Association of Elevated Plasma Interleukin-18 Level With Increased Mortality in a Clinical Trial of Statin Treatment for Acute Respiratory Distress Syndrome

Abstract

Objective: A high plasma level of inflammasome mediator interleukin-18 was associated with mortality in observational acute respiratory distress syndrome cohorts. Statin exposure increases both inflammasome activation and lung injury in mouse models. We tested whether randomization to statin therapy correlated with increased interleukin-18 in the ARDS Network Statins for Acutely Injured Lungs from Sepsis trial.

Design: Retrospective analysis of randomized controlled clinical trial.

Setting: Multicenter North American clinical trial, the ARDS Network Statins for Acutely Injured Lungs from Sepsis.

Patients: Six hundred eighty-three subjects with infection-related acute respiratory distress syndrome, representing 92% of the original trial population.

Interventions: Random assignment of rosuvastatin or placebo for up to 28 days or 3 days after ICU discharge.

Measurements and main results: We measured plasma interleukin-18 levels in all Statins for Acutely Injured Lungs from Sepsis patients with sample available at day 0 (baseline, n = 683) and day 3 (after randomization, n = 588). We tested the association among interleukin-18 level at baseline, rising interleukin-18, and the impact of statin therapy on 60-day mortality, adjusting for severity of illness. Baseline plasma interleukin-18 level greater than or equal to 800 pg/mL was highly associated with 60-day mortality, with a hazard of death of 2.3 (95% CI, 1.7-3.1). Rising plasma interleukin-18 was also associated with increased mortality. For each unit increase in log2 (interleukin-18) at day 3 compared with baseline, the hazard of death increased by 2.3 (95% CI, 1.5-3.5). Subjects randomized to statin were significantly more likely to experience a rise in plasma interleukin-18 levels. Subjects with acute kidney injury, shock, low baseline interleukin-18, and those not receiving systemic corticosteroids were more likely to experience rising interleukin-18. Randomization to statin therapy was associated with rising in interleukin-18 in all of those subsets, however.

Conclusions: Elevated baseline plasma interleukin-18 was associated with higher mortality in sepsis-induced acute respiratory distress syndrome. A rise in plasma interleukin-18 was also associated with increased mortality and was more common in subjects randomized to statin therapy in this clinical trial.

Figure 1:

Survival dichotomized by baseline plasma IL-18 level. Kaplan-Meier curve of survival from enrollment (day 0) to day 90. Subjects with low baseline IL-18 level (<800 pg/ml, blue) vs. those with high baseline IL-18 level (≥ 800 pg/ml, red), p value 1 × 10⁻⁵ by Cox proportional hazards.

Figure 2:

Survival grouped by day 3 IL-18 trajectory, Kaplan-Meier curve of survival from enrollment (day 0) to Day 90. Change characterized as increasing IL-18 (red, N=237), stable (green, within 10% of baseline, N = 229), falling (blue, N= 122). 2A: Mortality is highly associated with change in IL-18, (Chi squared p <.001). 2B: Subjects randomized to statin are shown with a dashed line, those randomized to placebo with a solid line. Mortality is highly associated with change in IL-18, and there is no detectable interaction by treatment group (p=.12).

Figure 2:

Survival grouped by day 3 IL-18 trajectory, Kaplan-Meier curve of survival from enrollment (day 0) to Day 90. Change characterized as increasing IL-18 (red, N=237), stable (green, within 10% of baseline, N = 229), falling (blue, N= 122). 2A: Mortality is highly associated with change in IL-18, (Chi squared p <.001). 2B: Subjects randomized to statin are shown with a dashed line, those randomized to placebo with a solid line. Mortality is highly associated with change in IL-18, and there is no detectable interaction by treatment group (p=.12).