Effect of cytomegalovirus reactivation on the time course of systemic host response biomarkers in previously immunocompetent critically ill patients with sepsis: a matched cohort study

K. Van De Groep; Stefan Nierkens; Olaf L. Cremer; Linda M. Peelen; Peter M.C. Klein Klouwenberg; Marcus J. Schultz; C. Erik Hack; Tom Van Der Poll; Marc J.M. Bonten; David S.Y. Ong; Friso M. De Beer; Lieuwe D.J. Bos; Gerie J. Glas; Arie J. Hoogendijk; Roosmarijn T.M. Van Hooijdonk; Janneke Horn; Mischa A. Huson; Nicole P. Juffermans; Laura R.A. Schouten; Brendon Scicluna; Marleen Straat; Lonneke A. Van Vught; Luuk Wieske; Maryse A. Wiewel; Esther Witteveen; Jos F. Frencken; K. Van De Groep; Maria E. Koster-Brouwer; Meri R.J. Varkila; Diana M. Verboom

doi:10.1186/s13054-018-2261-0

Effect of cytomegalovirus reactivation on the time course of systemic host response biomarkers in previously immunocompetent critically ill patients with sepsis: a matched cohort study

K. Van De Groep
, Stefan Nierkens
, Olaf L. Cremer
, Linda M. Peelen
, Peter M.C. Klein Klouwenberg
, Marcus J. Schultz
, C. Erik Hack
, Tom Van Der Poll
, Marc J.M. Bonten
, David S.Y. Ong
, Friso M. De Beer
, Lieuwe D.J. Bos
, Gerie J. Glas
, Arie J. Hoogendijk
, Roosmarijn T.M. Van Hooijdonk
, Janneke Horn
, Mischa A. Huson
, Nicole P. Juffermans
, Laura R.A. Schouten
, Brendon Scicluna

Marleen Straat, Lonneke A. Van Vught, Luuk Wieske, Maryse A. Wiewel, Esther Witteveen, Jos F. Frencken, K. Van De Groep, Maria E. Koster-Brouwer, Meri R.J. Varkila, Diana M. Verboom

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

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Abstract

BACKGROUND: Cytomegalovirus (CMV) reactivation in previously immunocompetent critically ill patients is associated with increased mortality, which has been hypothesized to result from virus-induced immunomodulation. Therefore, we studied the effects of CMV reactivation on the temporal course of host response biomarkers in patients with sepsis.

METHODS: In this matched cohort study, each sepsis patient developing CMV reactivation between day 3 and 17 (CMV+) was compared with one CMV seropositive patient without reactivation (CMVs+) and one CMV seronegative patient (CMVs-). CMV serostatus and plasma loads were determined by enzyme-linked immunoassays and real-time polymerase chain reaction, respectively. Systemic interleukin-6 (IL-6), IL-8, IL-18, interferon-gamma-induced protein-10 (IP-10), neutrophilic elastase, IL-1 receptor antagonist (RA), and IL-10 were measured at five time points by multiplex immunoassay. The effects of CMV reactivation on sequential concentrations of these biomarkers were assessed in multivariable mixed models.

RESULTS: Among 64 CMV+ patients, 45 could be matched to CMVs+ or CMVs- controls or both. The two baseline characteristics and host response biomarker levels at viremia onset were similar between groups. CMV+ patients had increased IP-10 on day 7 after viremia onset (symmetric percentage difference +44% versus -15% when compared with CMVs+ and +37% versus +4% when compared with CMVs-) and decreased IL-1RA (-41% versus 0% and -49% versus +10%, respectively). However, multivariable analyses did not show an independent association between CMV reactivation and time trends of IL-6, IP-10, IL-10, or IL-1RA.

CONCLUSION: CMV reactivation was not independently associated with changes in the temporal trends of host response biomarkers in comparison with non-reactivating patients. Therefore, these markers should not be used as surrogate clinical endpoints for interventional studies evaluating anti-CMV therapy.

