The DOI matches its Crossref record; 47 of the 48 references it cites were found in a registry or an index.
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*
Open accessAbstract
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference
Levy, M. M., Fink, M. P., Marshall, J. C., Abraham, E. H., Angus, D. C., Cook, D., Cohen, J., Opal, S. M., Vincent, J., & Ramsay, G. (2003) · Critical Care Medicine · doi:10.1097/01.ccm.0000050454.01978.3b · Cited by 5,976
Self-citationThe Pathophysiology and Treatment of Sepsis
Hotchkiss, R. S., & Karl, I. E. (2003) · New England Journal of Medicine · doi:10.1056/nejmra021333 · Cited by 4,132
An Expanded Definition of the Adult Respiratory Distress Syndrome
Murray, J. F., Matthay, M. A., Luce, J. M., & Flick, M. R. (1988) · American Review of Respiratory Disease · doi:10.1164/ajrccm/138.3.720 · Cited by 2,641
Interleukin-1 in the pathogenesis and treatment of inflammatory diseases
Dinarello, C. A. (2011) · Blood · doi:10.1182/blood-2010-07-273417 · Cited by 2,248
Self-citationTreating inflammation by blocking interleukin-1 in a broad spectrum of diseases
Dinarello, C. A., Simon, A., & van der Meer, J. W. M. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3800 · Cited by 1,810
Self-citationFardet, L., Galicier, L., Lambotte, O., Marzac, C., Aumont, C., Chahwan, D., Coppo, P., & Hejblum, G. (2014) · Arthritis & Rheumatology · doi:10.1002/art.38690 · Cited by 1,508
Interleukin-1 and the Pathogenesis of the Acute-Phase Response
Epstein, F. H., & Dinarello, C. A. (1984) · New England Journal of Medicine · doi:10.1056/nejm198411293112205 · Cited by 1,151
Self-citationConfirmatory interleukin-1 receptor antagonist trial in severe sepsis
Opal, S. M., Fisher, C. J., Dhainaut, J.-F., Vincent, J., Brase, R., Lowry, S. F., SADOFF, J. C., Slotman, G. J., Levy, H. A., BALK, R. A., et al. (1997) · Critical Care Medicine · doi:10.1097/00003246-199707000-00010 · Cited by 882
Self-citationHighly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis
Allen, C. E., Yu, X., Kozinetz, C. A., & McClain, K. L. (2007) · Pediatric Blood & Cancer · doi:10.1002/pbc.21423 · Cited by 637
Fisher, C. J., Slotman, G. J., Opal, S. M., Pribble, J. P., Bone, R. C., Emmanuel, G. E., Ng, D., Bloedow, D. C., & Catalano, M. A. (1994) · Critical Care Medicine · doi:10.1097/00003246-199401000-00008 · Cited by 490
Self-citationMinoia, F., Davì, S., Horne, A., Demirkaya, E., Bovis, F., Li, C., Lehmberg, K., Weitzman, S. S., Insalaco, A., Wouters, C. H., et al. (2014) · Arthritis & Rheumatology · doi:10.1002/art.38802 · Cited by 430
Self-citationRavelli, A., Magni‐Manzoni, S., Pistorio, A., Besana, C., Foti, T., Ruperto, N., Viola, S., & Martini, A. (2005) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2004.12.016 · Cited by 409
Pathogenesis of Macrophage Activation Syndrome and Potential for Cytokine- Directed Therapies
Schulert, G. S., & Grom, A. A. (2014) · Annual Review of Medicine · doi:10.1146/annurev-med-061813-012806 · Cited by 401
Ravelli, A., Grom, A. A., Behrens, E. M., & Cron, R. Q. (2012) · Genes and Immunity · doi:10.1038/gene.2012.3 · Cited by 381
Self-citationOccult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis.
