Baseline plasma IL-18 may predict simvastatin treatment response in patients with ARDS: a secondary analysis of the HARP-2 randomised clinical trial

Andrew James Boyle; Peter Ferris; Ian Bradbury; John Conlon; Manu Shankar-hari; Angela J. Rogers; Cecilia M. O’kane; Daniel F. Mcauley

doi:10.1186/s13054-022-04025-w

Baseline plasma IL-18 may predict simvastatin treatment response in patients with ARDS: a secondary analysis of the HARP-2 randomised clinical trial

Andrew James Boyle, Peter Ferris, Ian Bradbury, John Conlon, Manu Shankar-hari, Angela J. Rogers, Cecilia M. O’kane, Daniel F. Mcauley

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

Abstract / Description of output

Abstract
Background: Interleukin (IL)-18 is a marker of infammasome activation, and high baseline plasma IL-18 is associated with increased mortality in patients with sepsis-induced ARDS. The aim of this analysis was to determine if simvastatin
was associated with beneft in patients with ARDS and high plasma IL-18.
Methods: In this secondary analysis of the HARP-2 study, we compared 28-day mortality and response to simvasta‑ tin according to baseline plasma IL-18 using cox proportional hazards analysis. Separately, monocyte-derived macrophages from healthy volunteers were pre-incubated with simvastatin or rosuvastatin before stimulation with ATP and LPS, and the efect on secreted IL-18 and IL-1β compared.
Results: 511 patients from HARP-2 had available data. High baseline plasma IL-18 (≥800 pg/ml) was associated with increased 28-day mortality (high IL-18 30.6% vs. low IL-18 17.5%; HR 1.89 [95% CI 1.30–2.73]; p=0.001). Allocation to
simvastatin in patients with high baseline plasma IL-18 was associated with a lower probability of 28-day mortality compared with placebo (24.0% vs 36.8%; p=0.01). Finally, simvastatin, but not rosuvastatin, reduced stimulated mac‑
rophage secretion of IL-18 and IL-1β.
Conclusion: In patients with high baseline plasma IL-18, simvastatin is associated with a higher probability of survival, and this efect may be due to reduced infammasome activation. These data suggest that baseline plasma IL-18
may allow a personalised treatment approach by identifying patients with ARDS who could beneft from simvastatin therapy.
Keywords: Acute respiratory distress syndrome, Simvastatin, Infammasome, Interleukin-18, Personalised medicine

Original language	English
Journal	Critical Care
Volume	26
Issue number	1
DOIs	https://doi.org/10.1186/s13054-022-04025-w
Publication status	Published - 7 Jun 2022

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@article{308a495cdd8c44b2adeeeefce4697b5b,

title = "Baseline plasma IL-18 may predict simvastatin treatment response in patients with ARDS: a secondary analysis of the HARP-2 randomised clinical trial",

abstract = "AbstractBackground: Interleukin (IL)-18 is a marker of infammasome activation, and high baseline plasma IL-18 is associated with increased mortality in patients with sepsis-induced ARDS. The aim of this analysis was to determine if simvastatinwas associated with beneft in patients with ARDS and high plasma IL-18.Methods: In this secondary analysis of the HARP-2 study, we compared 28-day mortality and response to simvasta‑ tin according to baseline plasma IL-18 using cox proportional hazards analysis. Separately, monocyte-derived macrophages from healthy volunteers were pre-incubated with simvastatin or rosuvastatin before stimulation with ATP and LPS, and the efect on secreted IL-18 and IL-1β compared.Results: 511 patients from HARP-2 had available data. High baseline plasma IL-18 (≥800 pg/ml) was associated with increased 28-day mortality (high IL-18 30.6% vs. low IL-18 17.5%; HR 1.89 [95% CI 1.30–2.73]; p=0.001). Allocation tosimvastatin in patients with high baseline plasma IL-18 was associated with a lower probability of 28-day mortality compared with placebo (24.0% vs 36.8%; p=0.01). Finally, simvastatin, but not rosuvastatin, reduced stimulated mac‑rophage secretion of IL-18 and IL-1β.Conclusion: In patients with high baseline plasma IL-18, simvastatin is associated with a higher probability of survival, and this efect may be due to reduced infammasome activation. These data suggest that baseline plasma IL-18may allow a personalised treatment approach by identifying patients with ARDS who could beneft from simvastatin therapy.Keywords: Acute respiratory distress syndrome, Simvastatin, Infammasome, Interleukin-18, Personalised medicine",

