Toward personalized immunotherapy in sepsis: The PROVIDE randomized clinical trial

Konstantinos Leventogiannis, Evdoxia Kyriazopoulou, Nikolaos Antonakos, Antigone Kotsaki, Iraklis Tsangaris, Dimitra Markopoulou, Inge Grondman, Nikoleta Rovina, Vassiliki Theodorou, Eleni Antoniadou, Ioannis Koutsodimitropoulos, George Dalekos, Glykeria Vlachogianni, Karolina Akinosoglou, Vassileios Koulouras, Apostolos Komnos, Theano Kontopoulou, Athanassios Prekates, Antonia Koutsoukou, Jos W M van der Meer, George Dimopoulos, Miltiades Kyprianou, Mihai G Netea, Evangelos J Giamarellos-Bourboulis, Konstantinos Leventogiannis, Evdoxia Kyriazopoulou, Nikolaos Antonakos, Antigone Kotsaki, Iraklis Tsangaris, Dimitra Markopoulou, Inge Grondman, Nikoleta Rovina, Vassiliki Theodorou, Eleni Antoniadou, Ioannis Koutsodimitropoulos, George Dalekos, Glykeria Vlachogianni, Karolina Akinosoglou, Vassileios Koulouras, Apostolos Komnos, Theano Kontopoulou, Athanassios Prekates, Antonia Koutsoukou, Jos W M van der Meer, George Dimopoulos, Miltiades Kyprianou, Mihai G Netea, Evangelos J Giamarellos-Bourboulis

Abstract

The state of immune activation may guide targeted immunotherapy in sepsis. In a double-blind, double-dummy randomized clinical study, 240 patients with sepsis due to lung infection, bacteremia, or acute cholangitis were subjected to measurements of serum ferritin and HLA-DR/CD14. Patients with macrophage activation-like syndrome (MALS) or immunoparalysis were randomized to treatment with anakinra or recombinant interferon-gamma or placebo. Twenty-eight-day mortality was the primary endpoint; sepsis immune classification was the secondary endpoint. Using ferritin >4,420 ng/mL and <5,000 HLA-DR receptors/monocytes as biomarkers, patients were classified into MALS (20.0%), immunoparalysis (42.9%), and intermediate (37.1%). Mortality was 79.1%, 66.9%, and 41.6%, respectively. Survival after 7 days with SOFA score decrease was achieved in 42.9% of patients of the immunotherapy arm and 10.0% of the placebo arm (p = 0.042). Three independent immune classification strata are recognized in sepsis. MALS and immunoparalysis are proposed as stratification for personalized adjuvant immunotherapy. Clinicaltrials.gov registration NCT03332225.

Keywords: ferritin; immunoparalysis; macrophage activation; monocytes; mortality; sepsis.

Conflict of interest statement

Declaration of interests G.D. has acted as Advisor/Lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Novartis, Roche, Amgen, MSD, Janssen, Ipsen, Genkyotex, Sobi, and Pfizer; has received grant support from Bristol-Myers Squib, Gilead, Roche, Janssen, Abbvie, and Bayer; and was or is currently principal investigator in national and international protocols sponsored by Abbvie, Bristol-Myers Squibb, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Bayer, Astellas, Ipsen, Pfizer, Amyndas Pharamaceuticals, CymaBay Therapeutics Inc., and Roche. M.G.N. is supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. He is a scientific founder of TTxD and has received independent educational grants from TTxD, GSK, Ono Pharma, and ViiV HealthCare. E.J.G.-B. has received honoraria from Abbott CH, bioMérieux, ThermoFisherBrahms GmbH, GSK, InflaRx GmbH, Sobi, and XBiotech Inc; independent educational grants from Abbott CH, AxisShield, bioMérieux Inc, InflaRx GmbH, Johnson & Johnson, MSD, Sobi, and XBiotech Inc.; and funding from the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), the Horizon 2020 European Grants ImmunoSep and RISCinCOVID (granted to the Hellenic Institute for the Study of Sepsis), and the Horizon Health European Grant EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis).

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Flow of patients among the two stages of the PROVIDE trial The first stage of immunological screening was aiming to classify patients with septic shock and without septic shock into MALS (macrophage activation-like syndrome), immunoparalysis, and intermediate state. The second intervention stage was a double-blind, double-dummy randomized clinical trial where patients with septic shock and MALS or immunoparalysis received blind adjunctive treatment with placebo or personalized immunotherapy. SLE, systemic lupus erythematosus.
Figure 2
Figure 2
Development of the number of HLA-DR receptors/monocyte as diagnostic tool for sepsis-induced immunoparalysis (A and B) ROC curve (A) of percentage and (B) of number of HLA-DR receptors/monocyte of each day (day 1 and day 2) as a mortality predictor. (C) Prognostic performance of

Figure 3

Association of immune classification of…

Figure 3

Association of immune classification of sepsis and 28-day mortality (A) Survival curves of…

Figure 3
Association of immune classification of sepsis and 28-day mortality (A) Survival curves of each classification group: macrophage activation-like syndrome (MALS), immunoparalysis, and intermediate state. Log rank values and p values are presented. (Β) Twenty-eight-day mortality-related risk factors after univariate and multivariate Cox regression analysis. Hazard ratios (HRs), 95% confidence intervals (CIs), and p values are presented. APACHE, acute physiology and chronic health evaluation; SOFA, sequential organ failure assessment. ∗Values represent Youden Index of ROC curves for mortality. ∗∗Not entering the equation after four steps of forward analysis.

Figure 4

Effect of personalized immunotherapy (A)…

Figure 4

Effect of personalized immunotherapy (A) Survival curves of both treatment arms. Log rank…

Figure 4
Effect of personalized immunotherapy (A) Survival curves of both treatment arms. Log rank value and p value are presented. (B) State of patients at day 7; patients are presented according to the survival status, decrease of SOFA score from baseline, or both. (C–H) Comparison of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, absolute platelet count, international normalized ratio (INR), and activated partial thromboplastin time (aPTT) between days 1 and 7 for each treatment arms; p values of indicated statistical comparison are presented. CI, confidence interval; SOFA, sequential organ failure assessment.
Figure 3
Figure 3
Association of immune classification of sepsis and 28-day mortality (A) Survival curves of each classification group: macrophage activation-like syndrome (MALS), immunoparalysis, and intermediate state. Log rank values and p values are presented. (Β) Twenty-eight-day mortality-related risk factors after univariate and multivariate Cox regression analysis. Hazard ratios (HRs), 95% confidence intervals (CIs), and p values are presented. APACHE, acute physiology and chronic health evaluation; SOFA, sequential organ failure assessment. ∗Values represent Youden Index of ROC curves for mortality. ∗∗Not entering the equation after four steps of forward analysis.
Figure 4
Figure 4
Effect of personalized immunotherapy (A) Survival curves of both treatment arms. Log rank value and p value are presented. (B) State of patients at day 7; patients are presented according to the survival status, decrease of SOFA score from baseline, or both. (C–H) Comparison of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, absolute platelet count, international normalized ratio (INR), and activated partial thromboplastin time (aPTT) between days 1 and 7 for each treatment arms; p values of indicated statistical comparison are presented. CI, confidence interval; SOFA, sequential organ failure assessment.

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