Search

La septième édition du séminaire annuel de la Commission de la Recherche Translationnelle de la SRLF a permis un nouveau moment d’échange unique entre chercheurs et cliniciens autour des dernières données issues de la recherche translationnelle en pharmaco-toxicologie. Les études pharmacologiques et toxicologiques, chez les patients en situation critique, se sont longtemps résumées à des mesures de concentrations plasmatiques. Leur interprétation clinique étaient souvent limitées par les méthodes de dosage elles-mêmes, mais aussi par les différents mécanismes conduisant à une variation individuelle de l’absorption, de la distribution, du métabolisme ou de l’élimination des médicaments ou du toxique. Les évolutions récentes des méthodes de dosage, la meilleure compréhension des mécanismes de diffusion et de clairance des médicaments/toxiques dans les tissus ainsi que l’utilisation de techniques innovantes basées sur l’imagerie pharmacologique et les modélisations pharmacocinétiques, permettent une meilleure interprétation des dosages mais aussi de prédire des échecs ou la survenue d’une toxicité en lien avec un médicament ou un toxique. Les actes du séminaire ont été rédigés par les membres de la Commission de la Recherche Translationnelle de la SRLF et validés par les orateurs.

La deuxième édition de la Journée des Jeunes Chercheurs organisée par la Commission de la Recherche Translationnelle de la SRLF a eu lieu en distanciel Paris le 21 janvier 2021. Cette journée a offert aux jeunes acteurs de la Médecine Intensive Réanimation l’opportunité de présenter leurs travaux de recherche en Master 2 ou Thèse d’université à un collège de chercheurs experts. Pour cette deuxième Journée, Les professeurs Pierre Asfar (Angers), Bruno Levy (Nancy), Steve Lancel (Lille) et Fabio Taccone (Bruxelle) ont accepté de venir apporter aux jeunes candidats leur soutien critique et bienveillant. Les présentations couvrant les domaines des neurosciences à l’immunologie en passant par le métabolisme, l’hémodynamique ou la pharmacologie ont illustré la richesse et la diversité de la recherche translationnelle en réanimation.

The Translational Research Committee of the French Intensive Care Society organized the first Young Investigator’s Day on October 18th 2019. This seminar gave young Intensive Care students the opportunity to present their Master’s or PhD research work to a college of expert researchers. For this first event, Professors Jean-Marc Cavaillon (Paris), Laurent Papazian (Marseille), Peter Radermacher (Ulm) et Hafid Ait-Oufella (Paris) kindly accepted to give young candidates their critical support. The subjects of presentations, covering the fields of neuroscience, immunology, hemodynamics and pharmacology illustrated the richness and diversity of translational research in Intensive Care Medicine.

International audience; Background and purpose: Pseudomonas aeruginosa is a main cause of ventilator-associated pneumonia (VAP) with drug-resistant bacteria. Bacteriophage therapy has experienced resurgence to compensate for the limited development of novel antibiotics. However, phage therapy is limited to a compassionate use so far, resulting from lack of adequate studies in relevant pharmacological models. We used a pig model of pneumonia caused by P. aeruginosa that recapitulates essential features of human disease to study the antimicrobial efficacy of nebulized-phage therapy.Experimental approach: (i) Lysis kinetic assays were performed to evaluate in vitro phage antibacterial efficacy against P. aeruginosa and select relevant combinations of lytic phages. (ii) The efficacy of the phage combinations was investigated in vivo (murine model of P. aeruginosa lung infection). (iii) We determined the optimal conditions to ensure efficient phage delivery by aerosol during mechanical ventilation. (iv) Lung antimicrobial efficacy of inhaled-phage therapy was evaluated in pigs, which were anesthetized, mechanically ventilated and infected with P. aeruginosa.Key results: By selecting an active phage cocktail and optimizing aerosol delivery conditions, we were able to deliver high phage concentrations in the lungs, which resulted in a rapid and marked reduction in P. aeruginosa density (1.5 Log reduction, p

