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JAMA. 2017 Aug 22;318(8):731-740. doi: 10.1001/jama.2017.10569.

Effect of Ganciclovir on IL-6 Levels Among Cytomegalovirus-Seropositive Adults With Critical Illness: A Randomized Clinical Trial.

Author information

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

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.

PMID:
28829877
PMCID:
PMC5817487
DOI:
10.1001/jama.2017.10569
[Indexed for MEDLINE]
Free PMC Article

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