CMV Reactivation/Outcome in Critically Ill Patients
Abstract & Commentary
By Robert Muder, MD, Hospital Epidemiologist, Pittsburgh VA Medical Center. Dr. Muder does research for Aventis and Pharmacia. This article originally appeared in the October 2008 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, and peer reviewed by Connie Price, MD. Dr. Deresinski is Clinical Professor of Medicine, Stanford University; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, and Dr. Price is Assistant Professor, University of Colorado School of Medicine. Dr. Deresinski serves no the speaker's bureau for Merck, Pharmacia, GlaxoSmithKline, Pfizer, Bayer, and Wyeth, and does research for Merck, and Dr. Price reports no financial relationships relevant to this field of study.
Synopsis: In a prospective study of immunocompetent patients admitted to critical care units, CMV viremia showed a significant association with prolonged ICU stay and death.
Source: Limaye AP, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008;300: 413-422.
Although reactivation of CMV has significant adverse consequences for immunocompromised patients, such as those receiving organ transplants, the effect of CMV reactivation in critically ill immunocompetent patients is unclear. Limaye et al prospectively studied immunocompetent adult patients admitted to six burn, trauma, cardiac, and medical intensive care units. Limaye et al collected blood from CMV seropositive patients three times weekly for quantitative CMV assay by PCR. They collected clinical patient data without knowledge of CMV assay results; CMV assays were performed after all clinical and outcome data had been collected. They used a composite endpoint of death or continued hospitalization in the ICU at day 30. In addition to peak level of CMV viremia, Limaye et al also calculated seven-day moving averages of CMV level and CMV area under the curve (analogous to the more familiar antibiotic serum level AUC). In order to account for different lengths of ICU stay as a potential confounding factor, they used a partial proportional odds model for the association of degree of CMV viremia and length of stay at 14-day intervals.
CMV viremia occurred in 33% of patients at a median of 12 days after admission. Twenty percent of patients had viremia level greater than 1000 copies/mL. By logistic regression, there was a significant association between CMV viremia at any level (OR 4.3; 95% CI 1.6-11.9) and > 1000 copies/mL OR13.9; 95% CI 3.2-60) and death or continued hospitalization at 30 days. There was also a significant association with CMV AUC (OR 3.2; 95% CI 2.1-1.3-3.2). In the partial proportional odds models, both CMV seven-day moving average and CMV AUC were independently associated with hospital length of stay.
CMV reactivation occurs in immunocompetent patients following trauma or severe illness; whether reactivation has adverse consequences or is merely a marker for severity of illness is not clear. Limaye et al demonstrate a highly significant association between CMV reactivation and prolonged hospitalization and death in these patients. This study has a number of notable strengths which include a prospective design, inclusion of a large number of patients with a variety of underlying illness, and blinding of the determination of clinical risk factors and outcome to the results of CMV assays. The association was significant when CMV viremia was measured in a variety of ways, and the results suggest a dose-response effect.
As Limaye et al point out, the association does not prove cause and effect; CMV viremia could be a marker for severity of illness that was not adequately captured by the clinical variables measured. However, an independent adverse effect of CMV reactivation is definitely plausible, and a clinical trial and anti-viral therapy directed against CMV reactivation in critically ill immunocompetent patients is clearly warranted. Initiating anti-viral treatment in immunocompetent patients with CMV reactivation who do not have good evidence of CMV disease is premature based on current evidence.