Original language	English
Article number	348
Journal	Critical Care
Volume	22
Issue number	1
DOIs	https://doi.org/10.1186/s13054-018-2261-0
Publication status	Published - 18 Dec 2018

Keywords

Aged
Biomarkers/analysis
Chemokine CXCL10/analysis
Chi-Square Distribution
Cohort Studies
Critical Illness
Cytomegalovirus/immunology
Cytomegalovirus Infections/blood
Female
Humans
Immunity, Humoral/physiology
Intensive Care Units/organization & administration
Interleukin 1 Receptor Antagonist Protein/analysis
Interleukin-10/analysis
Interleukin-6/analysis
Male
Middle Aged
Sepsis/immunology
Virus Activation/physiology
Cytomegalovirus
Reactivation
Critically ill
Inflammation
Host response

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Van De Groep, K., Nierkens, S., Cremer, O. L., Peelen, L. M., Klein Klouwenberg, P. M. C., Schultz, M. J., Hack, C. E., Van Der Poll, T., Bonten, M. J. M., Ong, D. S. Y., De Beer, F. M., Bos, L. D. J., Glas, G. J., Hoogendijk, A. J., Van Hooijdonk, R. T. M., Horn, J., Huson, M. A., Juffermans, N. P., Schouten, L. R. A., ... Verboom, D. M. (2018). Effect of cytomegalovirus reactivation on the time course of systemic host response biomarkers in previously immunocompetent critically ill patients with sepsis: a matched cohort study. Critical Care, 22(1), Article 348. https://doi.org/10.1186/s13054-018-2261-0

@article{77d065a848ae406c88568abe43d17c95,

title = "Effect of cytomegalovirus reactivation on the time course of systemic host response biomarkers in previously immunocompetent critically ill patients with sepsis: a matched cohort study",

abstract = "BACKGROUND: Cytomegalovirus (CMV) reactivation in previously immunocompetent critically ill patients is associated with increased mortality, which has been hypothesized to result from virus-induced immunomodulation. Therefore, we studied the effects of CMV reactivation on the temporal course of host response biomarkers in patients with sepsis.METHODS: In this matched cohort study, each sepsis patient developing CMV reactivation between day 3 and 17 (CMV+) was compared with one CMV seropositive patient without reactivation (CMVs+) and one CMV seronegative patient (CMVs-). CMV serostatus and plasma loads were determined by enzyme-linked immunoassays and real-time polymerase chain reaction, respectively. Systemic interleukin-6 (IL-6), IL-8, IL-18, interferon-gamma-induced protein-10 (IP-10), neutrophilic elastase, IL-1 receptor antagonist (RA), and IL-10 were measured at five time points by multiplex immunoassay. The effects of CMV reactivation on sequential concentrations of these biomarkers were assessed in multivariable mixed models.RESULTS: Among 64 CMV+ patients, 45 could be matched to CMVs+ or CMVs- controls or both. The two baseline characteristics and host response biomarker levels at viremia onset were similar between groups. CMV+ patients had increased IP-10 on day 7 after viremia onset (symmetric percentage difference +44\% versus -15\% when compared with CMVs+ and +37\% versus +4\% when compared with CMVs-) and decreased IL-1RA (-41\% versus 0\% and -49\% versus +10\%, respectively). However, multivariable analyses did not show an independent association between CMV reactivation and time trends of IL-6, IP-10, IL-10, or IL-1RA.CONCLUSION: CMV reactivation was not independently associated with changes in the temporal trends of host response biomarkers in comparison with non-reactivating patients. Therefore, these markers should not be used as surrogate clinical endpoints for interventional studies evaluating anti-CMV therapy.",

keywords = "Aged, Biomarkers/analysis, Chemokine CXCL10/analysis, Chi-Square Distribution, Cohort Studies, Critical Illness, Cytomegalovirus/immunology, Cytomegalovirus Infections/blood, Female, Humans, Immunity, Humoral/physiology, Intensive Care Units/organization \& administration, Interleukin 1 Receptor Antagonist Protein/analysis, Interleukin-10/analysis, Interleukin-6/analysis, Male, Middle Aged, Sepsis/immunology, Virus Activation/physiology, Cytomegalovirus, Reactivation, Critically ill, Inflammation, Host response",

author = "\{Van De Groep\}, K. and Stefan Nierkens and Cremer, \{Olaf L.\} and Peelen, \{Linda M.\} and \{Klein Klouwenberg\}, \{Peter M.C.\} and Schultz, \{Marcus J.\} and Hack, \{C. Erik\} and \{Van Der Poll\}, Tom and Bonten, \{Marc J.M.\} and Ong, \{David S.Y.\} and \{De Beer\}, \{Friso M.\} and Bos, \{Lieuwe D.J.\} and Glas, \{Gerie J.\} and Hoogendijk, \{Arie J.\} and \{Van Hooijdonk\}, \{Roosmarijn T.M.\} and Janneke Horn and Huson, \{Mischa A.\} and Juffermans, \{Nicole P.\} and Schouten, \{Laura R.A.\} and Brendon Scicluna and Marleen Straat and \{Van Vught\}, \{Lonneke A.\} and Luuk Wieske and Wiewel, \{Maryse A.\} and Esther Witteveen and Frencken, \{Jos F.\} and \{Van De Groep\}, K. and Koster-Brouwer, \{Maria E.\} and Varkila, \{Meri R.J.\} and Verboom, \{Diana M.\}",

