Sepsis-trained macrophages promote antitumoral tissue-resident T cells.

Sepsis induces immune alterations, which last for months after the resolution of illness. The effect of this immunological reprogramming on the risk of developing cancer is unclear. Here we use a national claims database to show that sepsis survivors had a lower cumulative incidence of cancers than matched nonsevere infection survivors. We identify a chemokine network released from sepsis-trained resident macrophages that triggers tissue residency of T cells via CCR2 and CXCR6 stimulations as the immune mechanism responsible for this decreased risk of de novo tumor development after sepsis cure. While nonseptic inflammation does not provoke this network, laminarin injection could therapeutically reproduce the protective sepsis effect. This chemokine network and CXCR6 tissue-resident T cell accumulation were detected in humans with sepsis and were associated with prolonged survival in humans with cancer. These findings identify a therapeutically relevant antitumor consequence of sepsis-induced trained immunity.

Cost effectiveness and long-term outcomes of dexamethasone administration in major non-cardiac surgery.

STUDY OBJECTIVES: Postoperative administration of dexamethasone has been proposed to reduce morbidity and mortality in patients undergoing major non-cardiac surgery. In this ancillary study of the PACMAN trial, we aimed to evaluate the cost effectiveness of dexamethasone in patients undergoing major non-cardiac surgery. METHODS: Patients included in the multicentric randomized double-blind, placebo-controlled PACMAN trial were followed up for 12 months after their surgical procedure. Patients were randomized to receive either dexamethasone (0.2 mg/kg immediately after the surgical procedure, and on day 1) or placebo. Cost effectiveness between the dexamethasone and placebo groups was assessed for the 12-month postoperative period from a health payer perspective. RESULTS: Of 1222 randomized patients in PACMAN, 137 patients (11%) were followed up until 12 months after major surgery (71 in the DXM group and 66 in the placebo group). Postoperative dexamethasone administration reduced costs per patient at 1 year by €358.06 (95%CI -€1519.99 to €803.87). The probability of dexamethasone being cost effective was between 12% and 22% for a willingness to pay of €100,000 to €150,000 per life-year, which is the threshold that is usually used in France and was 52% for willingness to pay of €50,000 per life-year (threshold in USA). At 12 months, 9 patients (13.2%) in the DXM group and 10 patients (16.1%) in the placebo group had died. In conclusion, our study does not demonstrate the cost effectiveness of perioperative administration of DXM in major non-cardiac surgery.

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

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 versus Vt > = 8 ml/Kg of IBW, positive end-expiratory pressure (PEEP) < or > = 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, I2 = 20%], low and moderate to high PEEP [OR 0.8 (95% CI 0.59 to 1.07), p = 0.13, I2 = 80%] or protective and non-protective ventilation [OR 1.03 (95% CI 0.93 to 1.15), p = 0.6, I2 = 11]. Low tidal volume [OR 0.74 (95% CI 0.45 to 1.21, p = 0.23, I2 = 88%], moderate PEEP [OR 0.98 (95% CI 0.76 to 1.26), p = 0.9, I2 = 21%] or protective ventilation [OR 1.22 (95% CI 0.94 to 1.58), p = 0.13, I2 = 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.

High-flow oxygen therapy versus facemask preoxygenation in anticipated difficult airway management (PREOPTI-DAM): an open-label, single-centre, randomised controlled phase 3 trial.

Background: Difficult airway management remains a critical procedure with life-threatening adverse events. Current guidelines suggest high-flow therapy by nasal cannulae (HFNC) as a preoxygenation device in this setting. However, there is an evidence gap to support this recommendation. Methods: The PREOPTI-DAM study is an open-label, single-centre, randomised controlled phase 3 trial done at Nantes University Hospital, France. Patients were aged 18-90 years with one major or two minor criteria of anticipated difficult airway management, and requiring intubation for scheduled surgery, were eligible. Patients with body mass index >35 kg/m2 were excluded. Patients were randomly allocated (1:1) to receive 4-min preoxygenation by HFNC or facemask. Randomisation was stratified according to the intubation strategy (laryngoscopic versus fiberoptic intubation). The primary outcome was the incidence of oxygen desaturation ≤94% or of bag-mask ventilation during intubation. The primary and safety analyses included the intention to treat population. This trial is registered with ClinicalTrials.gov (NCT03604120) and EudraCT (2018-A00434-51). Findings: From September 4 2018 to March 31 2021, 186 patients were enrolled and randomly assigned. One participant withdrew consent and 185 (99.5%) were included in the primary analysis (HFNC, N = 95; Facemask, N = 90). The incidence of the primary outcome was not significantly different between the HFNC and the facemask groups, respectively 2 (2%) versus 7 (8%); adjusted difference, -5.6 [95% confidence interval (CI), -11.8 to 0.6], P = 0.10. In the HFNC group, 76 patients (80%) versus 53 (59%) in the facemask group, reported good or excellent intubation experiences; adjusted difference 20.5 [95% CI, 8.3-32.8], P = 0.016. Comparing HFNC with facemask, severe complication occurred in 22 (23%) versus 27 (30%) patients (P = 0.29), and moderate complication in 14 (15%) versus 18 (20%) patients (P = 0.35). No death or cardiac arrest occurred during the study. Interpretation: Compared with facemask, HFNC did not significantly reduce the incidence of desaturation ≤94% or bag-mask ventilation during anticipated difficult intubation but the trial was underpowered to rule out a clinically significant benefit. Patient satisfaction was improved with HFNC. Funding: Nantes University Hospital and Fisher & Paykel Healthcare.

