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Transcriptomic signatures in sepsis and a differential response to steroids: from the VANISH randomized trial

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Title: Transcriptomic signatures in sepsis and a differential response to steroids: from the VANISH randomized trial
Authors: Antcliffe, D
Burnham, K
Al-Beidh, F
Santhakumaran, S
Brett, S
Hinds, C
Ashby, D
Knight, J
Gordon, AC
Item Type: Journal Article
Abstract: Rationale: There remains uncertainty about the role of corticosteroids in sepsis with clear beneficial effects on shock duration but conflicting survival effects. Two transcriptomic sepsis response signatures (SRS) have been identified. SRS1 is relatively immunosuppressed whilst SRS2 is relatively immunocompetent. Objectives: We aimed to categorized patients based on SRS endotypes to determine if these profiles influenced response to either norepinephrine or vasopressin, or to corticosteroids in septic shock. Methods: A post-hoc analysis was performed of a double-blind randomized clinical trial in septic shock (VANISH). Patients were included within 6 hours of onset of shock and were randomized to receive norepinephrine or vasopressin followed by hydrocortisone or placebo. Genome-wide gene expression profiling was performed and SRS endotype was determined using a previously established model using seven discriminant genes. Measurements and Main Results: Samples were available from 176 patients, 83 SRS1 and 93 SRS2. There was no significant interaction between SRS group and vasopressor assignment (p=0·50). However, there was an interaction between assignment to hydrocortisone or placebo, and SRS endotype (p=0·02). Hydrocortisone use was associated with increased mortality in those with an SRS2 phenotype (OR 7·9, 95%CI 1·6-39·9). Conclusions: Transcriptomic profile at onset of septic shock was associated with response to corticosteroids. Those with the immuno-competent SRS2 endotype had significantly higher mortality when given corticosteroids compared to placebo. Clinical trial registration available at www.isrctn.com, ID ISRCTN20769191.
Issue Date: 15-Apr-2019
Date of Acceptance: 24-Oct-2018
URI: http://hdl.handle.net/10044/1/65779
DOI: https://dx.doi.org/10.1164/rccm.201807-1419OC
ISSN: 1073-449X
Publisher: American Thoracic Society
Start Page: 980
End Page: 986
Journal / Book Title: American Journal of Respiratory and Critical Care Medicine
Volume: 199
Issue: 8
Copyright Statement: © 2018 American Thoracic Society, All Rights Reserved. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/ licenses/by/4.0/).
Sponsor/Funder: National Institute for Health Research
National Institute for Health Research
Imperial College Healthcare NHS Trust
Funder's Grant Number: NIHR/CS/009/007
NIHR Fellowship
RDB17 79560
Keywords: Science & Technology
Life Sciences & Biomedicine
Critical Care Medicine
Respiratory System
General & Internal Medicine
Respiratory System
11 Medical and Health Sciences
Publication Status: Published
Online Publication Date: 2018-10-26
Appears in Collections:Department of Surgery and Cancer