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

Crit Care Med. 2016 Feb;44(2):275-81. doi: 10.1097/CCM.0000000000001402.

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.

Design: Reanalysis of deidentified data from the phase III randomized interleukin-1 receptor antagonist trial in severe sepsis.

Setting: Multicenter study recruiting through 91 centers from 11 countries in Europe and North America.

Patients: 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.

Intervention: Treatment with anakinra or placebo.

Measurements and main 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.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • APACHE
  • Acute Kidney Injury / epidemiology
  • Adolescent
  • Adult
  • Age Factors
  • Aged
  • Aged, 80 and over
  • Biliary Tract Diseases / epidemiology
  • Disseminated Intravascular Coagulation / epidemiology*
  • Double-Blind Method
  • Female
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use*
  • Liver Diseases / epidemiology
  • Macrophage Activation Syndrome / epidemiology*
  • Male
  • Middle Aged
  • Multiple Organ Failure / drug therapy
  • Multiple Organ Failure / epidemiology
  • Receptors, Interleukin-1 / antagonists & inhibitors*
  • Respiratory Distress Syndrome, Adult / epidemiology
  • Sepsis / drug therapy*
  • Sepsis / epidemiology*
  • Sepsis / mortality
  • Sex Factors
  • Shock, Septic / drug therapy
  • Shock, Septic / epidemiology
  • Young Adult

Substances

  • Interleukin 1 Receptor Antagonist Protein
  • Receptors, Interleukin-1