Effect of ganciclovir on IL-6 levels among cytomegalovirus-seropositive adults with critical illness: A randomized clinical trial

Ajit P. Limaye; Renee D. Stapleton; Lili Peng; Scott R. Gunn; Louise E. Kimball; Robert Hyzy; Matthew C. Exline; D. Clark Files; Peter E. Morris; Stephen K. Frankel; Mark E. Mikkelsen; Duncan Hite; Kyle B. Enfield; Jay Steingrub; James O’Brien; Polly E. Parsons; Joseph Cuschieri; Richard G. Wunderink; David L. Hotchkin; Ying Q. Chen; Gordon D. Rubenfeld; Michael Boeckh

doi:10.1001/jama.2017.10569

Effect of ganciclovir on IL-6 levels among cytomegalovirus-seropositive adults with critical illness: A randomized clinical trial

Ajit P. Limaye, Renee D. Stapleton, Lili Peng, Scott R. Gunn, Louise E. Kimball, Robert Hyzy, Matthew C. Exline, D. Clark Files, Peter E. Morris, Stephen K. Frankel, Mark E. Mikkelsen, Duncan Hite, Kyle B. Enfield, Jay Steingrub, James O’Brien, Polly E. Parsons, Joseph Cuschieri, Richard G. Wunderink, David L. Hotchkin, Ying Q. ChenGordon D. Rubenfeld, Michael Boeckh

Research output: Contribution to journal › Article › peer-review

72 Scopus citations

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 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. (Table Presented) 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.

Original language	English
Pages (from-to)	731-740
Number of pages	10
Journal	JAMA - Journal of the American Medical Association
Volume	318
Issue number	8
DOIs	https://doi.org/10.1001/jama.2017.10569
State	Published - Aug 22 2017

Bibliographical note

Funding Information:
Additional Contributions: We thank Taylor Thompson, MD (Massachusetts General Hospital), David Schoenfeld, PhD, (Harvard Medical School), Mitchell Levy, MD (Brown University), Lorraine Ware, MD (Vanderbilt University), and Paul Griffiths, MD (University College, London), who served on the data and safety monitoring board. They received payment from grant UO1 HL 102547. We thank the following study coordinators: Lesley De Souza (Baystate Medical Center), Helen Donnelly, BSN (Northwestern University), Michelle Ferrari (Cleveland Clinic), Luke Herren (Ohio State University), Meg Day (Oregon Clinic), Jeff McKeehan, MSN (National Jewish Health), Kristine Nelson (University of Michigan), Pam Fazio, BS (University of Pittsburg), Sara Arden, BS (University of Vermont), Lori Flores, BSN (Wake Forest University), Mary Marshall, MSN (University of Virginia), Michaela Kusumi, BS (University of Washington), Fatima Ali, BS (University of Washington), and Laura Hennessy (University of Washington) for site research coordination; Lisa Chung, BS (Fred Hutchinson Cancer Research Center), Terry Stevens-Ayers, MS (Fred Hutchinson Cancer Research Center), Michaela Kusumi, BS (University of Washington), and Fatima Ali, BS (University of Washington), for their help with preparing the figures and manuscript; and Hu Xie, MS (Fred Hutchinson Cancer Research Center) for assistance with statistical analysis. We also thank the staff and coordinators at the Statistical Center for HIV/AIDS Research and Prevention for data management and Sheree Miller, PharmD (University of Washington), for the management and dispensing of the study drug and placebo. They did not receive compensation for their contribution.

Funding Information:
was supported by grant UO1 HL 102547 from the US National Institutes of Health’s National Heart, Lung, and Blood Institute. Genentech supplied the initial batch of study drug (ganciclovir, valganciclovir, and placebo). Role of the Funder/Sponsor: The funders of the study had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript or the decision to submit for publication.

Publisher Copyright:
© 2017 American Medical Association. All rights reserved.