Behrens, E. M., Beukelman, T., Paessler, M. E., & Cron, R. Q. (2007) · PubMed · Cited by 364
Self-citationAnakinra for Rheumatoid Arthritis: A Systematic Review
Mertens, M. T., & Singh, J. A. (2009) · The Journal of Rheumatology · doi:10.3899/jrheum.090074 · Cited by 342
Reactive Hemophagocytic Syndrome in Adults: A Retrospective Analysis of 162 Patients
Rivière, S., Galicier, L., Coppo, P., Marzac, C., Aumont, C., Lambotte, O., & Fardet, L. (2014) · The American Journal of Medicine · doi:10.1016/j.amjmed.2014.04.034 · Cited by 325
Bleesing, J., Prada, A., Siegel, D. M., Villanueva, J., Olson, J., Ilowite, N. T., Brunner, H. I., Griffin, T., Graham, T. B., Sherry, D. D., et al. (2007) · Arthritis & Rheumatism · doi:10.1002/art.22416 · Cited by 321
Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome
Mazodier, K. (2005) · Blood · doi:10.1182/blood-2005-05-1980 · Cited by 290
Miettunen, P., Narendran, A., Jayanthan, A., Behrens, E. M., & Cron, R. Q. (2010) · Lara D. Veeken · doi:10.1093/rheumatology/keq218 · Cited by 284
Self-citationHuman leukocytic pyrogen: purification and development of a radioimmunoassay.
Dinarello, C. A., Renfer, L., & Wolff, S. M. (1977) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.74.10.4624 · Cited by 272
Self-citationCastillo, L., & Carcillo, J. A. (2009) · Pediatric Critical Care Medicine · doi:10.1097/pcc.0b013e3181a1ae08 · Cited by 272
Self-citationGranowitz, E. V., Clark, B. D., Mancilla-Ramı́rez, J., & Dinarello, C. A. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)98655-2 · Cited by 269
Self-citationGranowitz, E. V., Porat, R., Mier, J. W., Pribble, J. P., Stiles, D., Bloedow, D. C., Catalano, M. A., Wolff, S. M., & Dinarello, C. A. (1992) · Cytokine · doi:10.1016/1043-4666(92)90078-6 · Cited by 217
Self-citationSchaer, D. J., Schleiffenbaum, B. E., Kurrer, M. O., Imhof, A., Bächli, E., Fehr, J., Møller, H. J., Moestrup, S. K., & Schaffner, A. (2004) · European Journal Of Haematology · doi:10.1111/j.1600-0609.2004.00318.x · Cited by 203
Rajasekaran, S., Kruse, K. A., Kovey, K., Davis, A. T., Hassan, N. E., Ndika, A. N., Zuiderveen, S., & Birmingham, J. D. (2014) · Pediatric Critical Care Medicine · doi:10.1097/pcc.0000000000000078 · Cited by 198
Haemophagocytic syndromes in adults: current concepts and challenges ahead
Emmenegger, U., Schaer, D. J., Larroche, C., & Neftel, K. A. (2005) · Swiss Medical Weekly · doi:10.4414/smw.2005.10976 · Cited by 184
Strauss, R., Neureiter, D., Westenburger, B., Wehler, M., Kirchner, T., & Hahn, E. G. (2004) · Critical Care Medicine · doi:10.1097/01.ccm.0000127779.24232.15 · Cited by 157
A case of macrophage activation syndrome successfully treated with anakinra
Kelly, A., & Ramanan, A. V. (2008) · Nature Clinical Practice Rheumatology · doi:10.1038/ncprheum0919 · Cited by 147
Brück, N., Suttorp, M., Kabus, M., Heubner, G., Gahr, M. L., & Peßler, F. (2011) · JCR Journal of Clinical Rheumatology · doi:10.1097/rhu.0b013e318205092d · Cited by 142
Dinarello, C. A., Rosenwasser, L. J., & Wolff, S. (1981) · The Journal of Immunology · doi:10.4049/jimmunol.127.6.2517 · Cited by 132
Self-citationMacrophage serum markers in pneumococcal bacteremia: Prediction of survival by soluble CD163*
Møller, H. J., Moestrup, S. K., Weis, N. M., Wejse, C. M., Nielsen, H. I., Pedersen, S. S., Attermann, J., Nexø, E., & Kronborg, G. (2006) · Critical Care Medicine · doi:10.1097/01.ccm.0000239120.32490.ab · Cited by 130
High dose anakinra for treatment of severe neonatal Kawasaki disease: a case report
Shafferman, A., Birmingham, J. D., & Cron, R. Q. (2014) · Pediatric Rheumatology · doi:10.1186/1546-0096-12-26 · Cited by 115
Self-citationHuman recombinant protein C for severe sepsis and septic shock in adult and paediatric patients
