Cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome

David S Y Ong, 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, David S Y Ong, 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

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.

Keywords: ARDS; Cytomegalovirus; Mortality; Reactivation; Viremia.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Viral load in CMV seropositive ARDS patients over time. The quantitative PCR results were calibrated according to the CMV WHO standard; viral loads greater than or equal to 1000 IU/mL were denoted ‘high reactivation’. Viral loads of 100–999 IU/mL were denoted ‘low reactivation’, and undetectable loads or viral loads below 100 IU/mL were denoted ‘no reactivation’
Fig. 2
Fig. 2
Observed versus predicted ICU mortality in CMV seropositive ARDS patients. The blue line represents the observed ICU mortality in the study cohort of 271 CMV seropositive patients; the green line represents the predicted ICU mortality if all cases of CMV reactivation in the cohort are prevented. The population-attributable fraction of ICU mortality was 23 % by day 30 (absolute risk difference 4.4 %)

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