BackgroundGrowing evidence associates organ dysfunction(s) with impaired metabolism in sepsis. Recent research has increased our understanding of the role of substrate utilization and mitochondrial dysfunction in the pathophysiology of sepsis-related organ dysfunction. The purpose of this review is to present this evidence as a coherent whole and to highlight future research directions.Main textSepsis is characterized by systemic and organ-specific changes in metabolism. Alterations of oxygen consumption, increased levels of circulating substrates, impaired glucose and lipid oxidation, and mitochondrial dysfunction are all associated with organ dysfunction and poor outcomes in both animal models and patients. The pathophysiological relevance of bioenergetics and metabolism in the specific examples of sepsis-related immunodeficiency, cerebral dysfunction, cardiomyopathy, acute kidney injury and diaphragmatic failure is also described.ConclusionsRecent understandings in substrate utilization and mitochondrial dysfunction may pave the way for new diagnostic and therapeutic approaches. These findings could help physicians to identify distinct subgroups of sepsis and to develop personalized treatment strategies. Implications for their use as bioenergetic targets to identify metabolism- and mitochondria-targeted treatments need to be evaluated in future studies.

Summary Background Awake prone positioning has been reported to improve oxygenation for patients with COVID-19 in retrospective and observational studies, but whether it improves patient-centred outcomes is unknown. We aimed to evaluate the efficacy of awake prone positioning to prevent intubation or death in patients with severe COVID-19 in a large-scale randomised trial. Methods In this prospective, a priori set up and defined, collaborative meta-trial of six randomised controlled open-label superiority trials, adults who required respiratory support with high-flow nasal cannula for acute hypoxaemic respiratory failure due to COVID-19 were randomly assigned to awake prone positioning or standard care. Hospitals from six countries were involved: Canada, France, Ireland, Mexico, USA, Spain. Patients or their care providers were not masked to allocated treatment. The primary composite outcome was treatment failure, defined as the proportion of patients intubated or dying within 28 days of enrolment. The six trials are registered with ClinicalTrials.gov , NCT04325906 , NCT04347941 , NCT04358939 , NCT04395144 , NCT04391140 , and NCT04477655 . Findings Between April 2, 2020 and Jan 26, 2021, 1126 patients were enrolled and randomly assigned to awake prone positioning (n=567) or standard care (n=559). 1121 patients (excluding five who withdrew from the study) were included in the intention-to-treat analysis. Treatment failure occurred in 223 (40%) of 564 patients assigned to awake prone positioning and in 257 (46%) of 557 patients assigned to standard care (relative risk 0·86 [95% CI 0·75−0·98]). The hazard ratio (HR) for intubation was 0·75 (0·62−0·91), and the HR for mortality was 0·87 (0·68−1·11) with awake prone positioning compared with standard care within 28 days of enrolment. The incidence of prespecified adverse events was low and similar in both groups. Interpretation Awake prone positioning of patients with hypoxaemic respiratory failure due to COVID-19 reduces the incidence of treatment failure and the need for intubation without any signal of harm. These results support routine awake prone positioning of patients with COVID-19 who require support with high-flow nasal cannula. Funding Open AI inc, Rice Foundation, Projet Hospitalier de Recherche Clinique Interregional, Appel d'Offre 2020, Groupement Interregional de Recherche Clinique et d'Innovation Grand Ouest, Association pour la Promotion a Tours de la Reanimation Medicale, Fond de dotation du CHRU de Tours, Fisher & Paykel Healthcare Ltd.

Post-intensive care syndrome is an entity defined in 2010 and covering any sequelae following an extended hospitalization in intensive care unit. It comprises psychological, cognitive and physical disorders (neuromyopathy, respiratory dysfunction, joint stiffness, among others). These sequelae have important consequences on autonomy and quality of life of these patients, as well as on their healthcare consumption and on mortality. Psychological sequelae can also be seen in hospitalized patients' relatives. Screening and management of these disorders is more and more frequent but no method has formally proven effective. The number of patients surviving an intensive care unit hospitalization is increasing, and management of post-intensive care syndrome is a major issue. It seems important that the internist be aware of this syndrome, given his pivotal role in global management of patients and frequent implication into care after the intensive care unit.