author = "Boyle, {Andrew James} and Peter Ferris and Ian Bradbury and John Conlon and Manu Shankar-hari and Rogers, {Angela J.} and O{\textquoteright}kane, {Cecilia M.} and Mcauley, {Daniel F.}",

note = "Funding Information: This study was supported by the UK EME Programme, an MRC and NIHR partnership (08/99/08 and 16/33/01). The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland, the National Institute for Social Care and Health Research in Wales, and the Health and Social Care (HSC) Research and Development Division, Public Health Agency for Northern Ireland. Additionally, MS-H is supported by the NIHR Clinician Scientist Award (CS-2016-16-011). Funding Information: Outside of the submitted work, and in the past 36 months, Prof O{\textquoteright}Kane has received funding from Wellcome Trust, MRC, Northern Ireland Health and Social Care Research and Development Office, and Innovate UK, for ARDS research. Prof O{\textquoteright}Kane has received fees for grant panel membership, including the review of ARDS-related projects, from the California Institute for Regenerative Medicine (CIRM). Outside of the submitted work, the spouse of CO{\textquoteright}K has received consultancy/educational fees from Bayer, GSK, Boehringer Ingelheim, Eli Lilly, SOBI and Novartis, and fees for being a DMEC member for VIr Biotechnology and Faron. Prof O{\textquoteright}Kane has received consultancy fees from Insmed for unrelated work. Prof McAuley has received funding to his institution for studies outside of this submitted work from the NIHR, Wellcome Trust, Innovate UK, Northern Ireland Health and Social Care Research and Development Office and Randox. Prof McAuley has a patent application issued to his institution. Outside of the submitted work Prof McAuley has received fees for consultancy from Bayer, GSK, Boehringer Ingelheim, Eli Lilly and Novartis and SOBI and for being a member of the data monitoring and ethics committee for Vir Biotechnology and Faron studies and as an educational seminar speaker for GSK. The spouse of Prof McAuley has received consultancy fees from Insmed unrelated to this work, and fees for grant panel membership from CIRM. All other authors declare no competing interests. Funding Information: The views expressed in this article are those of the authors and not necessarily those of the Medical Research Council (MRC), National Health Service, NIHR, or Department of Health. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = jun,

day = "7",

doi = "10.1186/s13054-022-04025-w",

language = "English",

volume = "26",

journal = "Critical Care",

issn = "1364-8535",

publisher = "Springer",

number = "1",

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TY - JOUR

T1 - Baseline plasma IL-18 may predict simvastatin treatment response in patients with ARDS: a secondary analysis of the HARP-2 randomised clinical trial

AU - Boyle, Andrew James

AU - Ferris, Peter

AU - Bradbury, Ian

AU - Conlon, John

AU - Shankar-hari, Manu

AU - Rogers, Angela J.

AU - O’kane, Cecilia M.

AU - Mcauley, Daniel F.

N1 - Funding Information: This study was supported by the UK EME Programme, an MRC and NIHR partnership (08/99/08 and 16/33/01). The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland, the National Institute for Social Care and Health Research in Wales, and the Health and Social Care (HSC) Research and Development Division, Public Health Agency for Northern Ireland. Additionally, MS-H is supported by the NIHR Clinician Scientist Award (CS-2016-16-011). Funding Information: Outside of the submitted work, and in the past 36 months, Prof O’Kane has received funding from Wellcome Trust, MRC, Northern Ireland Health and Social Care Research and Development Office, and Innovate UK, for ARDS research. Prof O’Kane has received fees for grant panel membership, including the review of ARDS-related projects, from the California Institute for Regenerative Medicine (CIRM). Outside of the submitted work, the spouse of CO’K has received consultancy/educational fees from Bayer, GSK, Boehringer Ingelheim, Eli Lilly, SOBI and Novartis, and fees for being a DMEC member for VIr Biotechnology and Faron. Prof O’Kane has received consultancy fees from Insmed for unrelated work. Prof McAuley has received funding to his institution for studies outside of this submitted work from the NIHR, Wellcome Trust, Innovate UK, Northern Ireland Health and Social Care Research and Development Office and Randox. Prof McAuley has a patent application issued to his institution. Outside of the submitted work Prof McAuley has received fees for consultancy from Bayer, GSK, Boehringer Ingelheim, Eli Lilly and Novartis and SOBI and for being a member of the data monitoring and ethics committee for Vir Biotechnology and Faron studies and as an educational seminar speaker for GSK. The spouse of Prof McAuley has received consultancy fees from Insmed unrelated to this work, and fees for grant panel membership from CIRM. All other authors declare no competing interests. Funding Information: The views expressed in this article are those of the authors and not necessarily those of the Medical Research Council (MRC), National Health Service, NIHR, or Department of Health. Publisher Copyright: © 2022, The Author(s).

