Effect of Ganciclovir on IL-6 Levels Among Cytomegalovirus-Seropositive Adults With Critical Illness

Abstract

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. 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. DESIGN, SETTING, AND PARTICIPANTSINTERVENTIONS 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 MEASURESThe 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 received 1 or more dose(s) of treatment, and 132 (85%) completed the study. The mean between-group change in IL-6 level was not significantly different. Among secondary outcomes, CMV reactivation in plasma was significantly lower in the ganciclovir group. The ganciclovir group had more VFDs in both the intention-to-treat population and in the prespecified sepsis subgroup. There were no significant between-group differences in other secondary outcomes.

Surviving sepsis campaign: research priorities for sepsis and septic shock

“…Despite lower levels of CMV reactivation in the treatment group, no difference was noted in the primary outcome (IL-6 levels) although ventilator free days were higher in the treatment group [35]. In contrast, a single center trial of 124 CMV-seropositive patients undergoing mechanical ventilation randomized patients to receive anti-CMV prophylaxis with valacyclovir or low-dose valganciclovir.…”

Cytomegalovirus immunoglobulin G titers do not predict reactivation risk in immunocompetent hosts

“…In addition, interpretation in the current report is confounded by lack of concomitant T‐cell and innate immune function data. Recent studies of prophylactic antiviral drug therapy trials for prevention of CMV reactivation in immunocompetent humans have focused on safety and efficacy, and like most previously published observational trials largely ignore the contribution of underlying host immunity to reactivation resolution. Future trial designs should include such monitoring to enhance our understanding of how pre‐existing host immunity may contribute to the resolution of reactivation events.…”

The impact of inflationary cytomegalovirus‐specific memory T cells on anti‐tumour immune responses in patients with cancer

“…Furthermore, this treatment improved the T cells’ ability to kill tumour cells, accompanied by PD‐1 down‐regulation. A recent clinical study showed that ganciclovir treatment of CMV‐positive patients with sepsis does not affect serum IL‐6 levels while reducing the incidence of CMV reactivation, indicating that the drug does not have anti‐inflammatory effects . Although ganciclovir is not CMV‐specific, this observation prompts the discussion that many drugs used in clinical settings may have multiple functions and could therefore be repurposed for host‐directed therapy .…”