Background It is unknown whether the recommended mean arterial pressure (MAP) target of 65 mmHg during initial resuscitation of septic shock is sufficient to maintain cerebral perfusion. Thus, we tested the hypothesis that a higher MAP target in patients with septic shock may improve level of arousal. Methods We performed a post hoc exploratory analysis of the SEPSISPAM trial, which assessed the effect of a “high-target” level of MAP (80–85 mmHg) versus the recommended “low-target” MAP (65–70 mm Hg) on mortality in patients with septic shock. Among the 776 patients originally recruited in SEPSISPAM trial, we selected those who were mechanically ventilated and sedated and with available evaluation of arousal level assessed by the Richmond Agitation and Sedation Scale (RASS). Results We restricted our analysis to the period in which patients were treated with vasoactive drugs. Cumulative sedative drugs were assessed daily. A total of 532 patients were included in this study: 253 (47.6%) in the low-target group and 279 (52.4%) in the high-target group. Daily cumulative sedative drugs were similar in both groups. Compared to the low-target group, minimal and maximal RASS were significantly higher in the high-target group at day 2, 4 and 5. Furthermore, in order to consider the fact that multiple measures were done for each patient and to consider the global effect of time on these measures, we used a mixed linear regression and multivariate models: we confirmed that maximal RASS values were significantly higher in the high-target group. Conclusion In patients with septic shock who were mechanically ventilated and sedated, resuscitation with MAP target between 80 and 85 mmHg was associated with higher arousal level as compared to a MAP target between 65 and 70 mmHg. Electronic supplementary material The online version of this article (10.1186/s13613-019-0528-5) contains supplementary material, which is available to authorized users.

Pneumonia is frequently complicated by occurrence of acute respiratory distress syndrome (ARDS), consequently to dysregulated inflammatory response. However, mechanisms driving this dysregulation are poorly understood. To address this, "unconventional T-cells (UTC)" -γδT, NKT and MAIT cells- appear to be relevant targets due to their key role in orchestrating anti-microbial immune response in the lung. Thus, using an experimental and translational approach, we test the hypothesis that a tight regulation of UTC is mandatory to fine-tune host response, and, subsequently to prevent emergence of an aberrant response leading to excessive tissue damages, and eventually, ARDS.

International audience; Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.

Background and Purpose. Pseudomonas aeruginosa is a main cause of ventilator-associated pneumonia (VAP) with drug-resistant bacteria. Bacteriophage therapy has experienced resurgence to compensate for the limited development of novel antibiotics. However, phage therapy is limited to a compassionate use so far, resulting from lack of adequate studies in relevant pharmacological models. We used a pig model of VAP caused by P. aeruginosa that recapitulates essential features of human disease to study the antimicrobial efficacy of nebulized-phage therapy. Experimental Approach. (i) Lysis kinetic assays were performed to evaluate in vitro phage antibacterial efficacy against P. aeruginosa and select relevant combinations of lytic phages. (ii) The efficacy of the phage combinations was investigated in vivo (murine model of P. aeruginosa lung infection). (iii) We determined the optimal conditions to ensure efficient phage delivery by aerosol during mechanical ventilation. (iv) Lung antimicrobial efficacy of inhaled-phage therapy was evaluated in pigs, which were anesthetized, mechanically ventilated and infected with P. aeruginosa. Key Results. By selecting an active phage cocktail and optimizing aerosol delivery conditions, we were able to deliver high phage concentrations in the lungs, which resulted in a rapid and marked reduction in P. aeruginosa density (1.5 Log reduction, p

Importance Coronavirus disease 2019 (COVID-19) is associated with severe lung damage. Corticosteroids are a possible therapeutic option. Objective To determine the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute respiratory failure. Design, Setting, and Participants Multicenter randomized double-blind sequential trial conducted in France, with interim analyses planned every 50 patients. Patients admitted to the intensive care unit (ICU) for COVID-19–related acute respiratory failure were enrolled from March 7 to June 1, 2020, with last follow-up on June 29, 2020. The study intended to enroll 290 patients but was stopped early following the recommendation of the data and safety monitoring board. Interventions Patients were randomized to receive low-dose hydrocortisone (n = 76) or placebo (n = 73). Main Outcomes and Measures The primary outcome, treatment failure on day 21, was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy. Prespecified secondary outcomes included the need for tracheal intubation (among patients not intubated at baseline); cumulative incidences (until day 21) of prone position sessions, extracorporeal membrane oxygenation, and inhaled nitric oxide; Pao2:Fio2ratio measured daily from day 1 to day 7, then on days 14 and 21; and the proportion of patients with secondary infections during their ICU stay. Results The study was stopped after 149 patients (mean age, 62.2 years; 30.2% women; 81.2% mechanically ventilated) were enrolled. One hundred forty-eight patients (99.3%) completed the study, and there were 69 treatment failure events, including 11 deaths in the hydrocortisone group and 20 deaths in the placebo group. The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group (difference of proportions, –8.6% [95.48% CI, –24.9% to 7.7%];P = .29). Of the 4 prespecified secondary outcomes, none showed a significant difference. No serious adverse events were related to the study treatment. Conclusions and Relevance In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome. Trial Registration ClinicalTrials.gov Identifier:NCT02517489

