Contribution of Dendritic Cell Responses to Sepsis-Induced Immunosuppression and to Susceptibility to Secondary Pneumonia

Dendritic cells (DCs) are bone marrow derived cells which continuously seed in peripheral tissue. During infection, DCs play an essential interface between innate and adaptive immunity. Pneumonia is a lung inflammation triggered by pathogens and is characterized by excessive release of inflammatory cytokines that activate innate and acquired immunity. Pneumonia induces a rapid and protracted state of susceptibility to secondary infection, a state so-called sepsis-induced immunosuppression. In this review, we focus on the role of DCs in the development of this state of immunosuppression. Early during inflammation, activated DCs are characterized by decreased capacity of antigen (cross)- presentation of newly encountered antigens and decreased production of immunogenic cytokines, and sepsis-induced immunosuppression is mainly explained by a depletion of immature DCs which had all become mature. At a later stage, newly formed respiratory immature DCs are locally programmed by an immunological scare left-over by inflammation to induce tolerance. Tolerogenic Blimp1+ DCs produce suppressive cytokines such as tumor growth factor-B and participate to the maintenance of a local tolerogenic environment notably characterized by accumulation of Treg cells. In mice, the restoration of the immunogenic functions of DCs restores the mucosal immune response to pathogens. In humans, the modulation of inflammation by glucocorticoid during sepsis or trauma preserves DC immunogenic functions and is associated with resistance to secondary pneumonia. Finally, we propose that the alterations of DCs during and after inflammation can be used as biomarkers of susceptibility to secondary pneumonia and are promising therapeutic targets to enhance outcomes of patients with secondary pneumonia

Traumatic brain injury and pulmonary infection : human biomarkers and immunostimulatory effect of MSP (sulfated polysaccharide) in a mouse model

Le traumatisme crânien (TC) induit un état d’immunodépression par altération des principales fonctions des cellules de l’immunité innée. Cet état d’immunodépression favorise la survenue d’infections nosocomiales en réanimation, dont les pneumonies acquises sous ventilation mécanique (PAVM) sont les plus fréquentes. La survenue de PAVM en réanimation est de mauvais pronostic, il existe donc un enjeu majeur à les prédire ainsi qu’à les traiter précocement. Nous avons cherché à mettre en place un biomarqueur précoce de survenue de PAVM chez les patients TC. Nous avons montré qu’un ratio Cortisoltotal/CRP>3 dans le sang, reflet du déséquilibre entre les mécanismes pro- et anti-inflammatoires post traumatiques, était un facteur de risque de survenue de PAVM et pourrait permettre de discriminer les patients pouvant bénéficier d’une corticothérapie préventive. Par la suite nous avons évalué l’effet immunostimulant du MSP, un polysaccharide sulfaté issu d’Ulva Armoricana. Nous avons montré que le MSP avait des effets in vivo en limitant la dissémination bactérienne systémique lors d’une pneumonie post-traumatique à SAMS chez la souris. Ces effets sont médiés par les macrophages alvéolaires qui induisent une augmentation du nombre de cellules NK pulmonaires produisant de l’INF- γ. Les monocytes/macrophages pulmonaires sont activés en retour par les cellules NK et probablement par les polynucléaires neutrophiles. La poursuite de l’étude des mécanismes d’action du MSP pourrait en faire un candidat-traitement afin de traiter l’immunodépression induite par le TC.Traumatic brain injury (TBI) induces a state of immunosuppression by alteration of the main functions of the cells of innate immunity. This state of immunosuppression favors the occurrence of nosocomial infections in the ICU, of which ventilator-associated pneumonia (VAP) is the most frequent. The occurrence of VAP in the ICU has a poor prognosis, so there is a major challenge to predict them and to treat them early. We sought to establish an early biomarker of VAP occurrence in TBI patients. We have shown that a Cortisoltotal/CRP ratio >3, reflecting the imbalance between pro- and anti-inflammatory post-traumatic mechanisms, was a risk factor for the occurrence of VAP and could allow to discriminate the patients who could benefit from corticosteroid therapy in prevention. We then evaluated the immunostimulant effect of MSP, a sulfated polysaccharide from Ulva Armoricana. We showed that MSP had in vivo effects by limiting systemic bacterial dissemination during post-traumatic SAMS pneumonia in mice. These effects are mediated by alveolar macrophages that induce an increase in the number of INF- γ- producing lung NK cells. Lung monocytes/macrophages are activated in turn by NK cells and probably by neutrophils. Further study of the mechanisms of action of MSP may make it a candidate therapy for treating TBI-induced immunosuppression

Steroids in severe community-acquired pneumonia: dangerous, worthless, or miracle cure? The roller coaster of clinical trials

