Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock
Large clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may benefit of hydrocortisone treatment depending on their individual immune response. We performed an exploratory analysis of the database from the international randomized controlled c...
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.607217/full |
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| author | Rainer König Rainer König Amol Kolte Amol Kolte Olaf Ahlers Marcus Oswald Marcus Oswald Veiko Krauss Veiko Krauss Daniela Roell Daniela Roell Oliver Sommerfeld George Dimopoulos Iraklis Tsangaris Eleni Antoniadou Neeraja Jaishankar Holger Bogatsch Markus Löffler Markus Rödel Marina Garcia-Moreno Lorena Tuchscherr Charles L. Sprung Mervyn Singer Frank Brunkhorst Michael Oppert Herwig Gerlach Ralf A. Claus Sina M. Coldewey Sina M. Coldewey Sina M. Coldewey Josef Briegel Evangelos J. Giamarellos-Bourboulis Evangelos J. Giamarellos-Bourboulis Didier Keh Michael Bauer Michael Bauer |
| author_facet | Rainer König Rainer König Amol Kolte Amol Kolte Olaf Ahlers Marcus Oswald Marcus Oswald Veiko Krauss Veiko Krauss Daniela Roell Daniela Roell Oliver Sommerfeld George Dimopoulos Iraklis Tsangaris Eleni Antoniadou Neeraja Jaishankar Holger Bogatsch Markus Löffler Markus Rödel Marina Garcia-Moreno Lorena Tuchscherr Charles L. Sprung Mervyn Singer Frank Brunkhorst Michael Oppert Herwig Gerlach Ralf A. Claus Sina M. Coldewey Sina M. Coldewey Sina M. Coldewey Josef Briegel Evangelos J. Giamarellos-Bourboulis Evangelos J. Giamarellos-Bourboulis Didier Keh Michael Bauer Michael Bauer |
| author_sort | Rainer König |
| collection | DOAJ |
| description | Large clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may benefit of hydrocortisone treatment depending on their individual immune response. We performed an exploratory analysis of the database from the international randomized controlled clinical trial Corticosteroid Therapy of Septic Shock (CORTICUS) employing machine learning to a panel of 137 variables collected from the Berlin subcohort comprising 83 patients including demographic and clinical measures, organ failure scores, leukocyte counts and levels of circulating cytokines. The identified theranostic marker was validated against data from a cohort of the Hellenic Sepsis Study Group (HSSG) (n = 246), patients enrolled in the clinical trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT, n = 118), and another, smaller clinical trial (Crossover study, n = 20). In addition, in vitro blood culture experiments and in vivo experiments in mouse models were performed to assess biological plausibility. A low serum IFNγ/IL10 ratio predicted increased survival in the hydrocortisone group whereas a high ratio predicted better survival in the placebo group. Using this marker for a decision rule, we applied it to three validation sets and observed the same trend. Experimental studies in vitro revealed that IFNγ/IL10 was negatively associated with the load of (heat inactivated) pathogens in spiked human blood and in septic mouse models. Accordingly, an in silico analysis of published IFNγ and IL10 values in bacteremic and non-bacteremic patients with the Systemic Inflammatory Response Syndrome supported this association between the ratio and pathogen burden. We propose IFNγ/IL10 as a molecular marker supporting the decision to administer hydrocortisone to patients in septic shock. Prospective clinical studies are necessary and standard operating procedures need to be implemented, particularly to define a generic threshold. If confirmed, IFNγ/IL10 may become a suitable theranostic marker for an urging clinical need. |
| first_indexed | 2024-12-14T18:04:48Z |
| format | Article |
| id | doaj.art-594408ba31f8495d97a60fd7b13728f4 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T18:04:48Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-594408ba31f8495d97a60fd7b13728f42022-12-21T22:52:23ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-03-011210.3389/fimmu.2021.607217607217Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic ShockRainer König0Rainer König1Amol Kolte2Amol Kolte3Olaf Ahlers4Marcus Oswald5Marcus Oswald6Veiko Krauss7Veiko Krauss8Daniela Roell9Daniela Roell10Oliver Sommerfeld11George Dimopoulos12Iraklis Tsangaris13Eleni Antoniadou14Neeraja Jaishankar15Holger Bogatsch16Markus Löffler17Markus Rödel18Marina Garcia-Moreno19Lorena Tuchscherr20Charles L. Sprung21Mervyn Singer22Frank Brunkhorst23Michael Oppert24Herwig Gerlach25Ralf A. Claus26Sina M. Coldewey27Sina M. Coldewey28Sina M. Coldewey29Josef Briegel30Evangelos J. Giamarellos-Bourboulis31Evangelos J. Giamarellos-Bourboulis32Didier Keh33Michael Bauer34Michael Bauer35Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, GermanyInstitute of Infectious Diseases and Infection Control, Jena University Hospital, Jena, GermanyIntegrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, GermanyInstitute of Infectious Diseases and Infection Control, Jena University Hospital, Jena, GermanyDepartment of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, GermanyIntegrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, GermanyInstitute of Infectious Diseases and Infection Control, Jena University Hospital, Jena, GermanyIntegrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, GermanyInstitute of Infectious Diseases and Infection Control, Jena University Hospital, Jena, GermanyIntegrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, GermanyInstitute of Infectious Diseases and Infection Control, Jena