SummaryCD1d-restricted invariant Natural Killer T (iNKT) cells represent a unique class of T lymphocytes endowed with potent regulatory and effector immune functions. Although these functions are acquired during thymic ontogeny, the sequence of events that give rise to discrete effector subsets remains unclear. Using an unbiased single-cell transcriptomic analysis combined with functional assays, we revealed an unappreciated diversity among thymic iNKT cells, especially among iNKT1 cells. Mathematical modelling and biological methods unravelled a developmental map whereby iNKT2 cells constitute a transient branching point towards the generation of iNKT1 and iNKT17 cells, which reconciles the two previously proposed models. In addition, we identified the transcription co-factor Four-and-a-half LIM domains protein 2 (FHL2) as a critical cell-intrinsic regulator of iNKT1 specification. Thus, these data illustrate the changing transcriptional network that guides iNKT cell effector fate.

Covid-19 can induce lung infection ranging from mild pneumonia to life-threatening acute respiratory distress syndrome (ARDS). Dysregulated host immune response in the lung is a key feature in ARDS pathophysiology. However, cellular actors in Covid-19-driven ARDS are poorly understood. Here, we dynamically analyzed the biology of innate T cells, a heterogeneous class (MAIT, γδT and iNKT cells) of T lymphocytes, presenting potent anti-infective and regulatory functions. Patients presented a compartmentalized lung inflammation paralleled with a limited systemic inflammation. Circulating innate T cells of critically ill Covid-19 patients presented a profound and persistent phenotypic and functional alteration. Highly activated innate T cells were detected in airways of patients suggesting a recruitment to the inflamed site and a potential contribution in the regulation of the local inflammation. Finally, the expression of the CD69 activation marker on blood iNKT and MAIT cells at inclusion was predictive of disease severity. Thus, patients present an altered innate T cell biology that may account for the dysregulated immune response observed in Covid-19-related acute respiratory distress syndrome.

Background Obesity is associated with chronic low-grade inflammation, which has been linked to increased morbidity. However, inflammation variably and unpredictably improves after bariatric surgery. This study aimed at (1) evaluating the relationship between amplitude of weight loss and variation of inflammatory parameters after bariatric surgery, and (2) identifying, among clinical and biological baseline parameters, predictive factors of variation in inflammatory parameters. Methods In a prospective cohort of patients who underwent bariatric surgery, serum concentrations of interleukin (IL)-6, IL-10, resistin, leptin, adiponectin chemerin, and C-reactive protein (CRP) were measured preoperatively and 1 year after surgery, and routine clinical and biochemical parameters were retrieved. Univariate and multivariate analyses (partial least square method) were performed to assess how parameters were associated with weight loss and to predict improvement of inflammatory parameters. Results Eighty-seven patients were included (mean weight +/- SD 136.3 +/- 3.2 kg, 35 gastric bypasses, 52 sleeve gastrectomies). In parallel with weight loss (39.5 +/- 13.8 kg), pro-inflammatory markers (IL-6, CRP, leptin, resistin) significantly decreased, and anti-inflammatory markers (IL-10, adiponectin) increased. Multivariate analysis revealed a significant association between weight loss and improvement in inflammatory parameters. Among all the clinical and biological preoperative parameters, baseline chemerin level was the only parameter that was significantly associated with global improvement of the inflammatory status after surgery. Conclusion The amplitude of weight loss 1 year after bariatric surgery was strongly correlated with improvement of inflammatory profile, which could be predicted by baseline plasma level of chemerin. This suggests a key role of chemerin in obesity-driven inflammation, and a potential use as a biomarker.

