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Objectives: There is a crucial unmet need for biomarker-guided diagnostic and prognostic enrichment in clinical trials evaluating immune modulating therapies in critically ill patients. Low monocyte expression of human leukocyte antigen-DR (mHLA-DR), considered as a reference surrogate to identify immunosuppressed patients, has been proposed for patient stratification in immunostimulation approaches. However, its widespread use in clinic has been somewhat hampered by technical constraints inherent to flow cytometry technology. The objective of the present study was to evaluate the ability of a prototype multiplex polymerase chain reaction tool (immune profiling panel [IPP]) to identify immunosuppressed ICU patients characterized by a low mHLA-DR expression., Design: Retrospective observational cohort study., Setting: Adult ICU in a University Hospital, Lyon, France., Patients: Critically ill patients with various etiologies enrolled in the REAnimation Low Immune Status Marker study (NCT02638779)., Interventions: None., Measurements and Main Results: mHLA-DR and IPP data were obtained from 1,731 blood samples collected from critically ill patients with various etiologies and healthy volunteers. A partial least square regression model combining the expression levels of IPP markers was trained and used for the identification of samples from patients presenting with evidence of immunosuppression, defined here as mHLADR less than 8,000 antibodies bound per cell (AB/C). The IPP gene set had an area under the receiver operating characteristic curve (AUC) of 0.86 (95% CI 0.83-0.89) for the identification of immunosuppressed patients. In addition, when applied to the 123 patients still in the ICU at days 5-7 after admission, IPP similarly enriched the number of patients with ICU-acquired infections in the immunosuppressed group (26%), in comparison with low mHLA-DR (22%)., Conclusions: This study reports on the potential of the IPP gene set to identify ICU patients presenting with mHLA-DR less than 8,000 AB/C. Upon further optimization and validation, this molecular tool may help in the stratification of patients that could benefit from immunostimulation in the context of personalized medicine., Competing Interests: Drs. Peronnet, Blein, Cerrato, Fleurie, Llitjos, Textoris, and Brengel-Pesce are employees of bioMérieux. Drs. Peronnet, Cerrato, Fleurie, Llitjos, Kreitmann, Terraz, Conti, Rimmelé, Lukaszewicz, Brengel-Pesce, and Monneret work in a joint research unit, cofunded by the Hospices Civils de Lyon and bioMérieux. Drs. Peronnet, Venet, and Monneret are coinventors in patent applications covering the following markers: CX3CR1 and S100A9 . Drs. Peronnet, Venet, Rimmelé, Textoris, and Monneret are coinventors in patent applications covering the following markers: CX3CR1, IL1R2, C3AR1, CD177, CIITA, and TAP2 . BioFire—a bioMérieux company—holds patents on the technology. This does not alter the authors’ adherence to all the policies on sharing data and materials. Drs. Peronnet’s, Blein’s, Cerrato’s, Fleurie’s, Llitjos’, Terraz’s, and Lukaszewicz’s institutions received funding from the Agence Nationale de la Recherche; they received support for article research from bioMérieux, Sanofi, and GlaxoSmithKline. Drs. Peronnet, Blein, Cerrato, Fleurie, Kreitmann, Terraz, Textoris, and Brengel-Pesce received funding from bioMérieux. Drs. Peronnet, Cerrato, and Lukaszewicz disclosed that they are coinventors on patent applications. Dr. Peronnet disclosed that her partner is employed by bioMérieux. The remaining authors have disclosed that they do not have any potential conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Immune responses affiliated with COVID-19 severity have been characterized and associated with deleterious outcomes. These approaches were mainly based on research tools not usable in routine clinical practice at the bedside. We observed that a multiplex transcriptomic panel prototype termed Immune Profiling Panel (IPP) could capture the dysregulation of immune responses of ICU COVID-19 patients at admission. Nine transcripts were associated with mortality in univariate analysis and this 9-mRNA signature remained significantly associated with mortality in a multivariate analysis that included age, SOFA and Charlson scores. Using a machine learning model with these 9 mRNA, we could predict the 28-day survival status with an Area Under the Receiver Operating Curve (AUROC) of 0.764. Interestingly, adding patients' age to the model resulted in increased performance to predict the 28-day mortality (AUROC reaching 0.839). This prototype IPP demonstrated that such a tool, upon clinical/analytical validation and clearance by regulatory agencies could be used in clinical routine settings to quickly identify patients with higher risk of death requiring thus early aggressive intensive care., Competing Interests: CT, VC, EC, KI, KB-P, EP, MBo, LK, SB, and J-FL are bioMérieux’s employees. EP, GM, and FV are co-inventors in patent applications covering the following markers: CX3CR1, CD127, IL10 and S100A9. bioFire – a bioMérieux company - holds patents on the technology. This does not alter the authors’ adherence to all the policies on sharing data and materials. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tardiveau, Monneret, Lukaszewicz, Cheynet, Cerrato, Imhoff, Peronnet, Bodinier, Kreitmann, Blein, Llitjos, Conti, Gossez, Buisson, Yonis, Cour, Argaud, Delignette, Wallet, Dailler, Monard, Brengel-Pesce, Venet and the RICO study group.)