University Hospital, Jena, GermanyIntegrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany2nd Department of Critical Care Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece2nd Department of Critical Care Medicine, Medical School, National and Kapodistrian University of Athens, Athens, GreeceIntensive Care Unit, “George Gennimatas” Thessaloniki General Hospital, Thessaloniki, GreeceIntegrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, GermanyClinical Trial Centre, Leipzig University, Leipzig, GermanyInstitute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, GermanyIntegrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, GermanyInstitute of Medical Microbiology, Jena University Hospital, Jena, GermanyInstitute of Medical Microbiology, Jena University Hospital, Jena, GermanyDepartment of Anesthesiology and Critical Care Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel0Division of Medicine, Bloomsbury Institute of Intensive Care Medicine, University College London, London, United KingdomIntegrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany1Department of Emergency and Intensive Care Medicine, Klinikum Ernst von Bergmann, Potsdam, Germany2Department of Anesthesia, Operative Intensive Care Medicine, and Pain Management, Vivantes Neukölln Hospital, Berlin, Germany3Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, GermanyIntegrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany3Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany4Septomics Research Center, Jena University Hospital, Jena, Germany5Department of Anesthesiology, University Hospital, Ludwig Maximilian University of Munich, Munich, GermanyIntegrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany64th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, GreeceDepartment of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, GermanyIntegrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany3Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, GermanyLarge clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may benefit of hydrocortisone treatment depending on their individual immune response. We performed an exploratory analysis of the database from the international randomized controlled clinical trial Corticosteroid Therapy of Septic Shock (CORTICUS) employing machine learning to a panel of 137 variables collected from the Berlin subcohort comprising 83 patients including demographic and clinical measures, organ failure scores, leukocyte counts and levels of circulating cytokines. The identified theranostic marker was validated against data from a cohort of the Hellenic Sepsis Study Group (HSSG) (n = 246), patients enrolled in the clinical trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT, n = 118), and another, smaller clinical trial (Crossover study, n = 20). In addition, in vitro blood culture experiments and in vivo experiments in mouse models were performed to assess biological plausibility. A low serum IFNγ/IL10 ratio predicted increased survival in the hydrocortisone group whereas a high ratio predicted better survival in the placebo group. Using this marker for a decision rule, we applied it to three validation sets and observed the same trend. Experimental studies in vitro revealed that IFNγ/IL10 was negatively associated with the load of (heat inactivated) pathogens in spiked human blood and in septic mouse models. Accordingly, an in silico analysis of published IFNγ and IL10 values in bacteremic and non-bacteremic patients with the Systemic Inflammatory Response Syndrome supported this association between the ratio and pathogen burden. We propose IFNγ/IL10 as a molecular marker supporting the decision to administer hydrocortisone to patients in septic shock. Prospective clinical studies are necessary and standard operating procedures need to be implemented, particularly to define a generic threshold. If confirmed, IFNγ/IL10 may become a suitable theranostic marker for an urging clinical need.https://www.frontiersin.org/articles/10.3389/fimmu.2021.607217/fullsepsishydrocortisoneimmune therapymachine learningtheranosticssteroids |
| spellingShingle | Rainer König Rainer König Amol Kolte Amol Kolte Olaf Ahlers Marcus Oswald Marcus Oswald Veiko Krauss Veiko Krauss Daniela Roell Daniela Roell Oliver Sommerfeld George Dimopoulos Iraklis Tsangaris Eleni Antoniadou Neeraja Jaishankar Holger Bogatsch Markus Löffler Markus Rödel Marina Garcia-Moreno Lorena Tuchscherr Charles L. Sprung Mervyn Singer Frank Brunkhorst Michael Oppert Herwig Gerlach Ralf A. Claus Sina M. Coldewey Sina M. Coldewey Sina M. Coldewey Josef Briegel Evangelos J. Giamarellos-Bourboulis Evangelos J. Giamarellos-Bourboulis Didier Keh Michael Bauer Michael Bauer Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock Frontiers in Immunology sepsis hydrocortisone immune therapy machine learning theranostics steroids |
| title | Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock |
| title_full | Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock |
| title_fullStr | Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock |
| title_full_unstemmed | Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock |
| title_short | Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock |
| title_sort | use of ifnγ il10 ratio for stratification of hydrocortisone therapy in patients with septic shock |
| topic | sepsis hydrocortisone immune therapy machine learning theranostics steroids |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.607217/full |
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