International audience

International audience; Interleukin-7 (IL-7) is a critical cytokine in B- and T-lymphocyte development and maturation. Recent evidence suggests that IL-7 is a preferential homeostatic and survival factor for RORγt+ innate T cells such as natural killer T (NKT) cells, γδT cells, and mucosal-associated invariant T (MAIT) cells in the periphery. Given the important contribution of these populations in antibacterial immunity at barrier sites, we questioned whether IL-7 could be instrumental in boosting the local host immune response against respiratory bacterial infection. By using a cytokine-monoclonal antibody approach, we illustrated a role for topical IL-7 delivery in increasing the pool of RORγt+ IL-17A-producing innate T cells. Prophylactic IL-7 treatment prior to Streptococcus pneumoniae infection led to better bacterial containment, a process associated with increased neutrophilia and that depended on γδT cells and IL-17A. Last, combined delivery of IL-7 and α-galactosylceramide (α-GalCer), a potent agonist for invariant NKT (iNKT) cells, conferred an almost total protection in terms of survival, an effect associated with enhanced IL-17 production by innate T cells and neutrophilia. Collectively, we provide a proof of concept that IL-7 enables fine-tuning of innate T- cell functions. This might pave the way for considering IL-7 as an innovative biotherapeutic against bacterial infection.

Additional file 1: Supplementary information on Methods. ICD-10 diagnosis codes used.

International audience; Background: Iodinated contrast media may contribute to acute kidney injury. However, several recent works suggest that this toxicity is minimal in the clinical setting. Recently, urinary G1 cell-cycle arrest proteins tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin like growth factor binding protein 7 (IGFBP-7) were identified as highly sensitive and specific biomarkers for early detection of kidney aggression. The impact of contrast administration on those biomarkers has not been specifically evaluated but could provide clues about the toxicity of contrast media. This study aimed at measuring changes in TIMP-2 and IGFBP-7 urinary concentrations before and after a contrast-enhanced computed tomography in critically ill patients.Methods: 77 patients were included in a prospective observational cohort study. Urinary [TIMP -2]·[IGFBP-7] was measured before, 6 and 24 h after contrast infusion. Urine output and serum creatinine were followed 3 days.Results: Median [TIMP-2]·[IGFBP-7] was 0.06 [interquartile range 0.04;0.26], 0.07 [0.03;0.34] and 0.10 [0.04;0.37] (ng/mL)2/1000 respectively before, 6 and 24 h after contrast infusion. Individual changes from baseline were − 0.01 [− 0.11;0.11] and 0.00 [− 0.10;0.09] (ng/ml)2/1000 at 6 and 24 h. These changes were not higher among the patients increasing their Kidney Disease Improving Global Outcome (KDIGO) classification within 3 days after contrast infusion (n = 14 [18%] based on creatinine criterion only, n = 42 [55%] based on creatinine and urine output).Conclusions: Changes in [TIMP-2]·[IGFBP-7] urinary concentration after contrast-enhanced computed tomography were insignificant, suggesting minimal kidney aggression by modern iodinated contrast media.

Background The consequences of the ageing population concerning ICU hospitalisation need to be adequately described. We believe that this discussion should be disease specific. A focus on respiratory infections is of particular interest, because it is strongly associated with old age. Our objective was to assess trends in demographics over a decade among elderly patients admitted to the ICU for acute respiratory infections. Methods A cross-sectional study was performed between 2006 and 2015 based on hospital discharge databases in one French region (2.5 million inhabitants). Patients with acute respiratory infection were selected according to the specific ICD-10 diagnosis codes recorded, including acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and community-acquired pneumonia (CAP). We also identified comorbid conditions based on any significant ICD-10 secondary diagnoses adapted from the Charlson and Elixhauser indexes. Results A total of 98,381 hospital stays for acute respiratory infection were identified among the 3,856,785 stays over the 10-year period. The number of patients 75 y/o and younger increased 1.6-fold from 2006 to 2015, whereas the numbers of patients aged 85–89 and ≥ 90 y/o increased by 2.5- and 2.1-fold, respectively. Both CAP and AECOPD hospitalisations significantly increased for all age groups over the decade. ICU hospitalisations for respiratory infection increased 2.7-fold from 2006 to 2015 (p = 0.0002). The greatest increases in the use of ICU resources were for the 85–89 and ≥ 90 y/o groups, which corresponded to increases of 3.3- and 5.8-fold. Indeed, the proportion of patients hospitalized for respiratory infection in ICU that were elderly clearly grew during the decade: 11.3% were ≥ 85 y/o in 2006 versus 16.4% in 2015 (p

Additional file 4: Table S3. Univariate and multivariate analyses for the mixed linear models used to evaluate reported variables and maximal/minimal RASS values

Additional file 1: Table S1. Case definition for patient selection using primary and secondary diagnoses and procedure codes in discharge summaries.