ASJC Scopus subject areas

Medicine (all)

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10.1001/jama.2017.10569

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Limaye, A. P., Stapleton, R. D., Peng, L., Gunn, S. R., Kimball, L. E., Hyzy, R., Exline, M. C., Files, D. C., Morris, P. E., Frankel, S. K., Mikkelsen, M. E., Hite, D., Enfield, K. B., Steingrub, J., O’Brien, J., Parsons, P. E., Cuschieri, J., Wunderink, R. G., Hotchkin, D. L., ... Boeckh, M. (2017). Effect of ganciclovir on IL-6 levels among cytomegalovirus-seropositive adults with critical illness: A randomized clinical trial. JAMA - Journal of the American Medical Association, 318(8), 731-740. https://doi.org/10.1001/jama.2017.10569

@article{2d460ee86f094418b0581c05ebed78fa,

title = "Effect of ganciclovir on IL-6 levels among cytomegalovirus-seropositive adults with critical illness: A randomized clinical trial",

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 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. (Table Presented) 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.",

author = "Limaye, {Ajit P.} and Stapleton, {Renee D.} and Lili Peng and Gunn, {Scott R.} and Kimball, {Louise E.} and Robert Hyzy and Exline, {Matthew C.} and Files, {D. Clark} and Morris, {Peter E.} and Frankel, {Stephen K.} and Mikkelsen, {Mark E.} and Duncan Hite and Enfield, {Kyle B.} and Jay Steingrub and James O{\textquoteright}Brien and Parsons, {Polly E.} and Joseph Cuschieri and Wunderink, {Richard G.} and Hotchkin, {David L.} and Chen, {Ying Q.} and Rubenfeld, {Gordon D.} and Michael Boeckh",

note = "Funding Information: Additional Contributions: We thank Taylor Thompson, MD (Massachusetts General Hospital), David Schoenfeld, PhD, (Harvard Medical School), Mitchell Levy, MD (Brown University), Lorraine Ware, MD (Vanderbilt University), and Paul Griffiths, MD (University College, London), who served on the data and safety monitoring board. They received payment from grant UO1 HL 102547. We thank the following study coordinators: Lesley De Souza (Baystate Medical Center), Helen Donnelly, BSN (Northwestern University), Michelle Ferrari (Cleveland Clinic), Luke Herren (Ohio State University), Meg Day (Oregon Clinic), Jeff McKeehan, MSN (National Jewish Health), Kristine Nelson (University of Michigan), Pam Fazio, BS (University of Pittsburg), Sara Arden, BS (University of Vermont), Lori Flores, BSN (Wake Forest University), Mary Marshall, MSN (University of Virginia), Michaela Kusumi, BS (University of Washington), Fatima Ali, BS (University of Washington), and Laura Hennessy (University of Washington) for site research coordination; Lisa Chung, BS (Fred Hutchinson Cancer Research Center), Terry Stevens-Ayers, MS (Fred Hutchinson Cancer Research Center), Michaela Kusumi, BS (University of Washington), and Fatima Ali, BS (University of Washington), for their help with preparing the figures and manuscript; and Hu Xie, MS (Fred Hutchinson Cancer Research Center) for assistance with statistical analysis. We also thank the staff and coordinators at the Statistical Center for HIV/AIDS Research and Prevention for data management and Sheree Miller, PharmD (University of Washington), for the management and dispensing of the study drug and placebo. They did not receive compensation for their contribution. Funding Information: was supported by grant UO1 HL 102547 from the US National Institutes of Health{\textquoteright}s National Heart, Lung, and Blood Institute. Genentech supplied the initial batch of study drug (ganciclovir, valganciclovir, and placebo). Role of the Funder/Sponsor: The funders of the study had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript or the decision to submit for publication. Publisher Copyright: {\textcopyright} 2017 American Medical Association. All rights reserved.",