Background: Since the onset of the pandemic, only few studies focused on longitudinal immune monitoring in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) whereas their hospital stay may last for several weeks. Consequently, the question of whether immune parameters may drive or associate with delayed unfavorable outcome in these critically ill patients remains unsolved., Methods: We present a dynamic description of immuno-inflammatory derangements in 64 critically ill COVID-19 patients including plasma IFNα2 levels and IFN-stimulated genes (ISG) score measurements., Results: ARDS patients presented with persistently decreased lymphocyte count and mHLA-DR expression and increased cytokine levels. Type-I IFN response was initially induced with elevation of IFNα2 levels and ISG score followed by a rapid decrease over time. Survivors and non-survivors presented with apparent common immune responses over the first 3 weeks after ICU admission mixing gradual return to normal values of cellular markers and progressive decrease of cytokines levels including IFNα2. Only plasma TNF-α presented with a slow increase over time and higher values in non-survivors compared with survivors. This paralleled with an extremely high occurrence of secondary infections in COVID-19 patients with ARDS., Conclusions: Occurrence of ARDS in response to SARS-CoV2 infection appears to be strongly associated with the intensity of immune alterations upon ICU admission of COVID-19 patients. In these critically ill patients, immune profile presents with similarities with the delayed step of immunosuppression described in bacterial sepsis.

Background: Critical illness such as sepsis is a life-threatening syndrome defined as a dysregulated host response to infection and is characterized by patients exhibiting impaired immune response. In the field of diagnosis, a gap still remains in identifying the immune profile of critically ill patients in the intensive care unit (ICU)., Methods: A new multiplex immune profiling panel (IPP) prototype was assessed for its ability to semiquantify messenger RNA immune-related markers directly from blood, using the FilmArray System, in less than an hour. Samples from 30 healthy volunteers were used for the technical assessment of the IPP tool. Then the tool was clinically assessed using samples from 10 healthy volunteers and 20 septic shock patients stratified using human leukocyte antigen-DR expression on monocytes (mHLA-DR)., Results: The IPP prototype consists of 16 biomarkers that target the immune response. The majority of the assays had a linear expression with different RNA inputs and a coefficient of determination (R2) > 0.8. Results from the IPP pouch were comparable to standard quantitative polymerase chain reaction and the assays were within the limits of agreement in Bland-Altman analysis. Quantification cycle values of the target genes were normalized against reference genes and confirmed to account for the different cell count and technical variability. The clinical assessment of the IPP markers demonstrated various gene modulations that could distinctly differentiate 3 profiles: healthy volunteers, intermediate mHLA-DR septic shock patients, and low mHLA-DR septic shock patients., Conclusions: The use of IPP showed great potential for the development of a fully automated, rapid, and easy-to-use immune profiling tool. The IPP tool may be used in the future to stratify critically ill patients in the ICU according to their immune status. Such stratification will enable personalized management of patients and guide treatments to avoid secondary infections and lower mortality., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)