note = "Funding Information: This work was supported by the Center for Translation Molecular Medicine (http://www.ctmm.nl), project MARS (grant 041–201). The sponsor did not play a role in the design and conduct of the study (including collection, management, analysis, and interpretation of the data) or the preparation of the manuscript (including review or approval of the manuscript or decision to submit the manuscript for publication). Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = dec,

day = "18",

doi = "10.1186/s13054-018-2261-0",

language = "English",

volume = "22",

journal = "Critical Care",

issn = "1364-8535",

publisher = "BioMed Central Ltd.",

number = "1",

}

Van De Groep, K, Nierkens, S , Cremer, OL, Peelen, LM, Klein Klouwenberg, PMC, Schultz, MJ, Hack, CE, Van Der Poll, T, Bonten, MJM, Ong, DSY, De Beer, FM, Bos, LDJ, Glas, GJ, Hoogendijk, AJ, Van Hooijdonk, RTM, Horn, J, Huson, MA, Juffermans, NP, Schouten, LRA, Scicluna, B, Straat, M, Van Vught, LA, Wieske, L, Wiewel, MA, Witteveen, E, Frencken, JF, Van De Groep, K, Koster-Brouwer, ME, Varkila, MRJ & Verboom, DM 2018, 'Effect of cytomegalovirus reactivation on the time course of systemic host response biomarkers in previously immunocompetent critically ill patients with sepsis: a matched cohort study', Critical Care, vol. 22, no. 1, 348. https://doi.org/10.1186/s13054-018-2261-0

Effect of cytomegalovirus reactivation on the time course of systemic host response biomarkers in previously immunocompetent critically ill patients with sepsis: a matched cohort study. / Van De Groep, K.; Nierkens, Stefan ; Cremer, Olaf L. et al.
In: Critical Care, Vol. 22, No. 1, 348, 18.12.2018.

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

TY - JOUR

T1 - Effect of cytomegalovirus reactivation on the time course of systemic host response biomarkers in previously immunocompetent critically ill patients with sepsis

T2 - a matched cohort study

AU - Van De Groep, K.

AU - Nierkens, Stefan

AU - Cremer, Olaf L.

AU - Peelen, Linda M.

AU - Klein Klouwenberg, Peter M.C.

AU - Schultz, Marcus J.

AU - Hack, C. Erik

AU - Van Der Poll, Tom

AU - Bonten, Marc J.M.

AU - Ong, David S.Y.

AU - De Beer, Friso M.

AU - Bos, Lieuwe D.J.

AU - Glas, Gerie J.

AU - Hoogendijk, Arie J.

AU - Van Hooijdonk, Roosmarijn T.M.

AU - Horn, Janneke

AU - Huson, Mischa A.

AU - Juffermans, Nicole P.

AU - Schouten, Laura R.A.

AU - Scicluna, Brendon

AU - Straat, Marleen

AU - Van Vught, Lonneke A.

AU - Wieske, Luuk

AU - Wiewel, Maryse A.

AU - Witteveen, Esther

AU - Frencken, Jos F.

AU - Van De Groep, K.

AU - Koster-Brouwer, Maria E.

AU - Varkila, Meri R.J.

AU - Verboom, Diana M.

N1 - Funding Information: This work was supported by the Center for Translation Molecular Medicine (http://www.ctmm.nl), project MARS (grant 041–201). The sponsor did not play a role in the design and conduct of the study (including collection, management, analysis, and interpretation of the data) or the preparation of the manuscript (including review or approval of the manuscript or decision to submit the manuscript for publication). Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/18

