Cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome

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Abstract

Purpose

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).

Conclusion

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

Electronic supplementary material

The online version of this article (doi:10.1007/s00134-015-4071-z) contains supplementary material, which is available to authorized users.

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Most cited references 31

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Reactivation of Multiple Viruses in Patients with Sepsis

Andrew Walton, Jared Muenzer, David Rasche … (2014)

A current controversy is whether patients with sepsis progress to an immunosuppressed state. We hypothesized that reactivation of latent viruses occurred with prolonged sepsis thereby providing evidence of clinically-relevant immunosuppression and potentially providing a means to serially-monitor patients' immune status. Secondly, if viral loads are markedly elevated, they may contribute to morbidity and mortality. This study determined if reactivation of herpesviruses, polyomaviruses, and the anellovirus TTV occurred in sepsis and correlated with severity. Serial whole blood and plasma samples from 560 critically-ill septic, 161 critically-ill non-septic, and 164 healthy age-matched patients were analyzed by quantitative-polymerase-chain-reaction for cytomegalovirus (CMV), Epstein-Barr (EBV), herpes-simplex (HSV), human herpes virus-6 (HHV-6), and TTV. Polyomaviruses BK and JC were quantitated in urine. Detectable virus was analyzed with respect to secondary fungal and opportunistic bacterial infections, ICU duration, severity of illness, and survival. Patients with protracted sepsis had markedly increased frequency of detectable virus. Cumulative viral DNA detection rates in blood were: CMV (24.2%), EBV (53.2%), HSV (14.1%), HHV-6 (10.4%), and TTV (77.5%). 42.7% of septic patients had presence of two or more viruses. The 50% detection rate for herpesviruses was 5–8 days after sepsis onset. A small subgroup of septic patients had markedly elevated viral loads (>104–106 DNA copies/ml blood) for CMV, EBV, and HSV. Excluding TTV, DNAemia was uncommon in critically-ill non-septic patients and in age-matched healthy controls. Compared to septic patients without DNAemia, septic patients with viremia had increased fungal and opportunistic bacterial infections. Patients with detectable CMV in plasma had higher 90-day mortality compared to CMV-negative patients; p<0.05. Reactivation of latent viruses is common with prolonged sepsis, with frequencies similar to those occurring in transplant patients on immunosuppressive therapy and consistent with development of an immunosuppressive state. Whether reactivated latent viruses contribute to morbidity and mortality in sepsis remains unknown.

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Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments.

Pranav K. Gandhi, Rajiv Khanna (2004)

After initial infection, human cytomegalovirus remains in a persistent state with the host. Immunity against the virus controls replication, although intermitent viral shedding can still take place in the seropositive immunocompetent person. Replication of cytomegalovirus in the absence of an effective immune response is central to the pathogenesis of disease. Therefore, complications are primarily seen in individuals whose immune system is immature, or is suppressed by drug treatment or coinfection with other pathogens. Although our increasing knowledge of the host-virus relationship has lead to the development of new pharmacological strategies for cytomegalovirus-associated infections, these strategies all have limitations-eg, drug toxicities, development of resistance, poor oral bioavailability, and low potency. Immune-based therapies to complement pharmacological strategies for the successful treatment of virus-associated complications should be prospectively investigated.

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Interpreting and comparing risks in the presence of competing events.

Martin Wolkewitz, Ben Cooper, Marc J M Bonten … (2014)

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Author and article information

Contributors

David S. Y. Ong: +31 88 756 1124 , davidsyong@gmail.com

Journal

Journal ID (nlm-ta): Intensive Care Med

Journal ID (iso-abbrev): Intensive Care Med

Title: Intensive Care Medicine

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0342-4642

ISSN (Electronic): 1432-1238

Publication date (Electronic): 28 September 2015

Publication date PMC-release: 28 September 2015

Publication date (Print): 2016

Volume: 42

Pages: 333-341

Affiliations

[ ]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

[ ]Department of Mathematics, Utrecht University, Utrecht, The Netherlands

[ ]Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

[ ]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

Article

Publisher ID: 4071

DOI: 10.1007/s00134-015-4071-z

PMC ID: 4747999

PubMed ID: 26415682

SO-VID: 3a1bdbf6-fe96-40f5-9af6-66814e757070

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), 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.

History

Date received : 14 July 2015

Date accepted : 12 September 2015

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100006020, Center for Translational Molecular Medicine (NL);

Award ID: 04I-201

Custom metadata

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: cytomegalovirus,viremia,reactivation,ards,mortality

Data availability:

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: cytomegalovirus, viremia, reactivation, ards, mortality

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Cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome

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Abstract

Purpose

Methods

Results

Conclusion

Electronic supplementary material

Related collections

Irish Journal of Paramedicine

Most cited references 31

Reactivation of Multiple Viruses in Patients with Sepsis

Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments.

Interpreting and comparing risks in the presence of competing events.

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Contributors

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Affiliations

Article

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Funding

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Cited by 29

Most referenced authors 466