PMID- 37695136
OWN - NLM
STAT- MEDLINE
DCOM- 20231117
LR  - 20240327
IS  - 1530-0293 (Electronic)
IS  - 0090-3493 (Print)
IS  - 0090-3493 (Linking)
VI  - 51
IP  - 12
DP  - 2023 Dec 1
TI  - Elevated Plasma Interleukin-18 Identifies High-Risk Acute Respiratory Distress 
      Syndrome Patients not Distinguished by Prior Latent Class Analyses Using 
      Traditional Inflammatory Cytokines: A Retrospective Analysis of Two Randomized 
      Clinical Trials.
PG  - e269-e274
LID - 10.1097/CCM.0000000000006028 [doi]
AB  - 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.
CI  - Copyright (c) 2023 by the Society of Critical Care Medicine and Wolters Kluwer 
      Health, Inc. All Rights Reserved.
FAU - Moore, Andrew R
AU  - Moore AR
AD  - Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, 
      Stanford, CA.
FAU - Pienkos, Shaun M
AU  - Pienkos SM
AD  - Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, 
      Stanford, CA.
FAU - Sinha, Pratik
AU  - Sinha P
AD  - Division of Critical Care, Department of Anesthesia, Washington University, Saint 
      Louis, MO.
FAU - Guan, Jiazhen
AU  - Guan J
AD  - Division of Rheumatology, Brigham and Women's Hospital, and Harvard Medical 
      School, Boston, MA.
FAU - O'Kane, Cecilia M
AU  - O'Kane CM
AD  - Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, 
      Dentistry, and Biomedical Sciences, Queen's University of Belfast, Belfast, 
      United Kingdom.
FAU - Levitt, Joseph E
AU  - Levitt JE
AD  - Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, 
      Stanford, CA.
FAU - Wilson, Jennifer G
AU  - Wilson JG
AD  - Department of Emergency Medicine, Stanford University, Stanford, CA.
FAU - Shankar-Hari, Manu
AU  - Shankar-Hari M
AD  - The Queen's Medical Research Institute, Centre for Inflammation Research, 
      Institute for Regeneration and Repair, Edinburgh, United Kingdom.
FAU - Matthay, Michael A
AU  - Matthay MA
AD  - Department of Medicine, Cardiovascular Research Institute, University of 
      California, San Francisco, CA.
AD  - Department of Anesthesia, Cardiovascular Research Institute, University of 
      California, San Francisco, CA.
FAU - Calfee, Carolyn S
AU  - Calfee CS
AD  - Department of Medicine, Cardiovascular Research Institute, University of 
      California, San Francisco, CA.
AD  - Department of Anesthesia, Cardiovascular Research Institute, University of 
      California, San Francisco, CA.
FAU - Baron, Rebecca M
AU  - Baron RM
AD  - Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 
      and Harvard Medical School, Boston, MA.
FAU - McAuley, Daniel F
AU  - McAuley DF
AD  - Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, 
      Dentistry, and Biomedical Sciences, Queen's University of Belfast, Belfast, 
      United Kingdom.
FAU - Rogers, Angela J
AU  - Rogers AJ
AD  - Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, 
      Stanford, CA.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - R01 HL112747/HL/NHLBI NIH HHS/United States
GR  - R35 HL140026/HL/NHLBI NIH HHS/United States
GR  - T32 HL129970/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
DEP - 20230911
PL  - United States
TA  - Crit Care Med
JT  - Critical care medicine
JID - 0355501
RN  - 0 (Interleukin-18)
RN  - 0 (Cytokines)
RN  - 0 (Biomarkers)
RN  - 0 (Interleukin-8)
SB  - IM
MH  - Humans
MH  - *Interleukin-18
MH  - Latent Class Analysis
MH  - Retrospective Studies
MH  - Cytokines
MH  - Randomized Controlled Trials as Topic
MH  - *Respiratory Distress Syndrome/therapy
MH  - Biomarkers
MH  - Interleukin-8
PMC - PMC10840968
MID - NIHMS1921122
COIS- 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.
EDAT- 2023/09/11 12:42
MHDA- 2023/11/17 15:22
PMCR- 2024/12/01
CRDT- 2023/09/11 09:43
PHST- 2024/12/01 00:00 [pmc-release]
PHST- 2023/11/17 15:22 [medline]
PHST- 2023/09/11 12:42 [pubmed]
PHST- 2023/09/11 09:43 [entrez]
AID - 00003246-202312000-00031 [pii]
AID - 10.1097/CCM.0000000000006028 [doi]
PST - ppublish
SO  - Crit Care Med. 2023 Dec 1;51(12):e269-e274. doi: 10.1097/CCM.0000000000006028. 
      Epub 2023 Sep 11.