title: In Patients With Severe Alcoholic Hepatitis, Prednisolone Increases Susceptibility to Infection and Infection-Related Mortality, and Is Associated With High Circulating Levels of Bacterial DNA.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  Patients with SAH given prednisolone are at greater risk for developing serious infections and infections after treatment than patients not given prednisolone, which may 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.
authors.affiliation: Imperial College, London, United Kingdom. Electronic address: nvergis@ic.ac.uk.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Vergis
authors.affiliation: Imperial College, London, United Kingdom. Electronic address: stephen.atkinson@ic.ac.uk.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Atkinson
authors.affiliation: Imperial College, London, United Kingdom.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Imperial College, London, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Maurice
authors.affiliation: Addenbrookes Hospital, Cambridge, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Allison
authors.affiliation: Derby Hospital, Derby, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Austin
authors.affiliation: Glasgow Royal Infirmary, Glasgow, United Kingdom.
authors.forename: Ewan H
authors.initials: EH
authors.lastname: Forrest
authors.affiliation: Freeman Hospital, The Newcastle Upon Tyne Hospitals, National Health Service Foundation Trust, Newcastle Upon Tyne, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Masson
authors.affiliation: Bristol Royal Infirmary, Bristol, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: McCune
authors.affiliation: Royal Free Hospital, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Patch
authors.affiliation: Royal Liverpool University National Health Service Trust, Liverpool, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.affiliation: Sheffield Teaching Hospitals Foundation Trust, Sheffield, United Kingdom.
authors.forename: Dermot
authors.initials: D
authors.lastname: Gleeson
authors.affiliation: NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospitals National Health Service Trust and The University of Nottingham, Nottingham, United Kingdom.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Ryder
authors.affiliation: Southampton University Hospital, Southampton, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Wright
authors.affiliation: Imperial College, London, United Kingdom.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Thursz
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D004269:DNA, Bacterial / Q000097:blood*; D004198:Disease Susceptibility; D004311:Double-Blind Method; D005260:Female; D016166:Free Radical Scavengers / Q000627:therapeutic use; D005938:Glucocorticoids / Q000627:therapeutic use*; D006519:Hepatitis, Alcoholic / Q000188:drug therapy*; D006801:Humans; D015994:Incidence; D007239:Infections / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology* / Q000401:mortality; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010431:Pentoxifylline / Q000627:therapeutic use; D011239:Prednisolone / Q000627:therapeutic use*; D015995:Prevalence; D012307:Risk Factors; D012720:Severity of Illness Index; D006113:United Kingdom
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D016166:Free Radical Scavengers; D005938:Glucocorticoids; D011239:Prednisolone; D010431:Pentoxifylline
keywords: E coli; MELD; STOPAH Trial; Steroid