PY - 2022/6/7

Y1 - 2022/6/7

N2 - AbstractBackground: Interleukin (IL)-18 is a marker of infammasome activation, and high baseline plasma IL-18 is associated with increased mortality in patients with sepsis-induced ARDS. The aim of this analysis was to determine if simvastatinwas associated with beneft in patients with ARDS and high plasma IL-18.Methods: In this secondary analysis of the HARP-2 study, we compared 28-day mortality and response to simvasta‑ tin according to baseline plasma IL-18 using cox proportional hazards analysis. Separately, monocyte-derived macrophages from healthy volunteers were pre-incubated with simvastatin or rosuvastatin before stimulation with ATP and LPS, and the efect on secreted IL-18 and IL-1β compared.Results: 511 patients from HARP-2 had available data. High baseline plasma IL-18 (≥800 pg/ml) was associated with increased 28-day mortality (high IL-18 30.6% vs. low IL-18 17.5%; HR 1.89 [95% CI 1.30–2.73]; p=0.001). Allocation tosimvastatin in patients with high baseline plasma IL-18 was associated with a lower probability of 28-day mortality compared with placebo (24.0% vs 36.8%; p=0.01). Finally, simvastatin, but not rosuvastatin, reduced stimulated mac‑rophage secretion of IL-18 and IL-1β.Conclusion: In patients with high baseline plasma IL-18, simvastatin is associated with a higher probability of survival, and this efect may be due to reduced infammasome activation. These data suggest that baseline plasma IL-18may allow a personalised treatment approach by identifying patients with ARDS who could beneft from simvastatin therapy.Keywords: Acute respiratory distress syndrome, Simvastatin, Infammasome, Interleukin-18, Personalised medicine

AB - AbstractBackground: Interleukin (IL)-18 is a marker of infammasome activation, and high baseline plasma IL-18 is associated with increased mortality in patients with sepsis-induced ARDS. The aim of this analysis was to determine if simvastatinwas associated with beneft in patients with ARDS and high plasma IL-18.Methods: In this secondary analysis of the HARP-2 study, we compared 28-day mortality and response to simvasta‑ tin according to baseline plasma IL-18 using cox proportional hazards analysis. Separately, monocyte-derived macrophages from healthy volunteers were pre-incubated with simvastatin or rosuvastatin before stimulation with ATP and LPS, and the efect on secreted IL-18 and IL-1β compared.Results: 511 patients from HARP-2 had available data. High baseline plasma IL-18 (≥800 pg/ml) was associated with increased 28-day mortality (high IL-18 30.6% vs. low IL-18 17.5%; HR 1.89 [95% CI 1.30–2.73]; p=0.001). Allocation tosimvastatin in patients with high baseline plasma IL-18 was associated with a lower probability of 28-day mortality compared with placebo (24.0% vs 36.8%; p=0.01). Finally, simvastatin, but not rosuvastatin, reduced stimulated mac‑rophage secretion of IL-18 and IL-1β.Conclusion: In patients with high baseline plasma IL-18, simvastatin is associated with a higher probability of survival, and this efect may be due to reduced infammasome activation. These data suggest that baseline plasma IL-18may allow a personalised treatment approach by identifying patients with ARDS who could beneft from simvastatin therapy.Keywords: Acute respiratory distress syndrome, Simvastatin, Infammasome, Interleukin-18, Personalised medicine

U2 - 10.1186/s13054-022-04025-w

DO - 10.1186/s13054-022-04025-w

M3 - Article

SN - 1364-8535

VL - 26

JO - Critical Care

JF - Critical Care

IS - 1

ER -

Baseline plasma IL-18 may predict simvastatin treatment response in patients with ARDS: a secondary analysis of the HARP-2 randomised clinical trial

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