• Andrew James Boyle, Peter Ferris, Ian Bradbury, John Conlon, Manu Shankar-Hari, Angela J Rogers, Cecilia M O'Kane, and Daniel F McAuley.
• Wellcome-Wolfson Institute for Experimental Medicine, Centre for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland. aboyle26@qub.ac.uk.
• Crit Care. 2022 Jun 7; 26 (1): 164164.

BackgroundInterleukin (IL)-18 is a marker of inflammasome 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 benefit in patients with ARDS and high plasma IL-18.MethodsIn this secondary analysis of the HARP-2 study, we compared 28-day mortality and response to simvastatin 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 effect on secreted IL-18 and IL-1β compared.Results511 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 macrophage secretion of IL-18 and IL-1β.ConclusionIn patients with high baseline plasma IL-18, simvastatin is associated with a higher probability of survival, and this effect may be due to reduced inflammasome activation. These data suggest that baseline plasma IL-18 may allow a personalised treatment approach by identifying patients with ARDS who could benefit from simvastatin therapy.© 2022. The Author(s).

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