Low Interleukin-7 Receptor Messenger RNA Expression Is Independently Associated With Day 28 Mortality in Septic Shock Patients

Objectives: Septic shock is the primary cause of death in ICUs. A better comprehension of its pathophysiology, in particular, the immune alteration mechanisms, opened new therapeutic perspectives such as the recombinant interleukin-7. The use of biomarkers could improve the identification of eligible patients for this therapy. The soluble form of the interleukin-7 appears as a promising candidate in this regard since an association between its high plasmatic level and mortality in critically ill patients has been demonstrated. Because there are no data available on the transcriptional regulation of the interleukin-7 receptor in such patients, this study aimed to explore the expression level of different interleukin-7 receptor transcripts after septic shock and evaluate their association with mortality. Design: Retrospective discovery cohort (30 patients) and validation cohort (177 patients). Setting: Two French ICUs (discovery study) and six French ICUs (validation study). Patients: Adult septic shock patients. Interventions: None. Measurements and Main Results: The quantification of several interleukin-7 receptor transcripts using specific reverse transcription quantitative polymerase chain reaction designs allowed for global evaluation of interleukin-7 receptor gene expression in whole blood. In the discovery cohort, all interleukin-7 receptor transcripts studied were expressed at lower levels in septic shock patients than in healthy volunteers. Interleukin-7 receptor gene expression at day 3 after septic shock diagnosis was associated with day 28 mortality. Patients at a lower risk of death showed higher expression levels. These results were confirmed in the independent validation cohort. Interestingly, using a threshold obtained on the discovery cohort, we observed in the validation cohort a high negative predictive value for day 28 mortality for the transcript encoding the membrane form of interleukin-7 receptor (0.86; 95% CI, 0.79–0.93). Conclusions: Interleukin-7 receptor transcripts appear as biomarkers of impaired adaptive immune response in septic shock patients and as a promising tool for patient stratification in clinical trials evaluating immunoadjuvant therapies. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. The experimental work was performed at the Hospices Civils de Lyon – bioMérieux - Université Claude Bernard Lyon 1, Joint Research Unit, Lyon, France. Supported, in part, by grants from bioMérieux and Hospices Civils de Lyon, and was part of Advanced Diagnostic for New Therapeutic Approaches, a program dedicated to personalized medicine, coordinated by Institut Mérieux and supported by French public agency BPI France. Dr. Delwarde and Peronnet contributed equally to this work. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). All authors work in a Joint Research Unit cofunded by the Hospices Civils de Lyon, bioMérieux, and Université Claude Bernard Lyon 1. Drs. Delwarde and Venet, Mr. Meunier, and Drs. Lepape, Rimmelé, and Monneret are employees of Hospices Civils de Lyon. Dr. Peronnet, Ms. Cerrato, and Drs. Mouillaux, Pachot, and Textoris are employees of bioMérieux. This study was part of Advanced Diagnostic for New Therapeutic Approaches (ADNA), a program dedicated to personalized medicine, coordinated by Institut Mérieux, and supported by the French public agency Banque Publique d'Investissement (BPI) France. Drs. Delwarde, Peronnet, and Venet, Ms. Cerrato, and Drs. Lepape, Monneret, and Textoris are coinventors on three patent families covering interleukin-7 receptor biomarkers. This does not alter the authors' adherence to all Critical Care Medicine policies on sharing data and materials. Dr. Peronnet disclosed that she is a coinventor on the pending patent WO2017093672, and that this study was part of ADNA. Dr. Venet's institution received funding from bioMerieux (he works in a joint research unit between bioMerieux and the Hospices Civils de Lyon, but does not receive any financial retribution from bioMerieux based on this collaboration). Dr. Lepape disclosed that he is a coinventors of patents WO2013140103 and WO2015040328. Drs. Pachot and Textoris' institution received funding from ADNA. Dr. Pachot received funding from bioMérieux as an employee of bioMérieux; he received support for article research from ADNA, and he disclosed government work. Dr. Textoris disclosed that he is an employee of bioMeriaux and Hospices Civils de Lyon, and he is listed as an inventor of patent WO2017093672 (pending), for which he does not own rights. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: estelle.peronnet@biomerieux.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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