title: Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial.
abstract: OBJECTIVE
  To determine the efficacy of anakinra (recombinant interleukin-1 receptor antagonist) in improving 28-day survival in sepsis patients with features of macrophage activation syndrome. Despite equivocal results in sepsis trials, anakinra is effective in treating macrophage activation syndrome, a similar entity with fever, disseminated intravascular coagulation, hepatobiliary dysfunction, cytopenias, and hyperferritinemia. Hence, sepsis patients with macrophage activation syndrome features may benefit from interleukin-1 receptor blockade.
  
  
  METHODS
  Reanalysis of deidentified data from the phase III randomized interleukin-1 receptor antagonist trial in severe sepsis.
  
  
  METHODS
  Multicenter study recruiting through 91 centers from 11 countries in Europe and North America.
  
  
  METHODS
  Sepsis patients with multiorgan dysfunction syndrome and/or shock (original study) were regrouped based on the presence or the absence of concurrent hepatobiliary dysfunction and disseminated intravascular coagulation as features of macrophage activation syndrome. The non-hepatobiliary dysfunction/disseminated intravascular coagulation group included patients with only hepatobiliary dysfunction, only disseminated intravascular coagulation, or neither.
  
  
  METHODS
  Treatment with anakinra or placebo.
  
  
  RESULTS
  Main outcome was 28-day mortality. Descriptive and comparative statistics were performed. Data were available for 763 adults from the original study cohort, randomized to receive either anakinra or placebo. Concurrent hepatobiliary dysfunction/disseminated intravascular coagulation was noted in 43 patients (5.6% of total; 18-75 years old; 47% women). The 28-day survival was similar in both anakinra and placebo-treated non-hepatobiliary dysfunction/disseminated intravascular coagulation patients (71.4% vs 70.8%; p = 0.88). Treatment with anakinra was associated with significant improvement in the 28-day survival rate in hepatobiliary dysfunction/disseminated intravascular coagulation patients (65.4% anakinra vs 35.3% placebo), with hazard ratio for death 0.28 (0.11-0.71; p = 0.0071) for the treatment group in Cox regression.
  
  
  CONCLUSIONS
  In this subgroup analysis, interleukin-1 receptor blockade was associated with significant improvement in survival of patients with sepsis and concurrent hepatobiliary dysfunction/disseminated intravascular coagulation. A prospective randomized trial using features of macrophage activation syndrome for mortality risk stratification should be undertaken to confirm the role of interleukin-1 blockage.
authors.affiliation: 1Division of Rheumatology, Department of Medicine, George Washington University, Washington, DC. 2Department of Critical Care and Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, PA. 3Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL. 4Department of Clinical Research, Temple University, Philadelphia, PA. 5Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Aurora, CO. 6University of Alabama at Birmingham, Division of Pediatric Rheumatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL. 7Division of Infectious Diseases, Department of Medicine, Brown University, Providence, RI.
authors.forename: Bita
authors.initials: B
authors.lastname: Shakoory
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Carcillo
authors.forename: W Winn
authors.initials: WW
authors.lastname: Chatham
authors.forename: Richard L
authors.initials: RL
authors.lastname: Amdur
authors.forename: Huaqing
authors.initials: H
authors.lastname: Zhao
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Randall Q
authors.initials: RQ
authors.lastname: Cron
authors.forename: Steven M
authors.initials: SM
authors.lastname: Opal
mesh_terms: D018806:APACHE; D058186:Acute Kidney Injury / Q000453:epidemiology; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001660:Biliary Tract Diseases / Q000453:epidemiology; D004211:Disseminated Intravascular Coagulation / Q000453:epidemiology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use*; D008107:Liver Diseases / Q000453:epidemiology; D055501:Macrophage Activation Syndrome / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000188:drug therapy / Q000453:epidemiology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D012128:Respiratory Distress Syndrome / Q000453:epidemiology; D018805:Sepsis / Q000188:drug therapy* / Q000453:epidemiology* / Q000401:mortality; D012737:Sex Factors; D012772:Shock, Septic / Q000188:drug therapy / Q000453:epidemiology; D055815:Young Adult
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1