Sainte-Foy-lès-Lyon, France
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Septic syndromes (systemic inflammatory response associated with infection) remain a major although largely under-recognized health care problem and represent the first cause of mortality in intensive care units. Regarding immune response, it is now agreed that sepsis induces an anti-inflammatory process, acting as a negative feedback. This inhibitory mechanism becomes deleterious as nearly all immune functions are rapidly compromised. The magnitude and persistence over time of this immunosuppression is correlated with nosocomial infections and mortality. Decreased HLA-DR expression on monocytes/increased percentage of regulatory T cells are biomarkers identifying patients at risk who could benefit from immunotherapy. This review attempts to integrate these new facts into an up-to-date account of sepsis pathophysiology. © 2011 Elsevier Masson SAS.


Gouel-Cheron A.,Service de reanimation | Gouel-Cheron A.,University Claude Bernard Lyon 1 | Allaouchiche B.,Service de reanimation | Allaouchiche B.,University Claude Bernard Lyon 1 | And 5 more authors.
PLoS ONE | Year: 2012

Objective: Major trauma is characterized by a pro-inflammatory response, followed by an immunosuppression. Recently, in trauma patients, the lack of recovery of monocyte Human Leukocyte Antigen DR (mHLA-DR, a biomarker of ICU-acquired immunosuppression) between days 1-2 and days 3-4 has been demonstrated to be independently associated with sepsis development. The main objective of this study was to determine whether early measurements of IL-6 (interleukin-6) and IL-10 plasma concentrations (as markers of initial severity) could improve, in association with mHLA-DR recovery, the prediction of sepsis occurrence in severe trauma patients. Design: Prospective observational study over 24 months in a Trauma ICU at university hospital. Patients: Trauma patients with an ISS over 25 and age over 18 were included. Measurements and Main Results: mHLA-DR was assessed by flow cytometry, IL-6 and IL-10 concentrations by ELISA. 100 consecutive severely injured patients were monitored (mean ISS 37±10). 37 patients developed sepsis. IL-6 concentrations and slope of mHLA-DR expression between days 1-2 and days 3-4 were significantly different between septic and non-septic patients. IL-10 was not detectable in most patients. After adjustment for usual clinical confounders, when assessed as a pair, multivariate logistic regression analysis revealed that a slope of mHLA-DR expression (days 3-4/days 1-2)≤1.1 and a IL-6 concentration ≥ 67.1 pg/ml remained highly associated with the development of sepsis (adjusted OR 18.4, 95% CI 4.9; 69.4, p =. 00002). Conclusions: After multivariate regression logistic analysis, when assessed as a pair, a high IL-6 concentration and a persistent mHLA-DR decreased expression were found to be in relation with the development of sepsis with the best predictive value. This study underlines the usefulness of daily monitoring of immune function to identify trauma patients at a high risk of infection. © 2012 Gouel-Chéron et al.


PubMed | bioMerieux, Laboratoire dImmunologie Cellulaire, Nantes University Hospital Center and Hospices Civils de Lyon HCL
Type: Journal Article | Journal: Journal of proteome research | Year: 2016

Protein biomarker discovery has inherent challenges linked to the validation of the analytical method used or to the impact of biological matrices. Matrix influences must be mastered to guarantee the reliability of the identified biomarkers to monitor human diseases. In this study, multiplexed mass spectrometry assays in selected reaction monitoring (SRM) mode have been developed to measure 107 inflammatory putative proteins in matched serum and plasma from 36 ICU trauma patients. The assays validation directly in clinical samples was shown to be valuable to manage intersample variability. Using the validation process developed here, assays were validated for 58 biomarkers in serum, 57 in plasma, and 55 in both matrices. Correlation analyses demonstrated that the quantitation using SRM of most of the validated biomarkers (45/55) was impacted by the biological matrix and that the matrix impact was biomarker-dependent. Among the 45 impacted biomarkers, 23 were nevertheless correlated between serum and plasma, whereas the quantitation was shown to be equivalent in both for the 10 last proteins. Matrix selection using SRM is therefore suggested to be suitable prior to clinical evaluation of biomarkers in a large cohort of patients.


