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. 2025 Dec 8:e2524175.
doi: 10.1001/jama.2025.24175. Online ahead of print.

Precision Immunotherapy to Improve Sepsis Outcomes: The ImmunoSep Randomized Clinical Trial

Evangelos J Giamarellos-Bourboulis  1   2 , Antigone Kotsaki  1   2 , Ioanna Kotsamidi  3 , Aikaterini Efthymiou  4 , Vasiliki Koutsoukou  5 , Johannes Ehler  6 , Alexandra Paridou  7 , Frantzeska Frantzeskaki  8 , Marcella C A Müller  9 , Peter Pickkers  10 , Sylvain Meylan  11 , Ioannis Nikolopoulos  12 , Mihaela Lupse  13 , Alexandra Gavala  14 , Glykeria Vlachogianni  15 , Nicky Solomonidi  16 , Antonia Alevizou  2 , Eumorfia Kondili  17 , Eleni Antoniadou  18 , Maria Nakou  19 , Nikolaos Markou  20 , Erifili Hatziagelaki  21 , Athanassios Prekates  22 , Apostolos Komnos  23 , Lieke Bakkerus  24 , Marleen A Slim  25 , George N Dalekos  26 , Areti Karapanagiotou  18 , Sofia Ktena  2 , Gennaro De Pascale  27   28 , Vassileios Koulouras  29 , Christos Psarrakis  1 , Eleni Massa  3 , Konstantina Dakou  2 , Chrisoula Pazvanti  30 , Aikaterini Ioakeimidou  7 , Iraklis Tsangaris  8 , Nikolaos Antonakos  1   2 , Alexander P J Vlaar  9 , Souzana Anisoglou  31 , Thierry Calandra  32 , Vasilios Papaioannou  19 , Pavlos Myrianthefs  14 , Maria Patrani  16 , Ioannis Alamanos  33 , Massimo Antonelli  27   28 , Jos W M van der Meer  24 , Tom van der Poll  25 , W Joost Wiersinga  25 , Maria Ntaganou  5 , Eleni Gkeka  4 , Michael Bauer  6 , Eleni Mouloudi  3 , Mihai G Netea  24   34 ; ImmunoSep Study Group
Collaborators, Affiliations

Precision Immunotherapy to Improve Sepsis Outcomes: The ImmunoSep Randomized Clinical Trial

Evangelos J Giamarellos-Bourboulis et al. JAMA. .

Abstract

Importance: Sepsis is heterogeneous, and the optimal strategy for tailoring immunotherapy is uncertain.

Objective: To investigate whether precision immunotherapy guided by the presence of macrophage activation-like syndrome or sepsis-induced immunoparalysis improves organ dysfunction by day 9.

Design, setting, and participants: A randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted in 6 countries. Patients with sepsis, defined by Sepsis-3, were included if they had community-acquired or hospital-acquired pneumonia or ventilator-associated pneumonia or bacteremia and sepsis and had displayed either macrophage activation-like syndrome (blood ferritin >4420 ng/mL) or sepsis-induced immunoparalysis (blood ferritin ≤4420 ng/mL and <5000 human leukocyte antigen DR receptors on CD45/CD14 monocytes). The first patient was enrolled August 5, 2021, and the last follow-up, April 29, 2024.

Interventions: Eligible patients were randomized to receive standard care and precision immunotherapy or standard care and placebo. Those in the precision immunotherapy group with macrophage activation-like syndrome received anakinra intravenously (IV) and placebo subcutaneously, and those with sepsis-induced immunoparalysis received subcutaneous recombinant human interferon gamma and IV placebo. Those in the placebo group received both IV and subcutaneous placebo. Treatment was administered for up to 15 days.

