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In patients with severe alcoholic hepatitis, prednisolone increases susceptibility to infection and infection-related mortality, associated with high circulating levels of bacterial DNA

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Title: In patients with severe alcoholic hepatitis, prednisolone increases susceptibility to infection and infection-related mortality, associated with high circulating levels of bacterial DNA
Authors: Vergis, N
Atkinson, SR
Knapp, S
Maurice, J
Allison, M
Austin, A
Forrest, EH
Masson, S
McCune, A
Patch, D
Ryder, S
Wright, M
Thursz, MR
Item Type: Journal Article
Abstract: BACKGROUND & AIMS: Infections are common in patients with severe alcoholic hepatitis (SAH), but little information is available on how to predict their development or their effects on patients. Prednisolone is advocated for treatment of SAH, but can increase susceptibility to infection. We compared the effects of infection on clinical outcomes of patients treated with and without prednisolone, and identified risk factors for development of infection in SAH. METHODS: We analyzed data from 1092 patients enrolled in a double-blind placebo-controlled trial to evaluate the efficacy of treatment with prednisolone (40 mg daily) or pentoxifylline (400 mg 3 times each day) in patients with SAH. The 2 × 2 factorial design led to 547 patients receiving prednisolone; 546 were treated with pentoxifylline. The trial was conducted in the United Kingdom from January 2011 through February 2014. Data on development of infection were collected at evaluations performed at screening, baseline, weekly during admission, on discharge, and after 90 days. Patients were diagnosed with infection based on published clinical and microbiologic criteria. Risk factors for development of infection and effects on 90-day mortality were evaluated separately in patients treated with prednisolone (n = 547) and patients not treated with prednisolone (n = 545) using logistic regression. Pretreatment blood levels of bacterial DNA (bDNA) were measured in 731 patients. RESULTS: Of the 1092 patients in the study, 135 had an infection at baseline, 251 developed infections during treatment, and 89 patients developed an infection after treatment. There was no association between pentoxifylline therapy and the risk of serious infection (P = .084), infection during treatment (P = .20), or infection after treatment (P = .27). Infections classified as serious were more frequent in patients treated with prednisolone (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.27-2.92; P = .002). There was no association between prednisolone therapy and infection during treatment (OR, 1.04; 95% CI, 0.78-1.37; P = .80). However, a higher proportion (10%) of patients receiving prednisolone developed an infection after treatment than of patients not given prednisolone (6%) (OR, 1.70; 95% CI, 1.07-2.69; P = .024). Development of infection was associated with increased 90-day mortality in patients with SAH treated with prednisolone, independent of model for end-stage liver disease or Lille score (OR, 2.46; 95% CI, 1.41-4.30; P = .002). High circulating bDNA predicted infection that developed within 7 days of prednisolone therapy, independent of Model for End-Stage Liver Disease and white blood cell count (OR, 4.68; 95% CI, 1.80-12.17; P = .001). In patients who did not receive prednisolone, infection was not independently associated with 90-day mortality (OR, 0.94; 95% CI, 0.54-1.62; P = .82) or levels of bDNA (OR, 0.83; 95% CI, 0.39-1.75; P = .62). CONCLUSIONS: Patients with SAH given prednisolone are at greater risk for developing serious infections and infections after treatment than patients not given prednisolone, which can offset its therapeutic benefit. Level of circulating bDNA before treatment could identify patients at high risk of infection if given prednisolone; these data could be used to select therapies for patients with SAH. EudraCT no: 2009-013897-42; Current Controlled Trials no: ISRCTN88782125.
Issue Date: 30-Dec-2016
Date of Acceptance: 3-Dec-2016
URI: http://hdl.handle.net/10044/1/44797
DOI: https://dx.doi.org/10.1053/j.gastro.2016.12.019
ISSN: 0016-5085
Publisher: Elsevier
Start Page: 1068
End Page: 1077.e4
Journal / Book Title: Gastroenterology
Volume: 152
Issue: 5
Copyright Statement: © 2017 by the AGA Institute. Published by Elsevier Inc. This article is Open Access under a Creative Commons license (https://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: National Institute for Health Research
Wellcome Trust
Medical Research Council (MRC)
Imperial College Healthcare NHS Trust
Funder's Grant Number: 08/14/44
100566/Z/12/Z
MR/M003132/1
WSGH_P6338
Keywords: Science & Technology
Life Sciences & Biomedicine
Gastroenterology & Hepatology
STOPAH Trial
MELD
E coli
Steroid
POLYMERASE-CHAIN-REACTION
LIVER-DISEASE
BLOOD CULTURE
STEROIDS
PENTOXIFYLLINE
SEPSIS
TRIAL
CORTICOSTEROIDS
METAANALYSIS
CIRRHOSIS
Adult
Anti-Bacterial Agents
DNA, Bacterial
Disease Susceptibility
Double-Blind Method
Female
Free Radical Scavengers
Glucocorticoids
Hepatitis, Alcoholic
Humans
Incidence
Infection
Logistic Models
Male
Middle Aged
Odds Ratio
Pentoxifylline
Prednisolone
Prevalence
Risk Factors
Severity of Illness Index
United Kingdom
1103 Clinical Sciences
1114 Paediatrics And Reproductive Medicine
1109 Neurosciences
Publication Status: Published
Appears in Collections:Division of Surgery
Faculty of Medicine



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