In patients with severe alcoholic hepatitis, prednisolone increases susceptibility to infection and infection-related mortality, associated with high circulating levels of bacterial DNA
File(s)
Published version
Author(s)
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.
Date Issued
2016-12-30
Date Acceptance
2016-12-03
Citation
Gastroenterology, 2016, 152 (5), pp.1068-1077.e4
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/).
License URL
Sponsor
Medical Research Council (MRC)
Wellcome Trust
Imperial College Healthcare NHS Trust
National Institute for Health Research
Identifier
PII: S0016-5085(16)35533-0
Grant Number
MR/M003132/1
100566/Z/12/Z
WSGH_P6338
08/14/44
Subjects
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
E coli
MELD
STOPAH Trial
Steroid
Adult
Anti-Bacterial Agents
DNA, Bacterial
Disease Susceptibility
Double-Blind Method
Female
Free Radical Scavengers
Glucocorticoids
Hepatitis, Alcoholic
Humans
Incidence
Infections
Logistic Models
Male
Middle Aged
Odds Ratio
Pentoxifylline
Prednisolone
Prevalence
Risk Factors
Severity of Illness Index
United Kingdom
Humans
Hepatitis, Alcoholic
Disease Susceptibility
Pentoxifylline
Prednisolone
DNA, Bacterial
Free Radical Scavengers
Glucocorticoids
Anti-Bacterial Agents
Severity of Illness Index
Incidence
Prevalence
Logistic Models
Odds Ratio
Risk Factors
Double-Blind Method
Adult
Middle Aged
Female
Male
United Kingdom
Infections
Gastroenterology & Hepatology
1103 Clinical Sciences
1109 Neurosciences
1114 Paediatrics and Reproductive Medicine
Publication Status
Published
Date Publish Online
2016-12-30