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The REAnimation Low Immune Status Markers (REALISM) project: a protocol for broad characterisation and follow-up of injury-induced immunosuppression in intensive care unit (ICU) critically ill patients
  1. Mary-Luz Rol1,2,
  2. Fabienne Venet2,3,
  3. Thomas Rimmele2,4,
  4. Virginie Moucadel5,
  5. Pierre Cortez6,
  6. Laurence Quemeneur7,
  7. David Gardiner13,
  8. Andrew Griffiths8,
  9. Alexandre Pachot2,5,
  10. Julien Textoris2,4,5,
  11. Guillaume Monneret2,3
  12. On behalf of the REALISM study group
  1. 1 BIOASTER Technology Research Institute, Lyon, France
  2. 2 EA7426 “Pathophysiology of Injury-induced immunosuppression”, Université Claude Bernard Lyon 1 - Hospices Civils de Lyon - bioMérieux, Lyon, France
  3. 3 Immunology Laboratory, Hospices Civils de Lyon - Université Claude Bernard Lyon 1, Lyon, France
  4. 4 Anesthesiology and Critical Care Medicine, Hospices Civils de Lyon - Université Claude Bernard Lyon 1, Lyon, France
  5. 5 Medical Diagnostic Discovery Department (MD3), bioMérieux, Marcy-l'Étoile, France
  6. 6 R&D, Sanofi Aventis, Chilly-Mazarin, France
  7. 7 Sanofi-Pasteur SA, Lyon, France
  8. 8 ESPCI Paris, PSL Research University, Paris, France
  9. 13 GlaxoSmithKline, Collegeville, PA, USA
  1. Correspondence to Dr Julien Textoris; julien.textoris{at}


Introduction The host response to septic shock is dynamic and complex. A sepsis-induced immunosuppression phase has recently been acknowledged and linked to bad outcomes and increased healthcare costs. Moreover, a marked suppression of the immune response has also been partially described in patients hospitalized in intensive care unit (ICU) for severe trauma or burns. It has been hypothesized that immune monitoring could enable identification of patients who might most benefit from novel, adjunctive immune-stimulating therapies. However, there is currently neither a clear definition for such injury-induced immunosuppression nor a stratification biomarker compatible with clinical constraints.

Methods and analysis We set up a prospective, longitudinal single-centre clinical study to determine the incidence, severity and persistency of innate and adaptive immune alterations in ICU patients. We optimized a workflow to describe and follow the immunoinflammatory status of 550 patients (septic shock, severe trauma/burn and major surgery) during the first 2 months after their initial injury. On each time point, two immune functional tests will be performed to determine whole-blood TNF-α production in response to ex vivo lipopolysaccharide stimulation and the T lymphocyte proliferation in response to phytohaemagglutinin. In addition, a complete immunophenotyping using flow cytometry including monocyte HLA-DR expression and lymphocyte subsets will be obtained. New markers (ie, levels of expression of host mRNA and viral reactivation) will be also evaluated. Reference intervals will be determined from a cohort of 150 age-matched healthy volunteers. This clinical study will provide, for the first time, data describing the immune status of severe ICU patients over time.

Ethics and dissemination Ethical approval has been obtained from the institutional review board (no 69HCL15_0379) and the French National Security agency for drugs and health-related products. Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals.

Trial registration number Registration number: NCT02638779. Pre-results.

  • Injury-induced immunosuppression
  • Intensive care unit
  • Innate immunity
  • Adaptive immunity
  • Biomarkers
  • Healthcare-associated infections

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  • Contributors All authors (M-LR, FV, TR, VM, PC, LQ, DG, AG, AP, JT and GM) fulfilled ICMJE guidelines and provided substantial contributions to conception, design and acquisition of data; drafted and revised critically the manuscript; and approved the final version of the manuscript.

  • Competing interests AP, JT and VM are employees of bioMérieux SA, an in vitro diagnostic company. PC, LQ and DG are employees of Sanofi-Aventis R&D, Sanofi-Pasteur SA and GlaxoSmithKline, three pharmaceutical companies.

  • Ethics approval Comit de Protection des Personnes Lyon Sud-Est 2.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals. New markers and immune functional tests will be evaluated for the diagnostic immune deficiency and may be patentable.

  • Collaborators For Hospices Civils de Lyon: Asma BEN AMOR, André BOIBIEUX, Julien DAVIDSON, Laure FAYOLLE-PIVOT, Charline GENIN, Arnaud GREGOIRE, Alain LEPAPE, Anne Claire LUKASZEWICZ, Guillaume MARCOTTE, Delphine MAUCORT-BOULCH, Boris MEUNIER, Guillaume MONNERET, Nathalie PANEL, Thomas RIMMELE, Hélène VALLIN and Fabienne VENET. For bioMérieux: Sophie BLEIN, Karen BRENGEL-PESCE, Elisabeth CERRATO, Valérie CHEYNET, Emmanuelle GALLET-GORIUS, Audrey GUICHARD, François MALLET, Virginie MOUCADEL, Marine MOMMERT, Guy ORIOL, Alexandre PACHOT, Claire SCHREVEL, Olivier TABONE, Julien TEXTORIS and Javier YUGUEROS MARCOS. For BIOASTER: Jérémie BECKER, Frédéric BEQUET, Yacine BOUNAB, Nathalie GARCON, Irène GORSE, Cyril GUYARD, Fabien LAVOCAT, Philippe LEISSNER, Karen LOUIS, Maxime MISTRETTA, Yoann MOUSCAZ, Laura NOAILLES, Magali PERRET, Frédéric REYNIER, Cindy RIFFAUD, Mary Luz ROL, Nicolas SAPAY, Trang TRAN and Christophe VEDRINE. For Sanofi: Nicolas BURDIN, Christophe CARRE, Pierre CORTEZ, Aymeric DE MONFORT, Karine FLORIN, Laurent FRAISSE, Isabelle FUGIER, Sandrine PAYRARD, Annick PELERAUX and Laurence QUEMENEUR. For ESPCI Paris: Andrew GRIFFITHS and Stephanie TOETSCH. For GSK: Theresa ASHTON, Peter GOUGH, Scott BERGER, Lionel TAN, Iain GILLESPIE and David GARDINER.

  • Correction notice This paper has been amended since it was published Online First. Owing to a scripting error, some of the publisher names in the references were replaced with 'BMJ Publishing Group'. This only affected the full text version, not the PDF. We have since corrected these errors and the correct publishers have been inserted into the references.

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