Renaud Tissier1, Hakim Hocini2, Nicolas Tchitchek3, Nicolas Deye4, Stéphane Legriel5, Nicolas Pichon6, Cédric Daubin7, Olivier Hermine8, Pierre Carli9, Benoît Vivien9, Jean-Marc Tréluyer10, Cécile Lefebvre2, Pascaline Tisserand2, Jean-Luc Dubois-Randé11, Alain Berdeaux11, Bijan Ghaleh12, Jean-Daniel Lelièvre2, Yves Levy13, Alain Cariou14. 1. Inserm, U955, F94000, Créteil, France; Université Paris Est, UMR_S955, UPEC, Ecole Nationale Vétérinaire d'Alfort, F-94000, Créteil, France. Electronic address: renaud.tissier@inserm.fr. 2. Inserm, U955, F94000, Créteil, France; Vaccine Research Institute, Université Paris Est-Créteil, F-94000, Créteil, France. 3. Vaccine Research Institute, Université Paris Est-Créteil, F-94000, Créteil, France; CEA - Université Paris Sud 11 - INSERM U1184, Immunology of Viral Infections and Autoimmune Diseases, IDMIT Infrastructure, F-92265 Fontenay-aux-Roses, France. 4. Medical ICU, Inserm U942, Lariboisiere Hospital, APHP, F-75010, Paris, France. 5. Intensive Care Unit, Versailles Hospital, Le Chesnay, F-78150, France. 6. Intensive Care Unit, University Hospital Dupuytren, Limoges, F-87042, France. 7. CHU de Caen, Department of Medical Intensive Care, Caen, F-14000, France. 8. Department of Hematology and INSERM U1163 CNRS ERL 8654, Imagine Institute and Necker Hospital, Paris, F-75015, France. 9. SAMU de Paris, Service d'Anesthésie-Réanimation, Hôpital Universitaire Necker- Enfants Malades, Université Paris Descartes, F-75015, Paris, France. 10. Clinical Research Unit, Paris Centre and Paris Descartes University, Paris, France. 11. Inserm, U955, F94000, Créteil, France; Université Paris Est, UMR_S955, UPEC, Ecole Nationale Vétérinaire d'Alfort, F-94000, Créteil, France. 12. Inserm, U955, F94000, Créteil, France; Université Paris Est, UMR_S955, UPEC, Ecole Nationale Vétérinaire d'Alfort, F-94000, Créteil, France; APHP, Hôpitaux Universitaires Henri Mondor, Plateforme de Ressources Biologiques, F-94000, Créteil, France. 13. Inserm, U955, F94000, Créteil, France; Vaccine Research Institute, Université Paris Est-Créteil, F-94000, Créteil, France. Electronic address: yves.levy@inserm.fr. 14. Service de Réanimation Médicale, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France.
Abstract
BACKGROUND: Early prognostication is a major challenge after out-of-hospital cardiac arrest (OHCA). AIMS: We hypothesized that a genome-wide analysis of blood gene expression could offer new prognostic tools and lines of research. METHODS: Sixty-nine patients were enrolled from an ancillary study of the clinical trial NCT00999583 that tested the effect of erythropoietin (EPO) after OHCA. Blood samples were collected in comatose survivors of OHCA at hospital admission and 1 and 3 days after resuscitation. Gene expression profiles were analyzed (Illumina HumanHT-12 V4 BeadChip; >34,000 genes). Patients were classified into two categories representing neurological favorable outcome (cerebral performance category [CPC] = 1-2) vs unfavorable outcome (CPC > 2) at Day 60 after OHCA. Differential and functional enrichment analyses were performed to compare transcriptomic profiles between these two categories. RESULTS: Among the 69 enrolled patients, 33 and 36 patients were treated or not by EPO, respectively. Among them, 42% had a favorable neurological outcome in both groups. EPO did not affect the transcriptomic response at Day-0 and 1 after OHCA. In contrast, 76 transcripts differed at Day-0 between patients with unfavorable vs favorable neurological outcome. This signature persisted at Day-1 after OHCA. Functional enrichment analysis revealed a down-regulation of adaptive immunity with concomitant up-regulation of innate immunity and inflammation in patients with unfavorable vs favorable neurological outcome. The transcription of many genes of the HLA family was decreased in patients with unfavorable vs favorable neurological outcome. Concomitantly, neutrophil activation and inflammation were observed. Up-stream regulators analysis showed the implication of numerous factors involved in cell cycle and damages. A logistic regression including a set of genes allowed a reliable prediction of the clinical outcomes (specificity = 88%; Hit Rate = 83%). CONCLUSIONS: A transcriptomic signature involving a counterbalance between adaptive and innate immune responses is able to predict neurological outcome very early after hospital admission after OHCA. This deserves confirmation in a larger population.
BACKGROUND: Early prognostication is a major challenge after out-of-hospital cardiac arrest (OHCA). AIMS: We hypothesized that a genome-wide analysis of blood gene expression could offer new prognostic tools and lines of research. METHODS: Sixty-nine patients were enrolled from an ancillary study of the clinical trial NCT00999583 that tested the effect of erythropoietin (EPO) after OHCA. Blood samples were collected in comatose survivors of OHCA at hospital admission and 1 and 3 days after resuscitation. Gene expression profiles were analyzed (Illumina HumanHT-12 V4 BeadChip; >34,000 genes). Patients were classified into two categories representing neurological favorable outcome (cerebral performance category [CPC] = 1-2) vs unfavorable outcome (CPC > 2) at Day 60 after OHCA. Differential and functional enrichment analyses were performed to compare transcriptomic profiles between these two categories. RESULTS: Among the 69 enrolled patients, 33 and 36 patients were treated or not by EPO, respectively. Among them, 42% had a favorable neurological outcome in both groups. EPO did not affect the transcriptomic response at Day-0 and 1 after OHCA. In contrast, 76 transcripts differed at Day-0 between patients with unfavorable vs favorable neurological outcome. This signature persisted at Day-1 after OHCA. Functional enrichment analysis revealed a down-regulation of adaptive immunity with concomitant up-regulation of innate immunity and inflammation in patients with unfavorable vs favorable neurological outcome. The transcription of many genes of the HLA family was decreased in patients with unfavorable vs favorable neurological outcome. Concomitantly, neutrophil activation and inflammation were observed. Up-stream regulators analysis showed the implication of numerous factors involved in cell cycle and damages. A logistic regression including a set of genes allowed a reliable prediction of the clinical outcomes (specificity = 88%; Hit Rate = 83%). CONCLUSIONS: A transcriptomic signature involving a counterbalance between adaptive and innate immune responses is able to predict neurological outcome very early after hospital admission after OHCA. This deserves confirmation in a larger population.