Main outcomes and measures: The primary end point was a decrease of at least 1.4 points in the mean Sequential Organ Failure Assessment (SOFA) score from baseline by day 9. The SOFA score evaluates 6 organ systems, ranging from 0, no dysfunction, to 4, failure, and the total score ranges from 0, normal, to 24, most severe form of multiorgan failure. Key secondary outcomes included 28-day mortality.

Results: Of 672 patients assessed for eligibility, 281 were randomized and 276 were included in the primary analysis population (mean [SD] age, 70 [13] years; 93 females [33.7%]; median baseline SOFA score, 9 [IQR, 7-11]). The SOFA decrease end point was attained by 46 of 131 patients (35.1%) in the precision immunotherapy group and by 26 of 145 patients (17.9%) in the placebo group (difference, 17.2% [95% CI, 6.8% to 27.2%]; P = .002). Mortality at 28 days was not statistically significantly different between groups. A total of 1069 serious treatment-emergent adverse events (88.8%) were reported; increased incidence of anemia was noted in the anakinra group; and hemorrhage in the recombinant human interferon gamma group.

Conclusions and relevance: Among patients with sepsis, precision immunotherapy targeting macrophage activation-like syndrome and sepsis-induced immunoparalysis improved organ dysfunction by day 9 compared with placebo.

Trial registration: ClinicalTrials.gov Identifier: NCT04990232.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Giamarellos-Bourboulis reported receiving personal fees from Abbott Products Operations, BioMerieux, Brahms GmbH, Swedish Orphan BioVitrum, AbbVie, UCB, Sanofi, and Novartis to the National and Kapodistrian University of Athens and grants from Abbott Products Operations, Swedish Orphan BioVitrum, and Horizon Health grants ImmunoSep, Epic Crown-2, Risk in COVID, POINT, and Homi-Lung studies to the Hellenic Institute outside the submitted work. Dr Ehler reported receiving personal fees from B Braun Melsungen AG for attending study meetings of the GENIUS trial outside the submitted work. Dr Dalekos reported receiving grants from Gilead and Ipsen; and personal fees from Ipsen, Gilead, Genesis, Pfizer, Sanofi, and Sobi; and other from Amyndas Pharmaceuticals, Intercept Pharma, CymaBay Therapeutics, Genkyotex, Novo Nordisk, Pfizer, Regulus Therapeutics, Sobi, and Tiziana Life Sciences outside the submitted work. Dr Vlaar reported receiving European Horizon grants during the conduct of the study and personal fees from InflaRx and CSL Behring to his institution outside the submitted work. Dr Calandra reported serving on the executive committee and council of the International Sepsis Forum; serving on the data and safety monitoring boards of Basilea, Gilead Sciences, MSD, Moderna, Pfizer, and Shionogi, the European Infection in Leukemia conference organizing committee, and the national advisory board of the Swiss Sepsis Program; and receiving travel and conference participation fees from the International Symposium on Intensive Care and Emergency Medicine outside the submitted work. Dr Antonelli reported receiving personal fees from Menarini and Novartis and grants from Fisher & Paykel and serving on the board of Astra Zeneca outside the submitted work. Dr van der Poll reported receiving grants from the European Horizon commission, serving on the advisory board of Matisse to his institution during the conduct of the study; grants from Ministery of Economic Affairs & Health Holland; and serving on the data and safety monitoring board of the REMAP-CAP study outside the submitted work. Dr Wiersinga reported receiving grants from the Netherlands Organisation for Health Research and Development (ZonMw) and COVID-19–related research and consultancy fees from AstraZeneca, all fees paid to host institution (Amsterdam Medical Center) outside the submitted work. Dr Bauer reported receiving speaker fees from Sobi and personal fees from La Jolla Pharmaceutical Company, SNIPR Biome Denmark, CytoSorbents GmbH, Thermo Fisher Scientific (BRAHMS GmbH), Roche Diagnostics International, Bayer, ArtCline, Baxter, and deepull and nonfinancial support from the International Sepsis Forum outside the submitted work. No other disclosures were reported.

Comment in

References

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