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

Abstract

Background Interleukin (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. Methods In 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. 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 macrophage 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 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.

Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment

“…The broad biological role of the IL-18 cytokine on immune cells have revealed its potential role in inflammatory and autoimmune diseases. IL-18 have been shown to be a diagnostic marker and predictor of inflammatory conditions like myocardial ischemia ( 106 ), acute respiratory distress syndrome ( 107 , 108 ), chronic obstructive pulmonary disease ( 109 ), post infectious bronchiolitis obliterans ( 110 ) and sepsis-induced multi organ injury ( 111 ). IL-18 has also received increase attention in the pathophysiology of neuro-vascular diseases such as in intracerebral hemorrhage ( 112 ), Japanese encephalitis ( 113 ), ocular Behcet disease ( 114 ), abdominal aortic aneurysm ( 115 ), amyotrophic lateral sclerosis ( 116 ), glioma ( 117 ) and most interestingly in cognitive impairment ( 118 ) and agitation in severe mental disease ( 119 ).…”

High plasma IL-18 identifies high-risk ARDS patients not identified by latent class analysis sub-phenotyping: a secondary analysis of the SAILS and HARP-2 studies

“…As has been previously described, in both SAILS and HARP-2, IL-18 level ≥ 800pg/mL was associated with mortality [17,19]. Patients with IL-18 ≥ 800 in SAILS had a 60-day mortality of 44% compared to 22% in patients with IL-18 < 800 (Odds ratio (OR) 2.7, 95% con dence interval (CI) 1.8-4.1, Fisher's p < 0.001).…”

“…Retrospective analysis of the SAILS trial failed to show a mortality bene t to rosuvastatin in high-risk subgroups as de ned by either LCA or IL-18 levels [10,17]. However, in secondary analyses of HARP-2, both the hyper-in ammatory LCA subgroup and patients with IL-18 levels ≥ 800pg/mL experienced lower mortality when they received simvastatin relative to those that received placebo [13,19]. There is interest in future biomarker-guided randomized trials of simvastatin in high-risk ARDS patients, increasing the importance of understanding the overlap in classi cation by these two methods.…”

“…Interleukin-18 (IL-18) is a cytokine within the IL-1 family that is activated through the in ammasome pathway and has been associated with a variety of disease states [15,16]. IL-18 elevation has previously been shown to be associated with mortality in ARDS [17][18][19]. To date, however, IL-18 has rarely been included in "conventional" measures of in ammation in ARDS and has not been used as a class-de ning variable in the LCA algorithm.…”

Acute respiratory distress syndrome in adults: diagnosis, outcomes, long-term sequelae, and management

“…There is a need for continued translational research to identify novel treatable traits and therapeutic agents targeting these traits. [111][112][113] There might also be a role for a personalised approach to existing interventions in ARDS, and existing datasets could prove useful to identify populations that are most responsive.…”