Rodrigues V.,University of Paris Descartes | Rodrigues V.,University of Porto | Laforge M.,University of Paris Descartes | Campillo-Gimenez L.,University of Paris Descartes | And 10 more authors.
PLoS Pathogens | Year: 2014

Leishmania infantum causes a chronic infectious disease named visceral leishmaniasis (VL). We employed a non-human primate model to monitor immune parameters over time and gain new insights into the disease. Rhesus macaques were infected with L. infantum and the T helper and B cell immunological profiles characterized during acute and chronic phases of infection. Parasite detection in visceral compartments during the acute phase was associated with differentiation of effector memory CD4 T cells and increased levels of Th1 transcripts. At the chronic phase, parasites colonized novel lymphoid niches concomitant with increased expression of IL10. Despite the occurrence of hypergammaglobulinemia, the production of parasite-specific IgG was poor, being confined to the acute phase and positively correlated with the frequency of an activated memory splenic B cell population. We noticed the expansion of a splenic CD4 T cell population expressing CXCR5 and Bcl-6 during acute infection that was associated with the differentiation of the activated memory B cell population. Moreover, the number of splenic germinal centers peaked at one month after infection, hence paralleling the production of specific IgG. However, at chronic infection these populations contracted impacting the production of parasite-specific IgG. Our study provides new insights into the immune events taking place in a physiologically relevant host and a mechanistic basis for the inefficient humoral response during VL. © 2014 Rodrigues et al.


Cheron A.,Hospices Civils de Lyon | Floccard B.,Hospices Civils de Lyon | Allaouchiche B.,Hospices Civils de Lyon | Guignant C.,Laboratoire dimmunologie cellulaire | And 9 more authors.
Critical Care | Year: 2010

Introduction: Major trauma is characterized by an overwhelming pro-inflammatory response and an accompanying anti-inflammatory response that lead to a state of immunosuppression, as observed after septic shock. Diminished monocyte Human Leukocyte Antigen DR (mHLA-DR) is a reliable marker of monocyte dysfunction and immunosuppression. The main objective of this study was to determine the relation between mHLA-DR expression in severe trauma patients and the development of sepsis.Methods: We conducted a prospective observational study over 23 months in a trauma intensive care unit at a university hospital. Patients with an Injury Severity Score (ISS) over 25 and age over 18 were included. mHLA-DR was assessed by flow cytometry protocol according to standardized protocol. Mann-Whitney U-test for continuous non-parametric variables, independent paired t test for continuous parametric variables and chi-square test for categorical data were used.Results: mHLA-DR was measured three times a week during the first 14 days. One hundred five consecutive severely injured patients were monitored (ISS 38 ± 17, SAPS II 37 ± 16). Thirty-seven patients (35%) developed sepsis over the 14 days post-trauma. At days 1-2, mHLA-DR was diminished in the whole patient population, with no difference with the development of sepsis. At days 3-4, a highly significant difference appeared between septic and non-septic patients. Non- septic patients showed an increase in mHLA-DR levels, whereas septic patients did not (13,723 ± 7,766 versus 9,271 ± 6,029 antibodies per cell, p = .004). Most importantly, multivariate logistic regression analysis, after adjustment for usual clinical confounders (adjusted OR 5.41, 95% CI 1.42-20.52), revealed that a slope of mHLA-DR expression between days1-2 and days 3-4 below 1.2 remained associated with the development of sepsis.Conclusions: Major trauma induced an immunosuppression, characterized by a decrease in mHLA-DR expression. Importantly, after multivariate regression logistic analysis, persistent decreased expression was assessed to be in relation with the development of sepsis. This is the first study in trauma patients showing a link between the lack of immune recovery and the development of sepsis on the basis of the standardized protocol. Monitoring immune function by mHLA-DR measurement could be useful to identify trauma patients at a high risk of infection. © 2010 Cheron et al.; licensee BioMed Central Ltd.


Pene F.,Service de Reanimation Medicale | Pene F.,University of Paris Descartes | Ait-Oufella H.,Service de Reanimation Medicale | Ait-Oufella H.,University Pierre and Marie Curie | And 9 more authors.
Annals of Intensive Care | Year: 2015

Experimental research has always been the cornerstone of pathophysiological and therapeutic advances in critical care medicine, where clinical observations and basic research mutually fed each other in a so-called translational approach. The objective of this review is to address the different aspects of translational research in the field of critical care medicine. We herein highlighted some demonstrative examples including the animal-to-human approach to study host-pathogen interactions, the human-to-animal approach for sepsis-induced immunosuppression, the still restrictive human approach to study critical illness-related neuromyopathy, and the technological developments to assess the microcirculatory changes in critically ill patients. These examples not only emphasize how translational research resulted in major improvements in the comprehension of the pathophysiology of severe clinical conditions and offered promising perspectives in critical care medicine but also point out the obstacles to translate such achievements into clinical practice. © 2015, Pène et al.; licensee Springer.