Y1 - 2018/12/18

N2 - BACKGROUND: Cytomegalovirus (CMV) reactivation in previously immunocompetent critically ill patients is associated with increased mortality, which has been hypothesized to result from virus-induced immunomodulation. Therefore, we studied the effects of CMV reactivation on the temporal course of host response biomarkers in patients with sepsis.METHODS: In this matched cohort study, each sepsis patient developing CMV reactivation between day 3 and 17 (CMV+) was compared with one CMV seropositive patient without reactivation (CMVs+) and one CMV seronegative patient (CMVs-). CMV serostatus and plasma loads were determined by enzyme-linked immunoassays and real-time polymerase chain reaction, respectively. Systemic interleukin-6 (IL-6), IL-8, IL-18, interferon-gamma-induced protein-10 (IP-10), neutrophilic elastase, IL-1 receptor antagonist (RA), and IL-10 were measured at five time points by multiplex immunoassay. The effects of CMV reactivation on sequential concentrations of these biomarkers were assessed in multivariable mixed models.RESULTS: Among 64 CMV+ patients, 45 could be matched to CMVs+ or CMVs- controls or both. The two baseline characteristics and host response biomarker levels at viremia onset were similar between groups. CMV+ patients had increased IP-10 on day 7 after viremia onset (symmetric percentage difference +44% versus -15% when compared with CMVs+ and +37% versus +4% when compared with CMVs-) and decreased IL-1RA (-41% versus 0% and -49% versus +10%, respectively). However, multivariable analyses did not show an independent association between CMV reactivation and time trends of IL-6, IP-10, IL-10, or IL-1RA.CONCLUSION: CMV reactivation was not independently associated with changes in the temporal trends of host response biomarkers in comparison with non-reactivating patients. Therefore, these markers should not be used as surrogate clinical endpoints for interventional studies evaluating anti-CMV therapy.

AB - BACKGROUND: Cytomegalovirus (CMV) reactivation in previously immunocompetent critically ill patients is associated with increased mortality, which has been hypothesized to result from virus-induced immunomodulation. Therefore, we studied the effects of CMV reactivation on the temporal course of host response biomarkers in patients with sepsis.METHODS: In this matched cohort study, each sepsis patient developing CMV reactivation between day 3 and 17 (CMV+) was compared with one CMV seropositive patient without reactivation (CMVs+) and one CMV seronegative patient (CMVs-). CMV serostatus and plasma loads were determined by enzyme-linked immunoassays and real-time polymerase chain reaction, respectively. Systemic interleukin-6 (IL-6), IL-8, IL-18, interferon-gamma-induced protein-10 (IP-10), neutrophilic elastase, IL-1 receptor antagonist (RA), and IL-10 were measured at five time points by multiplex immunoassay. The effects of CMV reactivation on sequential concentrations of these biomarkers were assessed in multivariable mixed models.RESULTS: Among 64 CMV+ patients, 45 could be matched to CMVs+ or CMVs- controls or both. The two baseline characteristics and host response biomarker levels at viremia onset were similar between groups. CMV+ patients had increased IP-10 on day 7 after viremia onset (symmetric percentage difference +44% versus -15% when compared with CMVs+ and +37% versus +4% when compared with CMVs-) and decreased IL-1RA (-41% versus 0% and -49% versus +10%, respectively). However, multivariable analyses did not show an independent association between CMV reactivation and time trends of IL-6, IP-10, IL-10, or IL-1RA.CONCLUSION: CMV reactivation was not independently associated with changes in the temporal trends of host response biomarkers in comparison with non-reactivating patients. Therefore, these markers should not be used as surrogate clinical endpoints for interventional studies evaluating anti-CMV therapy.

KW - Aged

KW - Biomarkers/analysis

KW - Chemokine CXCL10/analysis

KW - Chi-Square Distribution

KW - Cohort Studies

KW - Critical Illness

KW - Cytomegalovirus/immunology

KW - Cytomegalovirus Infections/blood

KW - Female

KW - Humans

KW - Immunity, Humoral/physiology

KW - Intensive Care Units/organization & administration

KW - Interleukin 1 Receptor Antagonist Protein/analysis

KW - Interleukin-10/analysis

KW - Interleukin-6/analysis

KW - Male

KW - Middle Aged

KW - Sepsis/immunology

KW - Virus Activation/physiology

KW - Cytomegalovirus

KW - Reactivation

KW - Critically ill

KW - Inflammation

KW - Host response

UR - https://www.scopus.com/pages/publications/85058792224

U2 - 10.1186/s13054-018-2261-0

DO - 10.1186/s13054-018-2261-0

M3 - Article

C2 - 30563551

AN - SCOPUS:85058792224

SN - 1364-8535

VL - 22

JO - Critical Care

JF - Critical Care

IS - 1

M1 - 348

ER -

Effect of cytomegalovirus reactivation on the time course of systemic host response biomarkers in previously immunocompetent critically ill patients with sepsis: a matched cohort study

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