BACKGROUND In case of acute bacterial meningitis, a decision on the need for intensive care admission should be made within the first hour. The aim of this study was to assess the ability of a point-of-care glucometer to determine abnormal cerebrospinal fluid (CSF) glucose concentration at the bedside that contributes toward bacterial meningitis diagnosis. METHODS We carried out a prospective study and simultaneously measured the glucose concentrations in CSF and blood using a central laboratory and a point-of-care glucometer. We compared CSF/blood glucose ratios obtained at the bedside with a glucometer versus those obtained by the central laboratory. We determined the performance characteristics of the CSF/blood glucose ratio provided by a glucometer to detect bacterial infection in the CSF immediately after CSF sampling. RESULTS We screened 201 CSF collection procedures during the study period and included 172 samples for analysis. Acute bacterial meningitis was diagnosed in 17/172 (9.9%) of CSF samples. The median turnaround time for a point-of-care glucometer analysis was 5 (interquartile range 2-10) min versus 112 (interquartile range 86-154) min for the central laboratory (P

Background The post intensive care syndrome (PICS) gathers various disabilities, associated with a substantial healthcare use. However, patients’ comorbidities and active medical conditions prior to intensive care unit (ICU) admission may partly drive healthcare use after ICU discharge. To better understand retative contribution of critical illness and PICS—compared to pre-existing comorbidities—as potential determinant of post-critical illness healthcare use, we conducted a population-based evaluation of patients’ healthcare use trajectories. Results Using discharge databases in a 2.5-million-people region in France, we retrieved, over 3 years, all adult patients admitted in ICU for septic shock or acute respiratory distress syndrome (ARDS), intubated at least 5 days and discharged alive from hospital: 882 patients were included. Median duration of mechanical ventilation was 11 days (interquartile ranges [IQR] 8;20), mean SAPS2 was 49, and median hospital length of stay was 42 days (IQR 29;64). Healthcare use (days spent in healthcare facilities) was analyzed 2 years before and 2 years after ICU admission. Prior to ICU admission, we observed, at the scale of the whole study population, a progressive increase in healthcare use. Healthcare trajectories were then explored at individual level, and patients were assembled according to their individual pre-ICU healthcare use trajectory by clusterization with the K-Means method. Interestingly, this revealed diverse trajectories, identifying patients with elevated and increasing healthcare use (n = 126), and two main groups with low (n = 476) or no (n = 251) pre-ICU healthcare use. In ICU, however, SAPS2, duration of mechanical ventilation and length of stay were not different across the groups. Analysis of post-ICU healthcare trajectories for each group revealed that patients with low or no pre-ICU healthcare (which represented 83% of the population) switched to a persistent and elevated healthcare use during the 2 years post-ICU. Conclusion For 83% of ARDS/septic shock survivors, critical illness appears to have a pivotal role in healthcare trajectories, with a switch from a low and stable healthcare use prior to ICU to a sustained higher healthcare recourse 2 years after ICU discharge. This underpins the hypothesis of long-term critical illness and PICS-related quantifiable consequences in healthcare use, measurable at a population level.

Severe cases of pneumonia are frequently associated with acute respiratory distress syndrome (ARDS), which carries a mortality rate of about 40% [1]. Uncontrolled host inflammatory response in the lung is a key factor in the transition from pneumonia to ARDS, with alveolocapillary membrane disruption leading to interstitial and alveolar oedema [2]. Neutrophils are part of the innate immune system and are the first responders to local tissue damage and infection. Recruited neutrophils are considered important actors in lung tissue injury [3]. Indeed, their broad arsenal of antimicrobial weaponry can cause direct and indirect collateral damage. Neutrophil serine proteinases (NSPs), including elastase (NE), proteinase 3 (PR3) and cathepsin G (CatG), are released from activated cells and play a part in ARDS pathophysiology, as illustrated in both preclinical and clinical studies [4]. Thus, NSPs emerge as an untapped point for therapeutic interventions in pneumonia-induced ARDS [4]. These NSPs are readily synthesised in neutrophil precursors within the bone marrow and are converted into their active form by cathepsin C (CatC) [5]. They are stored together in cytoplasmic granules and secreted into the extracellular compartment upon stimulation [6]., COVID-19 ARDS is associated with release of biologically active neutrophil elastase-related proteinases to the airways and blood at a comparable level to non-COVID ARDS https://bit.ly/3nihveh

