Olaf L. Cremer



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.


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.


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).


CMV reactivation is independently associated with increased case fatality in immunocompetent ARDS patients who are CMV seropositive.


Cytomegalovirus Viremia Reactivation ARDS Mortality 



We thank Huberta Dekker (Department of Medical Microbiology, University Medical Center Utrecht, the Netherlands) for her logistical support in this project, and the participating ICUs and research nurses of the two medical centers for their help in data acquisition. This work was supported by the Center for Translational Molecular Medicine (, project MARS (Grant 04I-201). JK received a personal fee from Becton–Dickinson. The sponsor did not play a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no competing interests.

Supplementary material

134_2015_4071_MOESM1_ESM.docx (207 kb)
Supplementary material 1 (DOCX 206 kb)


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Copyright information

© The Author(s) 2015

Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (, which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  • David S. Y. Ong
    • 1
    • 2
    • 3
    Email author
  • Cristian Spitoni
    • 3
    • 4
  • Peter M. C. Klein Klouwenberg
    • 1
    • 2
    • 3
  • Frans M. Verduyn Lunel
    • 1
  • Jos F. Frencken
    • 2
    • 3
  • Marcus J. Schultz
    • 5
  • Tom van der Poll
    • 6
    • 7
  • Jozef Kesecioglu
    • 2
  • Marc J. M. Bonten
    • 1
    • 3
  • Olaf L. Cremer
    • 2
  1. 1.Department of Medical MicrobiologyUniversity Medical Center UtrechtUtrechtThe Netherlands
  2. 2.Department of Intensive Care MedicineUniversity Medical Center UtrechtUtrechtThe Netherlands
  3. 3.Julius Center for Health Sciences and Primary CareUniversity Medical Center UtrechtUtrechtThe Netherlands
  4. 4.Department of MathematicsUtrecht UniversityUtrechtThe Netherlands
  5. 5.Department of Intensive Care, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  6. 6.Center of Experimental and Molecular Medicine and Division of Infectious Diseases, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  7. 7.Center for Infection and Immunity Amsterdam, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands

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