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Objectives: Interleukin-18 (IL-18) plasma level and latent class analysis (LCA) have separately been shown to predict prognosis and treatment response in acute respiratory distress syndrome (ARDS). IL-18 is a measure of inflammasome activation, a pathway potentially distinct from inflammation captured by biomarkers defining previously published LCA classes. We hypothesized that elevated IL-18 would identify distinct "high-risk" patients not captured by prior LCA classifications., Design: Statins for acutely injured lungs from sepsis (SAILS) and hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) are two large randomized, controlled trials in ARDS in which both LCA assignments and IL-18 levels were shown to predict mortality. We first evaluated the overlap between high IL-18 levels (≥ 800 pg/mL) with prior LCA class assignments using McNemar's test and then tested the correlation between IL-18 and LCA biomarkers using Pearson's exact test on log-2 transformed values. Our primary analysis was the association of IL-18 level with 60-day mortality in the hypoinflammatory LCA class, which was assessed using the Fisher exact test and Cox proportional hazards modeling adjusting for age, Acute Physiology and Chronic Health Evaluation score, and gender. Secondary analyses included the association of IL-18 and LCA with mortality within each IL-18/LCA subgroup., Setting: Secondary analysis of two multicenter, randomized controlled clinical trials of ARDS patients., Subjects: Six hundred eighty-three patients in SAILS and 511 patients in HARP-2., Interventions: None., Measurements and Main Results: We found that 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. We further found that IL-18 level was only modestly correlated (0.17-0.47) with cytokines used in the LCA assignment. A substantial subset of individuals classified as hypoinflammatory by LCA (14% of SAILS and 43% of HARP-2) were classified as high risk by elevated IL-18. These individuals were at high risk for mortality in both SAILS (42% 60-d mortality, odds ratio [OR] 3.3; 95% CI, 1.8-6.1; p < 0.001) and HARP-2 (27% 60-d mortality, OR 2.1; 95% CI, 1.2-3.8; p = 0.009)., Conclusions: Plasma IL-18 level provides important additional prognostic information to LCA subphenotypes defined largely by traditional inflammatory biomarkers in two large ARDS cohorts., Competing Interests: Dr. Sinha received funding from the National Heart Lung and Blood Institute as part of the Acute Respiratory Distress Syndrome Network and AstraZeneca ( ClinicalTrials.gov number NCT00979121). Drs. Sinha, Matthay, and Calfee received support for article research from the National Institutes of Health (NIH). Dr. O’Kane’s institution received funding from National Intitute for Health and Care Research (NIHR) Efficacy and Evaluation Mechanism (EME); she received funding from Californian Institute for Regenerative Medicine and Insmed; she disclosed that her spouse has received funding from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Eli Lily, Sobi, Vir Biotech, and Faron Pharmaceuticals and disclosed that her spouse holds a patent with Queen’s University (USB962032) and director of the NIHR/Medical Research Council (MRC) EME program and co-director of research for intensive care society of the UK; she received support for article research from the Research Councils UK. Dr. Levitt disclosed the off-label product use of the Experimental use of simvastatin and rosuvastatin for acute respiratory distress syndrome. Dr. Matthay’s institution received funding from Roche-Genentech; received funding from Gilead Therapeutics, Novartis, Quantum Therapeutics, and Johnson and Johnson. Drs. Matthay and Calfee received funding from Gen1Life Science. Dr. Calfee’s institution received funding from the NIH; she received funding from Vasomune, Janssen, Cellenkos, and NGMBio. Dr. McAuley’s institution received funding from the NIHR; he received funding from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis Eli Lilly Vir Biotechnology, Inc SOBI Faron Pharmaceuticals Grants from NIHR, Wellcome Trust, MRC, Innovate UK, NI PHA HSC R&D division, Novavax and Randox; disclosed that his spouse received funding from California Institute for Regenerative Medicine. Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction trial (HARP-2) was supported by the UK EME program, an MRC and NIHR partnership (08/99/08 and 16/33/01). The EME program 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 Research and Development Division, Public Health Agency for Northern Ireland. Dr. Moore was supported by T32 HL129970. Dr. Calfee was supported by R35 HL140026. Dr. Baron was supported by R01 HL112747-01 for the original interleukin-18 analyses. Dr. Shankar-Hari was supported by the NIHR Clinician Scientist Award (CS-2016-16-011). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

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.