International audienceNo abstract availabl

Immune modulation after traumatic brain injury

Traumatic brain injury (TBI) induces instant activation of innate immunity in brain tissue, followed by a systematization of the inflammatory response. The subsequent response, evolved to limit an overwhelming systemic inflammatory response and to induce healing, involves the autonomic nervous system, hormonal systems, and the regulation of immune cells. This physiological response induces an immunosuppression and tolerance state that promotes to the occurrence of secondary infections. This review describes the immunological consequences of TBI and highlights potential novel therapeutic approaches using immune modulation to restore homeostasis between the nervous system and innate immunity

Mechanical ventilation in patients with acute brain injury: a systematic review with meta-analysis

Abstract Objective To describe the potential effects of ventilatory strategies on the outcome of acute brain-injured patients undergoing invasive mechanical ventilation. Design Systematic review with an individual data meta-analysis. Setting Observational and interventional (before/after) studies published up to August 22nd, 2022, were considered for inclusion. We investigated the effects of low tidal volume Vt   = 8 ml/Kg of IBW, positive end-expiratory pressure (PEEP)   = 5 cmH2O and protective ventilation (association of both) on relevant clinical outcomes. Population Patients with acute brain injury (trauma or haemorrhagic stroke) with invasive mechanical ventilation for ≥ 24 h. Main outcome measures The primary outcome was mortality at 28 days or in-hospital mortality. Secondary outcomes were the incidence of acute respiratory distress syndrome (ARDS), the duration of mechanical ventilation and the partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio. Results The meta-analysis included eight studies with a total of 5639 patients. There was no difference in mortality between low and high tidal volume [Odds Ratio, OR 0.88 (95%Confidence Interval, CI 0.74 to 1.05), p = 0.16, I 2 = 20%], low and moderate to high PEEP [OR 0.8 (95% CI 0.59 to 1.07), p = 0.13, I 2 = 80%] or protective and non-protective ventilation [OR 1.03 (95% CI 0.93 to 1.15), p = 0.6, I 2 = 11]. Low tidal volume [OR 0.74 (95% CI 0.45 to 1.21, p = 0.23, I 2 = 88%], moderate PEEP [OR 0.98 (95% CI 0.76 to 1.26), p = 0.9, I 2 = 21%] or protective ventilation [OR 1.22 (95% CI 0.94 to 1.58), p = 0.13, I 2 = 22%] did not affect the incidence of acute respiratory distress syndrome. Protective ventilation improved the PaO2/FiO2 ratio in the first five days of mechanical ventilation (p < 0.01). Conclusions Low tidal volume, moderate to high PEEP, or protective ventilation were not associated with mortality and lower incidence of ARDS in patients with acute brain injury undergoing invasive mechanical ventilation. However, protective ventilation improved oxygenation and could be safely considered in this setting. The exact role of ventilatory management on the outcome of patients with a severe brain injury needs to be more accurately delineated

Cortisol total/CRP ratio for the prediction of hospital-acquired pneumonia and initiation of corticosteroid therapy in traumatic brain- injured patients

International audienceBACKGROUND:To propose a combination of blood biomarkers for the prediction of hospital-acquired pneumonia (HAP) and for the selection of traumatic brain-injured (TBI) patients eligible for corticosteroid therapy for the prevention of HAP.METHODS:This was a sub-study of the CORTI-TC trial, a multicenter, randomized, double-blind, controlled trial evaluating the risk of HAP at day 28 in 336 TBI patients treated or not with corticosteroid therapy. Patients were between 15 and 65 years with severe traumatic brain injury (Glasgow coma scale score ≤ 8 and trauma-associated lesion on brain CT scan) and were enrolled within 24 h of trauma. The blood levels of CRP and cortisoltotal&free, as a surrogate marker of the pro/anti-inflammatory response balance, were measured in samples collected before the treatment initiation. Endpoint was HAP on day 28.RESULTS:Of the 179 patients with available samples, 89 (49.7%) developed an HAP. Cortisoltotal&free and CRP blood levels upon ICU admission were not significantly different between patients with or without HAP. The cortisoltotal/CRP ratio upon admission was 2.30 [1.25-3.91] in patients without HAP and 3.36 [1.74-5.09] in patients with HAP (p = 0.021). In multivariate analysis, a cortisoltotal/CRP ratio > 3, selected upon the best Youden index on the ROC curve, was independently associated with HAP (OR 2.50, CI95% [1.34-4.64] p = 0.004). The HR for HAP with corticosteroid treatment was 0.59 (CI95% [0.34-1.00], p = 0.005) in patients with a cortisoltotal/CRP ratio > 3, and 0.89 (CI95% [0.49-1.64], p = 0.85) in patients with a ratio  3 upon admission may predict the development of HAP in severe TBI. Among these patients, corticosteroids reduce the occurrence HAP. We suggest that this ratio may select the patients who may benefit from corticosteroid therapy for the prevention of HAP

Association of Dynamics of Anellovirus Loads With Hospital-Acquired Pneumonia in Patients With Brain Injury During the Intensive Care Unit Stay

