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

Rogers, Angela J. MD/MPH1; Guan, Jiazhen PhD2; Trtchounian, Anna MD2; Hunninghake, Gary M. MD/MPH2; Kaimal, Rajani PhD3; Desai, Manisha PhD3; Kozikowski, Lori-Ann RN4; DeSouza, Lesley RN4; Mogan, Susan RN, MSN5; Liu, Kathleen D. MD, PhD6,7; Matthay, Michael A. MD6,7; Steingrub, Jay MD4; Wheeler, Art MD5; Yoon, Joo Heon PhD8; Nakahira, Kiichi PhD9; Choi, Augustine M. MD9; Baron, Rebecca M. MD2

doi: 10.1097/CCM.0000000000003816
Clinical Investigations

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.

1Division of Pulmonary and Critical Care Medicine, Stanford University, Stanford, CA.

2Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA.

3Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA.

4Division of Pulmonary and Critical Care Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA.

5Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, TN.

6Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco, CA.

7Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, CA.

8Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea.

9Department of Medicine, Weill Cornell Medicine, New York, NY.

*See also p. 1161.

Drs. Rogers, Hunninghake, Matthay, Steingrub, Wheeler, and Baron helped with conception and design. Dr. Guan, Dr. Trtchounian, Ms. Kozikowski, Ms. DeSouza, Ms. Mogan, Dr. Liu, and Dr. Nakahira helped with experimental procedures. Drs. Rogers, Hunninghake, Kaimal, Desai, and Baron helped with analysis and interpretation. Drs. Rogers, Hunninghake, Kaimal, Desai, Liu, Matthay, Steingrub, Yoon, Nakahira, Choi, and Baron helped with manuscript preparation and revision.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Supported, in part, by grants from National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) R01 HL112747, HL111024, HL51856, HL55330, Global Research Laboratory grant number 2016K1A1A2910779, K23 HL125663, NIH/National Center for Advancing Translational Sciences KL2-TR-002385, and NHLBI ARDS Network investigators.

Drs. Rogers and Hunninghake, Ms. Kozikowski, Ms. DeSouza, and Drs. Liu, Matthay, Steingrub, Nakahira, Choi, and Baron received support for article research from National Institutes of Health (NIH). Dr. Hunninghake received funding from consulting for Genentech, Boehringer-Ingelheim, the Gerson Lehrman Group, and Mistubishi Chemical for work unrelated to this submission. Ms. Kozikowski’s institution received funding from Brigham and Womens Hospital. Ms. DeSouza disclosed work for hire. Dr. Liu’s institution received funding from NHLBI, National Institute of Diabetes and Digestive and Kidney Disease, and she received funding from National Policy Forum on Critical Care and Acute Renal Failure, Achaogen (consultant), Durect (consultant), Theravance (consultant), Quark (consultant), Potrero Med (consultant), Amgen (stockholder), and Baxter (presenter at sponsored meeting). Dr. Matthay’s institution received funding from Bayer Pharmaceuticals, Department of Defense, GlaxoSmithKline, and he received other support from CSL Behring, Roche-Genentec, Quark Pharmaceuticals, Boerhinger-Ingelheim, Cerus Therapeutics, and NHLBI. Dr. Choi’s institution received funding from NIH; he received funding from Teva Pharmaceuticals; and he disclosed that he is a cofounder, stock holder, and serves on the Scientific Advisory Board for Proterris, which develops therapeutic uses for carbon monoxide, and he has a use patent on carbon monoxide. Dr. Baron’s institution received funding from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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