International audience; We report acute tetraplegia caused by rat bite fever in a 59-year old man (snake keeper) and transmission of Streptobacillus moniliformis. We found an identical characteristic bacterial pattern in rat and human samples, which validated genotyping-based evidence for infection with the same strain, and identified diagnostic difficulties concerning infection with this microorganism.

Introduction La mucoviscidose est caracterisee par une inflammation bronchique chronique associee a des infections respiratoires a repetition. Les mecanismes qui entretiennent cette inflammation sont mal connus. Les lymphocytes T dits « non conventionnels » (LTNC) comprennent les lymphocytes T-γδ, les Mucosal-Associated Invariant T cells (MAIT) et les invariant Natural Killer T cells (i NKT). Les LTNC resident preferentiellement dans les muqueuses, notamment respiratoire, et jouent un role dans l’orchestration de la reponse inflammatoire via la production de cytokines et leur cytotoxicite. Notre hypothese est qu’une deregulation de l’activite des LTNC pourrait contribuer a l’inflammation chronique des patients mucoviscidosiques. Methodes Etude prospective portant sur des patients adultes suivis au CHU de Tours, debutee le 03/04/2019. Des echantillons de sang et d’expectorations sont regulierement preleves dans le cadre du suivi habituel des patients. L’abondance relative des LTNC et leur etat d’activation (marqueurs membranaires CD69 et PD-1) sont analyses en cytometrie en flux et compares a un groupe de sujets sains. Resultats A ce jour, 46 patients et 14 temoins ont ete inclus. Normalement absents des voies aeriennes, la presence de LTNC a ete mise en evidence dans les expectorations des patients. Dans le sang, la proportion de MAIT etait significativement diminuee par rapport aux donneurs sains. Aucune modification de frequence n’a ete observee pour les lymphocytes T-γδ et les i NKT. Les LTNC circulants des patients presentent des modifications du profil phenotypique (CD69 et PD-1), suggerant un etat d’activation important. Conclusion La presence de LTNC a ete mise en evidence dans les voies respiratoires des patients mucoviscidosiques ainsi que dans le sang dans un etat active, ce qui pourrait contribuer a l’inflammation pulmonaire chronique. L’etude fonctionnelle portant sur la capacite des LTNC a secreter differents types de cytokines et leur potentiel cytotoxique est en cours. Ces donnees seront comparees aux donnees cliniques et a leur evolution chez un meme patient.

Additional file 1: Table S1. Number of hospitalisation stays in the healthcare structures of the Centre-Val de Loire region (2.5 million inhabitants, France) attributable to acute respiratory infection (ARI) and according to age classes. Percentage refers to the proportion of the age class among all the patients hospitalised on the same year.

International audience; The role of sphingolipids (SLs) in the immune system has come under increasing scrutiny recently due to the emerging contributions that these important membrane components play in regulating a variety of immunological processes. The acyl chain length of SLs appears particularly critical in determining SL function. Here, we show a role for very-long acyl chain SLs (VLC-SLs) in invariant natural killer T (iNKT) cell maturation in the thymus and homeostasis in the liver. Ceramide synthase 2-null mice, which lack VLC-SLs, were susceptible to a hepatotropic strain of lymphocytic choriomeningitis virus, which is due to a reduction in the number of iNKT cells. Bone marrow chimera experiments indicated that hematopoietic-derived VLC-SLs are essential for maturation of iNKT cells in the thymus, whereas parenchymal-derived VLC-SLs are crucial for iNKT cell survival and maintenance in the liver. Our findings suggest a critical role for VLC-SL in iNKT cell physiology.