International audienceBackground : Critical illness induces immune disorders associated with an increased risk of hospital-acquired pneumonia (HAP) and acute respiratory distress syndrome (ARDS). Torque teno virus (TTV), from the Anelloviridae family, is proposed as a biomarker to measure the level of immunosuppression. Our objective was to describe the kinetics of TTV DNA loads and their association with critical illness–related complications. Methods : We performed a longitudinal study in 115 patients with brain injury from a prospective cohort, collected endotracheal and blood samples at 3 successive time points after admission in the intensive care unit (ICU) (T1, 0–4 days post ICU admission; T2, 5–10; T3, 11–18), and measured viral DNA loads using the TTV R-GENE kit (BioMérieux) and a pan-Anelloviridae in-house quantitative real-time polymerase chain reaction. Results : TTV DNA was detected in the blood of 69%, 71%, and 64% of patients with brain injury at T1, T2, and T3, respectively. Time-associated variations of TTV and anellovirus DNA loads were observed. Using a linear mixed-effects model, we found that HAP and ARDS were associated with lower blood anellovirus DNA loads. Conclusions : Our results show that HAP or ARDS in patients who are critically ill is associated with changes in anellovirus DNA loads and should be evaluated further as a biomarker of immune disorders leading to these complications

Clinical evaluation of the BioFire Respiratory Pathogen Panel for the guidance of empirical antimicrobial therapy in critically ill patients with hospital-acquired pneumonia: A multicenter, quality improvement project

International audienceBackground: We aimed to determine whether implementing antimicrobial stewardship based on multiplex bacterial PCR examination of respiratory fluid can enhance outcomes of critically ill patients with hospital-acquired pneumonia (HAP).Methods: We conducted a quality improvement study in two hospitals in France. Adult patients requiring invasive mechanical ventilation with a diagnosis of HAP were included. In the pre-intervention period (August 2019 to April 2020), antimicrobial therapy followed European guidelines. In the «intervention» phase (June 2020 to October 2021), treatment followed a multiplex PCR-guided protocol. The primary endpoint was a composite endpoint made of mortality on day 28, clinical cure between days 7 and 10, and duration of invasive mechanical ventilation on day 28. The primary outcome was analyzed with a DOOR strategy.Results: A total of 443 patients were included in 3 ICUs from 2 hospitals (220 pre-intervention; 223 intervention). No difference in the ranking of the primary composite outcome was found (DOOR: 50.3%; 95%CI, 49.9%-50.8%). The number of invasive mechanical ventilation-free days at day 28 was 10.0 [0.0; 19.0] in the baseline period and 9.0 [0.0; 20.0] days during the intervention period (p = 0.95). The time-to-efficient antimicrobial treatment was 0.43 ± 1.29 days before versus 0.55 ± 1.13 days after the intervention (p = 0.56).Conclusion: Implementation of Rapid Multiplex PCR to guide empirical antimicrobial therapy for critically ill patients with HAP was not associated with better outcomes. However, adherence to stewardship was low, and the study may have had limited power to detect a clinically important difference

Comment choisir la question de son essai clinique ? Les conseils du Réseau Recherche de la SFAR

National audienceEvery research project begins with a question. As its nature will influence all subsequent steps, including the methodology, the question should be clear and well-defined from the outset. This is therefore a major step in carrying out a research project, which requires expertise and work. It is indeed clinical experience and previous research that lead to a good question. For it to be relevant, it is necessary to master existing literature on the subject, to be open to new ideas, new techniques, new methodologies, imagination and creativity, as well as to pay attention to mentorship and expert advice. This question must meet criteria for feasibility, interest, novelty, ethics, and relevance (the FINER criteria). It should be formulated in a structured way to ensure maximum clarity, for example following the PICOT framework. Therefore, defining the main question of your clinical trial is not just a semantic exercise.Tous les travaux de recherche commencent par une question. Cette question doit être claire et bien définie dès le départ, car sa nature influencera toutes les étapes suivantes, notamment la méthodologie. Il s’agit donc d’une étape majeure dans la réalisation d’un projet de recherche, qui demande de l’expertise et du travail. Une bonne question émerge en effet de l’expérience clinique et des recherches réalisées antérieurement. Elle nécessite pour être pertinente une maîtrise de la littérature existante sur le sujet, une ouverture à de nouvelles idées, de nouvelles techniques, de nouvelles méthodologies, de l’imagination et de la créativité, mais aussi une grande attention aux conseils de ses mentors et des experts établis. Cette question doit répondre à des critères de faisabilité, d’intérêt, de nouveauté, d’éthique et de pertinence (les critères FINER). Elle doit être formulée de manière structurée pour assurer un maximum de clarté, en suivant par exemple le cadre PICOT (pour population, intervention étudiée, contrôle, outcome et timeframe). Choisir et formuler la question principale de son essai clinique n’est donc pas un exercice purement sémantique