Using a prospective, blinded study design and rigorous statistical analyses in a broad range of immunocompetent patients with critical illness, we demonstrated that reactivation of CMV occurs frequently and is independently and quantitatively associated with a clinically-relevant endpoint of continued hospitalization or death by 30 days after admission to the ICU. Thus, we have identified a novel and potentially modifiable risk factor for death or prolonged hospitalization in critically-ill patients.
Given the number, complexity, potential bi-directional relationships between CMV and other variables analyzed, and the time-varying nature of the endpoints, we used a variety of statistical methods to comprehensively assess the relationship between CMV and adverse clinical outcomes. These included use of partial proportional odds models, use of a novel parameter of seven-day moving average of CMV viral load throughout the hospital stay, and use of a composite endpoint of death or continued hospitalization by 30 days. In particular, use of the composite endpoint was objective, clinically relevant and one that could be used as a primary endpoint in subsequent interventional studies of CMV prevention in this setting. Furthermore, the composite endpoint (rather than use of only length of stay alone) was used to reduce the potential impact that early deaths might have on assessment of the relationship between CMV reactivation and LOS. Similarly, use of the partial proportional odds models allowed us to control for the observed relationship between length of stay and onset of CMV reactivation, thereby allowing the relationship of CMV reactivation and subsequent LOS to be assessed throughout the hospital stay. In addition, given the concern that longer LOS would lead to a greater opportunity to detect CMV reactivation (and thus potentially lead to a spurious association between CMV reactivation and LOS), we performed a landmark analysis among those who were hospitalized for at least 30 days (a time-point by which 95% of those who ultimately ever reactivated CMV had done so, and also a subset who all had a uniform duration of monitoring for CMV). And, as in the previous analyses, CMV reactivation was associated with longer durations of subsequent hospitalization compared to those who did not reactivate by day 30 (). The association between CMV reactivation and prolonged hospitalization or death remained robust throughout all of the analyses. Thus, our data are consistent with the possibility that CMV reactivation is causally related to prolongation of hospital stay in this clinical setting and this contention is also supported by animal studies.28
However, we are careful to emphasize that an observational study design cannot establish causality, and that the data presented here are also consistent with the possibility that CMV reactivation is simply a marker (rather than determinant) for prolonged hospital stay. Importantly, we did not find an association between severity of illness (as assessed by the APACHE score) and risk of CMV reactivation, thereby diminishing the likelihood that CMV reactivation was simply a surrogate marker of illness severity.
The only definitive means of differentiating between a role of CMV as a cause versus marker for adverse clinical outcomes is by means of a randomized controlled trial of antiviral prophylaxis in this clinical setting. Given the major importance of the clinical problem, the availability of generally safe and well-tolerated antiviral agents with activity against CMV, combined with the data regarding CMV incidence and endpoint estimates generated in this study, we feel that a randomized placebo-controlled trial of antiviral prophylaxis is both warranted and feasible, and should be a priority among studies to improve the outcomes of patients with critical illness.
The mechanism(s) underlying the observed association between CMV and adverse clinical outcomes are not defined in the present study. One possibility is direct CMV pathogenicity and this has previously been reported in the setting of otherwise immunocompetent patients with critical illness, but appears to be uncommon.16
Another possibility is that one or more CMV indirect effects are responsible for the observed association between CMV reactivation and adverse clinical outcomes. CMV-mediated immunosuppression leading to an increased risk for secondary infections 2–5
and CMV-mediated lung injury 28, 29
are the most plausible mechanisms in this clinical setting. In support of these possibilities are in vitro
and animal model experimental data,28, 30, 31
clinical observational studies1, 9, 32
and the demonstration that antiviral therapy reduces these effects in animal models28
and in controlled clinical trials in certain patient populations.2–5
Larger prospective studies that include laboratory investigations will be necessary to define the mechanism(s) underlying the association of CMV reactivation with adverse clinical outcomes in patients with critical illness.
There were several strengths of the present study, including the prospective, blinded study design, inclusion of a broad range of critically-ill patients, use of quantitative CMV assessments, and the use of comprehensive statistical analyses with an adequate number and frequency of clinically-relevant endpoints. This is the largest study conducted to date and the results are statistically robust. It is reassuring that factors previously reported to be associated with increased LOS (bacteremia, pneumonia) were confirmed to be associated with LOS in the present study.33–35
We also acknowledge potential limitations. Monitoring for CMV reactivation was not performed in discharged patients, and while we think it is unlikely, it is possible that some discharged patients may have first reactivated CMV after hospital discharge. Although this would not have altered the statistical assessment of the association between CMV and LOS, it would make it more difficult to conclude that CMV was having a biologically significant impact in this clinical setting. There is also the potential concern that the association between CMV reactivation and prolonged hospital stay could, in part, be related to a greater opportunity to detect CMV reactivation in those with longer hospital stays (i.e., “circular reasoning”). However, the known biological time-lag of CMV effects in other settings, the quantitative nature of the association demonstrated in the present study, and the consistent finding of the association between CMV reactivation and prolonged LOS in the landmark analysis and partial proportional odds models (both of which directly addressed the time-dependent nature of CMV reactivation) all support the contention that CMV reactivation was associated with prolongation of hospital stay rather than a spurious finding. We are careful to emphasize that our study design (or any observational study design) cannot prove causality between CMV and adverse clinical outcomes in this setting. Rather, we consider these results to be hypothesis-generating and provide useful background data, which when combined with prior investigations, provide the rationale for performing definitive interventional studies. Even though a strong association between CMV reactivation and prolonged length of stay was identified, the mechanism(s) underlying this association could not be defined in this study. And, not all variables previously reported to be associated with an increased LOS were examined in the present study.
In summary, we have demonstrated an independent and quantitative association between CMV viral load and prolonged length of stay in a broad range of immunocompetent patients with critical illness. These findings, combined with data from prior investigations, provide a strong rationale for a randomized controlled trial of antiviral prophylaxis in this clinical setting.