year = "2017",

month = aug,

day = "22",

doi = "10.1001/jama.2017.10569",

language = "English",

volume = "318",

pages = "731--740",

number = "8",

}

Limaye, AP, Stapleton, RD, Peng, L, Gunn, SR, Kimball, LE, Hyzy, R, Exline, MC, Files, DC, Morris, PE, Frankel, SK, Mikkelsen, ME, Hite, D, Enfield, KB, Steingrub, J, O’Brien, J, Parsons, PE, Cuschieri, J, Wunderink, RG, Hotchkin, DL, Chen, YQ, Rubenfeld, GD & Boeckh, M 2017, 'Effect of ganciclovir on IL-6 levels among cytomegalovirus-seropositive adults with critical illness: A randomized clinical trial', JAMA - Journal of the American Medical Association, vol. 318, no. 8, pp. 731-740. https://doi.org/10.1001/jama.2017.10569

TY - JOUR

T1 - Effect of ganciclovir on IL-6 levels among cytomegalovirus-seropositive adults with critical illness

T2 - A randomized clinical trial

AU - Limaye, Ajit P.

AU - Stapleton, Renee D.

AU - Peng, Lili

AU - Gunn, Scott R.

AU - Kimball, Louise E.

AU - Hyzy, Robert

AU - Exline, Matthew C.

AU - Files, D. Clark

AU - Morris, Peter E.

AU - Frankel, Stephen K.

AU - Mikkelsen, Mark E.

AU - Hite, Duncan

AU - Enfield, Kyle B.

AU - Steingrub, Jay

AU - O’Brien, James

AU - Parsons, Polly E.

AU - Cuschieri, Joseph

AU - Wunderink, Richard G.

AU - Hotchkin, David L.

AU - Chen, Ying Q.

AU - Rubenfeld, Gordon D.

AU - Boeckh, Michael

N1 - Funding Information: Additional Contributions: We thank Taylor Thompson, MD (Massachusetts General Hospital), David Schoenfeld, PhD, (Harvard Medical School), Mitchell Levy, MD (Brown University), Lorraine Ware, MD (Vanderbilt University), and Paul Griffiths, MD (University College, London), who served on the data and safety monitoring board. They received payment from grant UO1 HL 102547. We thank the following study coordinators: Lesley De Souza (Baystate Medical Center), Helen Donnelly, BSN (Northwestern University), Michelle Ferrari (Cleveland Clinic), Luke Herren (Ohio State University), Meg Day (Oregon Clinic), Jeff McKeehan, MSN (National Jewish Health), Kristine Nelson (University of Michigan), Pam Fazio, BS (University of Pittsburg), Sara Arden, BS (University of Vermont), Lori Flores, BSN (Wake Forest University), Mary Marshall, MSN (University of Virginia), Michaela Kusumi, BS (University of Washington), Fatima Ali, BS (University of Washington), and Laura Hennessy (University of Washington) for site research coordination; Lisa Chung, BS (Fred Hutchinson Cancer Research Center), Terry Stevens-Ayers, MS (Fred Hutchinson Cancer Research Center), Michaela Kusumi, BS (University of Washington), and Fatima Ali, BS (University of Washington), for their help with preparing the figures and manuscript; and Hu Xie, MS (Fred Hutchinson Cancer Research Center) for assistance with statistical analysis. We also thank the staff and coordinators at the Statistical Center for HIV/AIDS Research and Prevention for data management and Sheree Miller, PharmD (University of Washington), for the management and dispensing of the study drug and placebo. They did not receive compensation for their contribution. Funding Information: was supported by grant UO1 HL 102547 from the US National Institutes of Health’s National Heart, Lung, and Blood Institute. Genentech supplied the initial batch of study drug (ganciclovir, valganciclovir, and placebo). Role of the Funder/Sponsor: The funders of the study had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript or the decision to submit for publication. Publisher Copyright: © 2017 American Medical Association. All rights reserved.

PY - 2017/8/22

Y1 - 2017/8/22

N2 - 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 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. (Table Presented) 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.

AB - 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 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. (Table Presented) 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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Effect of ganciclovir on IL-6 levels among cytomegalovirus-seropositive adults with critical illness: A randomized clinical trial

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