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Preliminary Communication
August 22/29, 2017

Effect of Ganciclovir on IL-6 Levels Among Cytomegalovirus-Seropositive Adults With Critical IllnessA Randomized Clinical Trial

Author Affiliations
  • 1Division of Allergy and Infectious Diseases, University of Washington, Seattle
  • 2Pulmonary and Critical Care Division, University of Vermont College of Medicine, Burlington
  • 3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
  • 4Critical Care Division, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
  • 5Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor
  • 6Division of Pulmonary, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Columbus
  • 7Department of Pulmonary and Critical Care Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
  • 8Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Sleep Center, Denver, Colorado
  • 9Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 10Department of Critical Care Medicine, Cleveland Clinic, Cleveland, Ohio
  • 11Department of Medicine, University of Virginia, Charlottesville
  • 12Division of Critical Care Pulmonary Medicine, Baystate Medical Center, Springfield, Massachusetts
  • 13Department of Surgery, University of Washington, Seattle
  • 14Division of Pulmonary and Critical Care, Northwestern Feinberg School of Medicine, Chicago, Illinois
  • 15Division of Pulmonary and Critical Care Medicine, Oregon Clinic, Portland
  • 16Interdepartmental Division of Critical Care Medicine, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada
JAMA. 2017;318(8):731-740. doi:10.1001/jama.2017.10569
Key Points

Question  Does prevention of cytomegalovirus (CMV) reactivation with ganciclovir reduce plasma interleukin 6 (IL-6) levels among CMV-seropositive adults with critical illness due to sepsis or trauma?

Findings  In this multicenter randomized clinical trial of 160 adults, treatment with ganciclovir vs placebo did not significantly reduce plasma IL-6 levels (mean change from days 1 to 14, −0.79 and −0.79 log10 units, respectively).

Meaning  Treatment with ganciclovir in adults who were critically ill did not significantly reduce IL-6 levels, and these findings do not support routine prophylactic use in this setting.

Abstract

Importance  The role of cytomegalovirus (CMV) reactivation in mediating adverse clinical outcomes in nonimmunosuppressed adults with critical illness is unknown.

Objective  To determine whether ganciclovir prophylaxis reduces plasma interleukin 6 (IL-6) levels in CMV-seropositive adults who are critically ill.

Design, Setting, and Participants  Double-blind, placebo-controlled, randomized clinical trial (conducted March 10, 2011-April 29, 2016) with a follow-up of 180 days (November 10, 2016) that included 160 CMV-seropositive adults with either sepsis or trauma and respiratory failure at 14 university intensive care units (ICUs) across the United States.

Interventions  Patients were randomized (1:1) to receive either intravenous ganciclovir (5 mg/kg twice daily for 5 days), followed by either intravenous ganciclovir or oral valganciclovir once daily until hospital discharge (n = 84) or to receive matching placebo (n = 76).

Main Outcomes and Measures  The primary outcome was change in IL-6 level from day 1 to 14. Secondary outcomes were incidence of CMV reactivation in plasma, mechanical ventilation days, incidence of secondary bacteremia or fungemia, ICU length of stay, mortality, and ventilator-free days (VFDs) at 28 days.

Results  Among 160 randomized patients (mean age, 57 years; women, 43%), 156 patients received 1or more dose(s) of study medication, and 132 patients (85%) completed the study. The mean change in plasma IL-6 levels between groups was −0.79 log10 units (−2.06 to 0.48) in the ganciclovir group and −0.79 log10 units (−2.14 to 0.56) in the placebo group (point estimate of difference, 0 [95% CI, −0.3 to 0.3]; P > .99). Among secondary outcomes, CMV reactivation in plasma was significantly lower in the ganciclovir group (12% [10 of 84 patients] vs 39% [28 of 72 patients]); absolute risk difference, −27 (95% CI, −40 to −14), P < .001. The ganciclovir group had more median VFDs in both the intention-to-treat (ITT) group and in the prespecified sepsis subgroup (ITT group: 23 days in ganciclovir group vs 20 days in the placebo group, P = .05; sepsis subgroup, 23 days in the ganciclovir group vs 20 days in the placebo group, P = .03). There were no significant differences between the ganciclovir and placebo groups in duration of mechanical ventilation (5 days for the ganciclovir group vs 6 days for the placebo group, P = .16), incidence of secondary bacteremia or fungemia (15% for the ganciclovir group vs 15% for the placebo group, P = .67), ICU length of stay (8 days for the ganciclovir group vs 8 days for the placebo group, P = .76), or mortality (12% for the ganciclovir group vs 15% for the placebo group, P = .54).

Conclusions and Relevance  Among CMV-seropositive adults with critical illness due to sepsis or trauma, ganciclovir did not reduce IL-6 levels and the current study does not support routine clinical use of ganciclovir as a prophylactic agent in patients with sepsis. Additional research is necessary to determine the clinical efficacy and safety of CMV suppression in this setting.

Trial Registration  clinicaltrials.gov Identifier: NCT01335932

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