Macrolides have a variety of physiological activi- ties other than antimicrobial effects. The non-antimicrobial properties of macrolides are grouped under the concept of immunomodulation. The spectrum of action of these antibio- tics extends to regulation of leukocyte function and produc- tion of inflammatory mediators, control of mucus produc- tion, and modulation of respiratory epithelial defense. In addition, macrolides present anti-viral effects and are able to inhibit biofilm formation and reduce production of viru- lence factors from Pseudomonas aeruginosa. These proper- ties of macrolides are mainly observed at low doses and for long-term treatments. There is a growing interest for the use of these drugs as immunomodulatory therapy for chronic lung diseases, mainly inflammatory diseases with acute exa- cerbation triggered by infections. The clinical benefits of macrolides to prevent acute exacerbation in chronic obstruc- tive pulmonary disease and cystic fibrosis are well demons- trated. On the other side, there is no evidence that macrolides are efficient in asthma. Here, we review the physiological activities of macrolides including mechanisms by which they contribute to the clinical effects observed in chronic lung diseases. We also present the main clinical investiga- tions regarding the use of macrolides in chronic obstructive pulmonary disease, cystic fibrosis, and asthma.

La muqueuse respiratoire est en contact permanent avec le milieu exterieur et represente la premiere defense face a une agression exterieure, notamment microbienne. Elle est ainsi une barriere physique, mais elle possede egalement des fonctions immunitaires. L’epithelium respiratoire possede en effet une capacite de detection demotifsmoleculaires presents sur les pathogenes rencontres, grâce a la presence de recepteurs de l’immunite : les pathogen recognition receptors. L’activation de ces recepteurs entraine une reponse inflammatoire d’intensite variable. La muqueuse respiratoire possede egalement la capacite de reguler et de diminuer la reponse inflammatoire. La regulation de la reponse inflammatoire de la muqueuse respiratoire est complexe et implique de nombreux autres acteurs cellulaires et moleculaires, mais deux cytokines, l’interleukine (IL)-17 et l’IL-22, ont des roles majeurs. L’epithelium a donc un double role, de « senseur » et d’effecteur immunitaire. Ces fonctions peuvent etre deregulees dans differentes situations pathologiques respiratoires. Une defaillance de la fonction epitheliale peut ainsi etre induite par les therapeutiques mises en oeuvre, notamment la ventilation mecanique. Cependant, les alterations de la reponse epitheliale respiratoire les plus frequentes sont observees lors de pathologies infectieuses ou inflammatoires, qu’elles soient aigues (comme dans le cadre du syndrome de detresse respiratoire aigue) ou chroniques (comme dans la bronchopneumopathie chronique obstructive). L’epithelium etant par ailleurs un acteur cle de la restauration physique et fonctionnelle de la muqueuse respiratoire, le developpement de moyens innovants pour proteger l’integrite epitheliale permettra de prevenir efficacement l’amplification pathologique de l’inflammation pulmonaire et/ou de limiter la dissemination de pathogenes.

International audience; The IL-22 signaling pathway is critical for regulating mucosal defense and limiting bacterial dissemination. IL-22 is unusual among interleukins because it does not directly regulate the function of conventional immune cells, but instead targets cells at outer body barriers, such as respiratory epithelial cells. Consequently, IL-22 signaling participates in the maintenance of the lung mucosal barrier by controlling cell proliferation and tissue repair, and enhancing the production of specific chemokines and anti-microbial peptides. Pseudomonas aeruginosa is a major pathogen of ventilator-associated pneumonia and causes considerable lung tissue damage. A feature underlying the pathogenicity of this bacterium is its capacity to persist and develop in the host, particularly in the clinical context of nosocomial lung infections. We aimed to investigate the ability of P. auruginosa to disrupt immune-epithelial cells cross-talk. We found that P. aeruginosa escapes the host mucosal defenses by degrading IL-22, leading to severe inhibition of IL-22-mediated immune responses. We demonstrated in vitro that, protease IV, a type 2 secretion system-dependent serine protease, is responsible for the degradation of IL-22 by P. aeruginosa. Moreover, the major anti-proteases molecules present in the lungs were unable to inhibit protease IV enzymatic activity. In addition, tracheal aspirates of patients infected by P. aeruginosa contain protease IV activity which further results in IL-22 degradation. This so far undescribed cleavage of IL-22 by a bacterial protease is likely to be an immune-evasion strategy that contributes to P. aeruginosa-triggered respiratory infections.