Interferon-gamma driven elevation of CXCL9: a new sepsis endotype independently associated with mortalityResearch in context
Evangelos J. Giamarellos-Bourboulis,
Massimo Antonelli,
Frank Bloos,
Ioanna Kotsamidi,
Christos Psarrakis,
Konstantina Dakou,
Daniel Thomas-Rüddel,
Luca Montini,
Josef Briegel,
Georgia Damoraki,
Panagiotis Koufargyris,
Souzana Anisoglou,
Eleni Antoniadou,
Glykeria Vlachogianni,
Christos Tsiantas,
Matteo Masullo,
Aikaterini Ioakeimidou,
Eumorfia Kondili,
Maria Ntaganou,
Eleni Gkeka,
Vassileios Papaioannou,
Effie Polyzogopoulou,
Armin J. Reininger,
Gennaro De Pascale,
Michael Kiehntopf,
Eleni Mouloudi,
Michael Bauer
Affiliations
Evangelos J. Giamarellos-Bourboulis
4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece; Hellenic Institute for the Study of Sepsis, Athens, Greece; Corresponding author. Professor of Internal Medicine and Infectious Diseases, 4th Department of Internal Medicine, ATTIKON University General Hospital, 1 Rimini Str, 12462, Athens, Greece.
Massimo Antonelli
Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy; Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Frank Bloos
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Greece
Ioanna Kotsamidi
Intensive Care Unit, General Hospital “Ippokrateion”, Thessaloniki, Greece
Christos Psarrakis
4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
Konstantina Dakou
Hellenic Institute for the Study of Sepsis, Athens, Greece
Daniel Thomas-Rüddel
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Greece
Luca Montini
Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy; Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Josef Briegel
Department of Anesthesiology, LMU Klinikum, LMU Munich, Munich, Greece
Georgia Damoraki
4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
Panagiotis Koufargyris
4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
Souzana Anisoglou
Intensive Care Unit, Theageneio General Hospital, Thessaloniki, Greece
Eleni Antoniadou
Intensive Care Unit, General Hospital “G.Gennimatas”, Thessaloniki, Greece
Glykeria Vlachogianni
Intensive Care Unit, General Hospital “Aghios Dimitrios”, Thessaloniki, Greece
Christos Tsiantas
Intensive Care Unit, General Hospital AHEPA, Thessaloniki, Greece
Matteo Masullo
Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy; Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Aikaterini Ioakeimidou
Intensive Care Unit, General Hospital Asklipeion, Voula, Greece
Eumorfia Kondili
Department of Critical Care Medicine, University of Crete, Medical School, Herakleion, Greece
Maria Ntaganou
Multivalent Intensive Care Unit, General Hospital of Chest Diseases “Sotiria”, Athens, Greece
Eleni Gkeka
Intensive Care Unit, General Hospital AHEPA, Thessaloniki, Greece
Vassileios Papaioannou
Department of Critical Care Medicine, Democritus University of Thrace Medical School, Alexandroupolis, Greece
Effie Polyzogopoulou
Department of Emergency Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
Armin J. Reininger
Swedish Orphan Biovitrum, Basel, Switzerland
Gennaro De Pascale
Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy; Dipartimento di Scienze dell'Emergenza, Anestesiologiche e della Rianimazione, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Michael Kiehntopf
Institute of Clinical Chemistry and Laboratory Diagnostics and Integrated Biobank Jena, Jena University Hospital, Jena, Germany
Eleni Mouloudi
Intensive Care Unit, General Hospital “Ippokrateion”, Thessaloniki, Greece
Michael Bauer
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Greece
Summary: Background: Endotype classification becomes the cornerstone of understanding sepsis pathogenesis. Macrophage activation-like syndrome (MALS) and immunoparalysis are the best recognized major endotypes, so far. Interferon-gamma (IFNγ) action on tissue macrophages stimulates the release of the cytotoxic chemokine CXCL9. It was investigated if this mechanism may be an independent sepsis endotype. Methods: In this cohort study, 14 patient cohorts from Greece, Germany and Italy were studied. The cohorts were 2:1 randomly split into discovery and validation sets. Sepsis was defined by the Sepsis-3 definitions and blood was sampled the first 24 h from meeting the Sepsis-3 definitions. Concentrations of IFNγ, CXCL9, IP-10 (IFNγ induced protein-10), soluble CD163 and ferritin were measured. The endotype of IFNγ-driven sepsis (IDS) was defined in the discovery set as the combination of a) blood IFNγ above a specified cut-off associated with the minimal risk for immunoparalysis (defined as ≥8000 HLA-DR receptors on CD45/CD14-monoytes); and b) increase of CXCL9. Results were compared to the validation set. Findings: 5503 patients were studied; 3670 in the discovery set and 1833 in the validation set. IDS was defined as IFNγ more than 3 pg/ml and CXCL9 more than 2200 pg/ml. The frequency of IDS in the discovery set was 19.9% (732 patients; 95% confidence intervals-CIs 18.7–21.3%) and in the validation set 20.0% (366 patients; 95% CIs 18.2–21.9%). Soluble CD163, a marker of macrophage activation, was greater in IDS and IDS had features distinct from MALS. The mortality in IDS patients was 43.0% (315 patients; 95% CIs 39.5–46.6%) in the discovery set and 40.4% in the validation set (148 patients; 95% CIs 35.5–45.5%) (p = 0.44 compared to patients of the discovery set). IDS was an independent risk factor for death in the presence of other endotypes, severity scores and organ dysfunctions of the multivariate model [hazard ratio 1.71 (95% CIs 1.45–2.01) in the discovery set and 1.70 (95% CIs 1.34–2.16) in the validation set]. Decreases of IFNγ and CXCL9 blood levels within the first 72 h were associated with better outcome. Interpretation: IDS is a new sepsis endotype independently associated with unfavorable outcome. Funding: Hellenic Institute for the Study of Sepsis; Horizon 2020 project ImmunoSep; Swedish Orphan BioVitrum AB (publ) and German Federal Ministry of Education and Research.
