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Randomized Controlled Trial
. 2024 Mar 12;28(1):73.
doi: 10.1186/s13054-024-04852-z.

Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial

Evdoxia Kyriazopoulou  1 , Yehudit Hasin-Brumshtein  2 , Uros Midic  2 , Garyfallia Poulakou  3 , Haralampos Milionis  4 , Simeon Metallidis  5 , Myrto Astriti  6 , Archontoula Fragkou  7 , Aggeliki Rapti  8 , Eleonora Taddei  9 , Ioannis Kalomenidis  10 , Georgios Chrysos  11 , Andrea Angheben  12 , Ilias Kainis  13 , Zoi Alexiou  14 , Francesco Castelli  15 , Francesco Saverio Serino  16 , Petros Bakakos  17 , Emanuele Nicastri  18 , Vasiliki Tzavara  19 , Sofia Ioannou  20 , Lorenzo Dagna  21 , Katerina Dimakou  22 , Glykeria Tzatzagou  23 , Maria Chini  24 , Matteo Bassetti  25 , Vasileios Kotsis  26 , Dionysios G Tsoukalas  27 , Carlo Selmi  28 , Alexandra Konstantinou  29 , Michael Samarkos  30 , Michael Doumas  31 , Aikaterini Masgala  32 , Konstantinos Pagkratis  33 , Aikaterini Argyraki  34 , Karolina Akinosoglou  35 , Styliani Symbardi  36 , Mihai G Netea  37   38 , Periklis Panagopoulos  39 , George N Dalekos  40 , Oliver Liesenfeld  2 , Timothy E Sweeney  2 , Purvesh Khatri  41   42 , Evangelos J Giamarellos-Bourboulis  43   44
Affiliations
Randomized Controlled Trial

Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial

Evdoxia Kyriazopoulou et al. Crit Care. .

Abstract

Background: Endotype classification may guide immunomodulatory management of patients with bacterial and viral sepsis. We aimed to identify immune endotypes and transitions associated with response to anakinra (human interleukin 1 receptor antagonist) in participants in the SAVE-MORE trial.

Methods: Adult patients hospitalized with radiological findings of PCR-confirmed severe pneumonia caused by SARS-CoV-2 and plasma-soluble urokinase plasminogen activator receptor levels of ≥ 6 ng/ml in the SAVE-MORE trial (NCT04680949) were characterized at baseline and days 4 and 7 of treatment using a previously defined 33-messenger RNA classifier to assign an immunological endotype in blood. Endpoints were changes in endotypes and progression to severe respiratory failure (SRF) associated with anakinra treatment.

Results: At baseline, 23.2% of 393 patients were designated as inflammopathic, 41.1% as adaptive, and 35.7% as coagulopathic. Only 23.9% were designated as the same endotype at days 4 and 7 compared to baseline, while all other patients transitioned between endotypes. Anakinra-treated patients were more likely to remain in the adaptive endotype during 7-day treatment (24.4% vs. 9.9%; p < 0.001). Anakinra also protected patients with coagulopathic endotype at day 7 against SRF compared to placebo (27.8% vs. 55.9%; p = 0.013).

Conclusion: We identify an association between endotypes defined using blood transcriptome and anakinra therapy for COVID-19 pneumonia, with anakinra-treated patients shifting toward endotypes associated with a better outcome, mainly the adaptive endotype. Trial registration ClinicalTrials.gov, NCT04680949, December 23, 2020.

Keywords: Anakinra; COVID-19; Endotypes; Viral sepsis.

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Conflict of interest statement

GND is an advisor or lecturer for Pfizer, Roche, Sanofi, Sobi, and Genesis and received research grants from Gilead and has served as PI in studies for Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics Inc., Sobi and Intercept Pharmaceuticals. MGN is a scientific founder of TTxD, Biotrip and Lemba and was supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. PK is a co-founder of, holds stock options of and a consultant to Inflammatix, Inc. YH-B, UM, OL and TES are employees and stock option holders of Inflammatix, Inc. EJGΒ has received honoraria from Abbott Products Operations, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH and Swedish Orphan BioVitrum; independent educational grants from Abbott Products Operations, bioMérieux Inc, InCyte, Johnson & Johnson, MSD, UCB and Swedish Orphan BioVitrum; and funding from the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grant EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis). All other authors do not declare conflicts of interest.

Figures

Fig. 1
Fig. 1
Alluvial plots of distribution of endotype transitions of patients of the SAVE-MORE trial treated with standard-of-care (SoC) and anakinra (left panel) and standard-of-care (SoC) and placebo (right panel), from baseline endotype to the endotype of days 4 and 7 of treatment
Fig. 2
Fig. 2
Endotype transitions between days of follow-up. Upper panel: Alluvial plot of distribution of endotype transitions of patients of the SAVE-MORE trial from baseline endotype to the endotype at days 4 and 7 of treatment. Lower panel left: Proportion of patients that develop severe respiratory failure (SRF) and/or die by day 28, as function of number of timepoints they spent in the adaptive endotype. Lower panel right: Kaplan–Meier curves for the time of progression to severe respiratory failure and/or death by day 28 of patients with adaptive endotype at baseline and treated with Standard-of-Care (SoC) and placebo or SoC and anakinra. Abbreviations: CI, confidence interval; HR, hazard ratio
Fig. 3
Fig. 3
Stabilization over the first 7 days of follow-up to the adaptive endotype. The upper panel shows the univariate and multivariate logistic regression analyses of variables associated with the stabilization of patients in the adaptive endotype between baseline day 1 and follow-up days 4 and 7. The lower panel shows the Kaplan–Meier curves for the time of progression to severe respiratory failure and/or death by day 28 between patients of the entire SAVE-MORE cohort remaining by day 7 in the adaptive endotype and those not stabilized by day 7 in adaptive endotype. Abbreviations: BMI, body mass index; CCI, Charlson’s comorbidity index; CI, confidence interval; HR, hazard ratio; n, number; OR, odds ratio; SOFA, sequential organ failure assessment score; SRF, severe respiratory failure; suPAR, soluble urokinase plasminogen activator receptor
Fig. 4
Fig. 4
Association between the prevailing endotype at day 7 and 28-day outcome. Kaplan–Meier curves for the time of progression to severe respiratory failure and/or death by day 28 between patients treated with Standard-of-Care (SoC) and placebo versus Standard-of-Care (SoC) and anakinra and classified at day 7 into the coagulopathic endotype (upper panel left); the adaptive endotype (upper panel right); and the inflammopathic endotype (lower panel). Abbreviations: CI, confidence interval; HR, hazard ratio
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