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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*

Shakoory, Bita MD¹; Carcillo, Joseph A. MD²; Chatham, W. Winn MD³; Amdur, Richard L. PhD⁴; Zhao, Huaqing PhD⁴; Dinarello, Charles A. MD⁵; Cron, Randall Q. MD, PhD⁶; Opal, Steven M. MD⁷

Author Information

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.

*See also p. 443.

Dr. Carcillo received support for article research from the National Institutes of Health (NIH). His institution received grant support (support from National Institute of General Medical Sciences (NIGMS) for his research related to multiorgan dysfunction syndrome [MODS] and support from NIGMS for his research in MODS/macrophage activation syndrome [MAS]). Dr. Chatham’s institution received grant support from Swedish Orphan Biovitrum (SOBI) (pending grant for clinical trial re: anakinra in MAS). Dr. Cron provided expert testimony for Wicker Smith O’Hara McCoy and Ford P.A. (peds rheum case expert evaluation). His institution received grant support from SOBI (clinical trial of anakinra for MAS). Dr. Dinarello served as a board member for Bio-Techne. Dr. Opal consulted for BioAegis (advice on phase 2 study in severe pneumonia), Battelle (advice on preclinical development on hemoperfusion columns for sepsis), Biocardis (advice on rapid blood steam genomic diagnostic methodologies), ImmuneXpress (advice on rapid diagnosis of sepsis based on host response gene response), Grifolds (advice on protein C use in sepsis studies), Octopharma (advice on plasma component therapy in sepsis), and Becton Dickinson (advice on new therapies for multidrug-resistant bacterial pathogens). He received royalties from Elsevier Publishers (royalties for a textbook in infectious diseases) and received support from Archeogen and Ketotek (data and safety monitoring boards). His institution received grant support from Asahi Kasei (clinical coordinating center for their phase 3 trial in sepsis) and Cardeas (clinical coordinating center for their phase 2 trial in severe pneumonia), Arsanis (preclinical study of monoclonal antibodies for blood stream infection). The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Bita Shakoory, MD, 2150 Pennsylvania Ave, NW. #G-404. Washington, DC 20037. E-mail: [email protected]

Critical Care Medicine 44(2):p 275-281, February 2016. | 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.

Article Keywords

Keywords
anakinra, disseminated intravascular coagulation, hepatobiliary dysfunction, interleukin-1 receptor antagonist, macrophage activation syndrome, multiorgan dysfunction syndrome, sepsis mortality

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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*