Blaise B.J.,Hospices Civils de Lyon | Gouel-Cheron A.,Hospices Civils de Lyon | Floccard B.,Hospices Civils de Lyon | Monneret G.,Laboratoire dImmunologie Cellulaire | Allaouchiche B.,Hospices Civils de Lyon
Analytical Chemistry | Year: 2013

Sepsis is one of the leading causes of morbidity and mortality in patients admitted in intensive care units (ICU) for trauma. The identification of biochemical mechanisms and prediction of patients at risk of early sepsis remain unsolved. Metabolic phenotyping allows the recovery of coordinated metabolic concentration variations. There are no predictive metabolic phenotyping studies based on noninvasive human samples to identify the later development of sepsis in traumatized patients. The aim of this study was to investigate whether the metabolic phenotype could help in the discrimination of patients according to the later development of sepsis. Plasma samples were taken from severely injured patients in the hours following their admission in the ICU. Nuclear magnetic resonance (NMR) based metabolic phenotyping was performed on this prospective cohort. Statistical analyses were run on NMR spectra to discriminate patients according to the later development of sepsis. Twenty-two patients were included. One was excluded because of aberrant metabolic phenotype. Orthogonal partial least-squares analysis allowed the recovery of a predictive metabolic phenotype identifying patients with a later development of sepsis (1 + 4 component model, R2 = 0.855, Q2 = 0.384). A cross-validated receiver operator characteristic curve showed a remarkable prediction capacity (AUC = 0.778). Eight metabolic hotspots were identified. NMR-based metabolic phenotyping allows the prediction of patients at high risk of early sepsis after ICU admission for trauma. A larger cohort is necessary to validate and complete this study, understand biochemical mechanisms promoting sepsis development, and identify patients at risk. © 2013 American Chemical Society.


PubMed | laboratoire dimmunologie cellulaire and University of Lyon
Type: Journal Article | Journal: Medecine sciences : M/S | Year: 2014

Sepsis-induced immunosuppression is a new paradigm in sepsis pathophysiology. This up-to-date review integrates recent facts in the field. It focuses on immune dysfunctions described so far in septic patients (especially regarding T lymphocytes), on the mechanisms sustaining this immune failure, on the monitoring of the pro-/anti-inflammatory balance rapidly changing over time and on new promising therapeutic avenues emerging from those recent findings. Of them, the case of interleukin-7 is more specifically envisaged.


PubMed | Laboratoire dImmunologie Cellulaire
Type: Journal Article | Journal: Pathologie-biologie | Year: 2011

Septic syndromes (systemic inflammatory response associated with infection) remain a major although largely under-recognized health care problem and represent the first cause of mortality in intensive care units. Regarding immune response, it is now agreed that sepsis induces an anti-inflammatory process, acting as a negative feedback. This inhibitory mechanism becomes deleterious as nearly all immune functions are rapidly compromised. The magnitude and persistence over time of this immunosuppression is correlated with nosocomial infections and mortality. Decreased HLA-DR expression on monocytes/increased percentage of regulatory T cells are biomarkers identifying patients at risk who could benefit from immunotherapy. This review attempts to integrate these new facts into an up-to-date account of sepsis pathophysiology.


PubMed | Laboratoire dImmunologie Cellulaire
Type: Clinical Trial | Journal: Journal of immunology (Baltimore, Md. : 1950) | Year: 2012

Septic syndrome is the leading cause of mortality for critically ill patients worldwide. Patients develop lymphocyte dysfunctions associated with increased risk of death and nosocomial infections. In this study, we performed preclinical experiments testing the potential of recombinant human IL-7 (rhIL-7) as a lymphostimulating therapy in sepsis. Circulating IL-7 and soluble IL-7 receptor -chain (soluble CD127) concentrations were measured in plasma, whereas cellular CD127 expression was evaluated on circulating CD4(+) and CD8(+) lymphocytes from septic shock patients and healthy volunteers. Lymphocyte proliferation, IFN- production, STAT5 phosphorylation, and B cell lymphoma 2 induction were measured ex vivo in response to T cell stimulation in the presence or not of rhIL-7. We show that IL-7 pathway (plasmatic IL-7 concentration and cellular and soluble CD127 expressions) is not overtly altered and remains activable in septic patients. Most importantly ex vivo treatment of patients cells with rhIL-7 significantly improves lymphocyte functionality (CD4(+) and CD8(+) lymphocyte proliferations, IFN- production, STAT5 phosphorylation, and B cell lymphoma 2 induction after stimulation). To our knowledge, this constitutes the first report of rhIL-7 ability to restore normal lymphocyte functions in septic patients. These results support the rational for initiating a clinical trial testing rhIL-7 in septic shock.

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