Martí-Carvajal, A. J., Solà, I., Gluud, C. N., Lathyris, D., & Anand, V. (2012) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd004388.pub6 · Cited by 115
Shabbir, M., Lucas, J. T., Lazarchick, J., & Shirai, K. (2010) · Hematological Oncology · doi:10.1002/hon.960 · Cited by 114
Association between Endothelial Dysfunction and Acute Brain Dysfunction during Critical Illness
Hughes, C. G., Morandi, A., Girard, T. D., Riedel, B., Thompson, J. L., Shintani, A., Pun, B. T., Ely, E. W., & Pandharipande, P. P. (2012) · Anesthesiology · doi:10.1097/aln.0b013e31827bd193 · Cited by 100
Clinical features and correct diagnosis of macrophage activation syndrome
Cron, R. Q., Davì, S., Minoia, F., & Ravelli, A. (2015) · Expert Review of Clinical Immunology · doi:10.1586/1744666x.2015.1058159 · Cited by 97
Self-citationMacrophage Activation Syndrome Treated with Anakinra
DURAND, M., TROYANOV, Y., LAFLAMME, P., & GREGOIRE, G. (2010) · The Journal of Rheumatology · doi:10.3899/jrheum.091046 · Cited by 86
Hemophagocytic macrophages constitute a major compartment of heme oxygenase expression in sepsis
Schaer, D. J., Schaer, C. A., Schoedon, G., Imhof, A., & Kurrer, M. O. (2006) · European Journal Of Haematology · doi:10.1111/j.1600-0609.2006.00730.x · Cited by 83
Behrens, E. M., Kreiger, P. A., Cherian, S., & Cron, R. Q. (2006) · PubMed · Cited by 75
Self-citationHigher-dose Anakinra Is Effective in a Case of Medically Refractory Macrophage Activation Syndrome
Kahn, P. J., & Cron, R. Q. (2013) · The Journal of Rheumatology · doi:10.3899/jrheum.121098 · Cited by 72
Self-citationLoh, N. K., Lucas, M., Fernández, S., & Prentice, D. A. (2012) · Internal Medicine Journal · doi:10.1111/imj.12002 · Cited by 42
Macrophage Activation Syndrome Secondary to Human Monocytic Ehrlichiosis
Kumar, N., Goyal, J., Goel, A., Shakoory, B., & Chatham, W. W. (2013) · Indian Journal of Hematology and Blood Transfusion · doi:10.1007/s12288-013-0299-3 · Cited by 29
Self-citationTayer-Shifman, O. E., & Ben‐Chetrit, E. (2013) · Modern Rheumatology · doi:10.3109/14397595.2013.844403 · Cited by 26
Simon, D. W., Aneja, R. K., Carcillo, J. A., & Halstead, E. S. (2014) · Pediatric Critical Care Medicine · doi:10.1097/pcc.0000000000000098 · Cited by 25
Self-citationHigh elevated ferritin levels and the diagnosis of HLH/Sepsis/SIRS/MODS/MAS
Castillo, L. (2008) · Pediatric Blood & Cancer · doi:10.1002/pbc.21681 · Cited by 15
Research works printed but not linked: 4
- Emmenegger, 2005, Swiss Med Wkly, 135, 299
- Behrens, 2007, J Rheumatol, 34, 1133
- Behrens, 2006, J Rheumatol, 33, 2081
- Marti-Carvajal, 2012, Cochrane Database Syst Rev, 12, CD004388
Cited by
Sorted by citations
COVID-19: consider cytokine storm syndromes and immunosuppression
Mehta, P., McAuley, D. F., Brown, M., Sanchez, E., Tattersall, R. S., & Manson, J. J. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30628-0 · Cited by 9,664
Fajgenbaum, D. C., & June, C. H. (2020) · New England Journal of Medicine · doi:10.1056/nejmra2026131 · Cited by 3,196
The pathogenesis and treatment of the `Cytokine Storm' in COVID-19
Ye, Q., Wang, B., & Mao, J. (2020) · Journal of Infection · doi:10.1016/j.jinf.2020.03.037 · Cited by 2,761
Overview of the IL ‐1 family in innate inflammation and acquired immunity
Dinarello, C. A. (2018) · Immunological Reviews · doi:10.1111/imr.12621 · Cited by 1,866
Self-citationRecommendations for the management of hemophagocytic lymphohistiocytosis in adults
Rosée, P. G. L., Horne, A., Hines, M., Greenwood, T. V. B., Machowicz, R., Berliner, N., Birndt, S., Gil-Herrera, J., Girschikofsky, M., Jordan, M. B., et al. (2019) · Blood · doi:10.1182/blood.2018894618 · Cited by 1,127
Metadata
- 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
- 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 › Critical Care and Intensive Care Medicine › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
