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. 2025 Jun 30;13(1):67.
doi: 10.1186/s40635-025-00777-1.

29-mRNA host response signatures for classification of bacterial infection, viral infection and disease progression in COVID-19 pneumonia: a post hoc analysis of the SAVE-MORE randomized clinical trial

Evdoxia Kyriazopoulou  1 , Antigone Kotsaki  1 , Asimina Safarika  1 , Garyfallia Poulakou  2 , Haralampos Milionis  3 , Simeon Metallidis  4 , Georgios Adamis  5 , Archontoula Fragkou  6 , Aggeliki Rapti  7 , Pierluigi Del Vecchio  8 , Ioannis Kalomenidis  9 , Danae Kitzoglou  10 , Andrea Angheben  11 , Ilias Kainis  12 , Konstantina Iliopoulou  13 , Francesco Saverio Serino  14 , Petros Bakakos  15 , Vassiliki Tzavara  16 , Sofia Ioannou  17 , Lorenzo Dagna  18 , Katerina Dimakou  19 , Glykeria Tzatzagou  20 , Maria Chini  21 , Matteo Bassetti  22 , Vasileios Kotsis  23 , George Tsoukalas  24 , Carlo Selmi  25 , Sofia Nikolakopoulou  26 , Michael Samarkos  27 , Michael Doumas  28 , Aikaterini Masgala  29 , Ilias Papanikolaou  30 , Aikaterini Argyraki  31 , Karolina Akinosoglou  32 , Styliani Symbardi  33 , Periklis Panagopoulos  34 , George N Dalekos  35 , Oliver Liesenfeld  36 , Timothy E Sweeney  36 , Purvesh Khatri  37   38 , Evangelos J Giamarellos-Bourboulis  39   40   41
Affiliations

29-mRNA host response signatures for classification of bacterial infection, viral infection and disease progression in COVID-19 pneumonia: a post hoc analysis of the SAVE-MORE randomized clinical trial

Evdoxia Kyriazopoulou et al. Intensive Care Med Exp. .

Abstract

Background: Biomarkers based on host response signatures are currently under development for the critically ill. We applied a 29-mRNA classifier for the diagnosis and prognosis of suspected acute infection and sepsis (TriVerity™, Inflammatix Inc.) in patients hospitalized with COVID-19.

Methods: We applied three scores from locked classifiers (IMX-BVN-4 and IMX-SEV-4) from the 29-mRNA TriVerity™ blood test in participants of the SAVE-MORE randomized clinical trial (ClinicalTrials.gov NCT04680949) at baseline and days 4 and 7 of treatment, to classify bacterial infection, viral infection and decompensation. Participants were adults hospitalized with confirmed COVID-19 pneumonia and plasma soluble urokinase plasminogen activator receptor (suPAR) levels of ≥ 6 ng/ml, randomized to placebo or anakinra treatment.

Results: A total of 471 patients were studied. At baseline nearly 90% had a Very Low or Low IMX-BVN-4 Bacterial Score and Moderate, High or Very High IMX-BVN-4 Viral Score. Anakinra treatment had an effect on the expression of genes indicating IMX-SEV-4 High or Very High scores after a 7 day treatment compared to baseline (12.9% of anakinra-treated patients continued being classified as high severity vs 20.4% of placebo-treated patients, p 0.046).

Conclusions: The classifiers were well tested in COVID-19 pneumonia and may become a useful tool for hospitalized patients.

Keywords: Anakinra; Bacterial infection; COVID-19; Diagnostics; Gene expression; Host response; Mortality; Secondary infection; Severity; Viral infection.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The SAVE-MORE trial (NCT04680949) was approved by the National Ethics Committee of Greece (approval 161/20) and by the Ethics Committee of the National Institute for Infectious Diseases Lazzaro Spallanzani, IRCCS, in Rome (1 February 2021). All patients or their legal representatives provided written informed consent before enrollment. Consent for publication: Not applicable. Competing interests: TS is an employee of and shareholder in Inflammatix, Inc. OL and PK are shareholders in Inflammatix, Inc. EJG-B reports honoraria from Abbott Products Operations, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH, Sobi and Xbiotech Inc; independent educational grants from Abbott Products Operations, bioMérieux Inc, Johnson & Johnson, MSD, UCB, Swedish Orphan Biovitrum AB; and funding from the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grants EPIC-CROWN-2, POINT and Homi-Lung (granted to the Hellenic Institute for the Study of Sepsis). The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Classification of patients according to the likelihood of A bacterial infection at baseline; B viral infection at baseline; C bacterial infection at day 4; D viral infection at day 4; E bacterial infection at day 7; F viral infection at day 7. Arm of treatment (anakinra or placebo) is indicated in the left of each panel. p values of comparison between the two arms of treatment at baseline by the Chi-square test are provided. p values, odds ratios (OR) and 95% confidence intervals (CI) of ordinal regression analysis between the two arms of treatment at days 4 and 7 are provided
Fig. 2
Fig. 2
A Classification of patients according to the IMX-SEV-4 Severity Score at baseline, between anakinra- and placebo-treated patients. p value of comparison by the Chi-square test is provided. Proportions of patients of both arms who B developed severe respiratory failure (SRF) and/or died; and C required admission in intensive care unit (ICU) by day 28 according to the likelihood of severity at baseline. Odds ratios (OR) and 95% confidence intervals (CI) of categorical logistic regression analysis are provided
Fig. 3
Fig. 3
Alluvial plots of classification according to the IMX-SEV-4 Severity Score among SAVE-MORE participants treated with A standard-of-care (SoC) and placebo and B standard-of-care (SoC) and anakinra, from baseline to days 4 and 7 of treatment
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