CMV Disease in the Non-immunosuppressed ICU Patient

Hello. I am Paul Auwaerter from the Johns Hopkins University School of Medicine, speaking for Medscape Infectious Diseases.

Patients in the intensive care unit (ICU), perhaps with fever or unexplained infiltrates on chest radiograph, often are checked for cytomegalovirus (CMV) viremia. We typically do not think of these non-immunosuppressed patients as being subject to end-organ CMV disease. However, this had not been well studied until about 10 years ago. Limaye and colleagues^[1] looked at a non-immunosuppressed ICU populations and found that up to 33% of patients who had sepsis and were critically ill had CMV reactivation. This seemed to be linked to longer ICU stay and mortality.

In immunosuppressed patients, CMV is well known to cause end-organ disease or, in transplant patients, to abet organ rejection. The role of CMV in the non-immunosuppressed critically ill is quite unclear, however. Limaye's study did not clarify whether CMV was just a bystander in the setting of critical illness, with a well-known herpes virus that reactivates, or whether it was really participating as a co-pathogen in critical illness.

A more recent study from Greece^[2] found that about 14% of non-immunosuppressed critically ill patients had reactivation of CMV. This study was smaller and investigators checked for plasma CMV once weekly compared with thrice weekly in the earlier study. The authors correlated the presence of CMV with more frequent transfusions, and cytokine analysis also suggested that reactivation was linked to higher levels of IL-10, indicating inflammation.

Could Suppressing CMV Help Critically Ill Patients?

Interest in whether suppressing CMV may reduce adverse outcomes in critically ill patients prompted a new study by Limaye and colleagues,^[3] published in August 2017 in the Journal of the American Medical Association. This was a randomized controlled trial of CMV-seropositive patients who were in the ICU because of trauma or sepsis. In all, 160 patients were randomly assigned to receive 5 days of intravenous ganciclovir, 5 mg/kg twice daily, with conversion to oral or continued IV therapy after 5 days versus placebo.

The primary endpoint was interleukin 6 (IL-6) levels, chosen because prior studies have suggested that high levels of IL-6 strongly correlate with mortality. Secondary clinical endpoints included CMV reactivation, reduced number of days on the ventilator, and reduced ICU length of stay, among others.

The study failed to find any significant differences in IL-6 levels between the treatment versus placebo arms. Likewise, length of ICU stay and mortality was similar in treatment and placebo groups. Patients in the ganciclovir arm did have more ventilator-free days as well as a reduction in CMV reactivation, at 12% of patients compared with 39% of patients in the placebo arm.

Overall, the authors concluded that there is no role at this time for antiviral CMV prophylaxis in this population. Some of the secondary endpoints did indicate a basis for CMV suppression, however, including whether CMV participates in lung injury, as indicated by fewer days on the ventilator for patients who received ganciclovir. Perhaps future studies can use some of these clinical endpoints as primary endpoints and subject them to more rigorous study.

I believe that this study is helpful for infectious disease consultants in critical care and others who may face this CMV question sometimes just because people are checking lab values, or at other times perhaps being more thoughtful and seeing CMV on a bronchoalveolar lavage culture and such. At the moment, there is not much stomach for routine use of antivirals. This study has tried to address some of these issues, but more could be explored in future research.

Thanks very much for listening.