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*
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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.
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Reanalysis of a negative trial of interleukin-1β blockade in patients with sepsis identified a subgroup of patients with elevated ferritin levels who seemed to benefit from the treatment.
“For example, reanalysis of a negative trial of interleukin-1β blockade in patients with sepsis identified a subgroup of patients with elevated ferritin levels who seemed to benefit from the treatment.63”
From Cytokine storm (2020) · cites this paper as [63]
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- Authors
- Shakoory, B., Carcillo, J. A., Chatham, W. W., Amdur, R. L., Zhao, H., Dinarello, C. A., Cron, R. Q., & Opal, S. M.
- Affiliations
- George Washington University (US)
- University of Pittsburgh Medical Center (US)
- University of Alabama at Birmingham (US)
- Temple University (US)
- University of Colorado Anschutz (US)
- Brown University (US)
- ORCID
- Venue
- Critical Care Medicine
- Published
- 2016-02
- Volume
- 44
- Issue
- 2
- Pages
- 275-281
- ISSN
- 0090-3493 (ISSN-L)
- PMC
- PMC5378312
- OpenAlex
- W2177407033
- Cited by
- 867
- References
- 48
- Citations by year
- 2026: 66 · 2025: 64 · 2024: 68 · 2023: 76 · 2022: 87 · 2021: 141 · 2020: 226 · 2019: 43 · 2018: 36 · 2017: 42 · 2016: 15 · 2015: 1
- FWCI
- 24.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Critical Care Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM108618)
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- sepsis, anakinra, interleukin-1 receptor antagonist, interleukin-1 blockade, 28-day mortality, hepatobiliary dysfunction, disseminated intravascular coagulation, multiple organ failure, septic shock, subgroup analysis, hyperferritinemia, cytokine storm
- MeSH terms
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Biliary Tract Diseases, Disseminated Intravascular Coagulation, Double-Blind Method, Female, Humans, Liver Diseases, Male, Middle Aged, Multiple Organ Failure, Respiratory Distress Syndrome, Sex Factors, Shock, Septic, Receptors, Interleukin-1, Sepsis, APACHE, Interleukin 1 Receptor Antagonist Protein, Macrophage Activation Syndrome, Young Adult, Acute Kidney Injury
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