Transfusion-Related Renal Dysfunction After Cardiac Surgery: The Role of Myeloid-Related Protein_14 in Neutrophil-Mediated Tubular Damage.

Transfusion is a specific cause of acute kidney injury (AKI) after cardiac surgery. Whether there is an association between the composition of blood products and the onset of AKI is unknown. The present study suggests that the transfusion of packed red blood cells containing a high amount of myeloid-related protein 14 (MRP_14) could increase the incidence of AKI after cardiac surgery. In a mouse model, MRP_14 increased the influx of neutrophils in the kidney after ischemia-reperfusion and their ability to damage tubular cells. Higher concentrations of MRP_14 were found in packed red blood cells from female donors or prepared by whole blood filtration.

Intraoperative protective mechanical ventilation in patients requiring emergency abdominal surgery: the multicentre prospective randomised IMPROVE-2 study protocol.

IntroductionEmergency abdominal surgery is associated with a high risk of postoperative complications. One of the most serious is postoperative respiratory failure (PRF), with reported rates up to 20%-30% and attributable 30-day mortality that can exceed 20%.Lung-protective ventilation, especially the use of low tidal volume, may help reducing the risk of lung injury. The role of positive end-expiratory pressure (PEEP) and recruitment manoeuvre (RM) remains however debated. We aim to evaluate whether a strategy aimed at increasing alveolar recruitment by using higher PEEP levels and RM could be more effective at reducing PRF and mortality after emergency abdominal surgery than a strategy aimed at minimising alveolar distension by using lower PEEP levels without RM. METHODS AND ANALYSIS: The IMPROVE-2 study is a multicentre randomised, parallel-group clinical trial of 680 patients requiring emergency abdominal surgery under general anaesthesia. Patients will be randomly allocated in a 1:1 ratio to receive either low PEEP levels (≤5 cm H2O) without RM or high PEEP levels individually adjusted according to driving pressure in addition to RM, stratified by centre and according to the presence of shock and hypoxaemia at randomisation. The primary endpoint is a composite of PRF and all-cause mortality by day 30 or hospital discharge. Data will be analysed on the intention-to-treat principle and a per-protocol basis. ETHICS AND DISSEMINATION: IMPROVE-2 trial has been approved by an independent ethics committee for all study centres. Participant recruitment began in February 2021. Results will be submitted for publication in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03987789.

Ventilation practices in burn patients-an international prospective observational cohort study.

BACKGROUND: It is unknown whether lung-protective ventilation is applied in burn patients and whether they benefit from it. This study aimed to determine ventilation practices in burn intensive care units (ICUs) and investigate the association between lung-protective ventilation and the number of ventilator-free days and alive at day 28 (VFD-28). METHODS: This is an international prospective observational cohort study including adult burn patients requiring mechanical ventilation. Low tidal volume (V T) was defined as V T ≤ 8 mL/kg predicted body weight (PBW). Levels of positive end-expiratory pressure (PEEP) and maximum airway pressures were collected. The association between V T and VFD-28 was analyzed using a competing risk model. Ventilation settings were presented for all patients, focusing on the first day of ventilation. We also compared ventilation settings between patients with and without inhalation trauma. RESULTS: A total of 160 patients from 28 ICUs in 16 countries were included. Low V T was used in 74% of patients, median V T size was 7.3 [interquartile range (IQR) 6.2-8.3] mL/kg PBW and did not differ between patients with and without inhalation trauma (p = 0.58). Median VFD-28 was 17 (IQR 0-26), without a difference between ventilation with low or high V T (p = 0.98). All patients were ventilated with PEEP levels ≥5 cmH2O; 80% of patients had maximum airway pressures <30 cmH2O. CONCLUSION: In this international cohort study we found that lung-protective ventilation is used in the majority of burn patients, irrespective of the presence of inhalation trauma. Use of low V T was not associated with a reduction in VFD-28. TRIAL REGISTRATION: Clinicaltrials.gov NCT02312869. Date of registration: 9 December 2014.

Effect of dexamethasone on complications or all cause mortality after major non-cardiac surgery: multicentre, double blind, randomised controlled trial.

OBJECTIVE: To assess the effect of dexamethasone on complications or all cause mortality after major non-cardiac surgery. DESIGN: Phase III, randomised, double blind, placebo controlled trial. SETTING: 34 centres in France, December 2017 to March 2019. PARTICIPANTS: 1222 adults (>50 years) requiring major non-cardiac surgery with an expected duration of more than 90 minutes. The anticipated time frame for recruitment was 24 months. INTERVENTIONS: Participants were randomised to receive either dexamethasone (0.2 mg/kg immediately after the surgical procedure, and on day 1) or placebo. Randomisation was stratified on the two prespecified criteria of cancer and thoracic procedure. MAIN OUTCOMES MEASURES: The primary outcome was a composite of postoperative complications or all cause mortality within 14 days after surgery, assessed in the modified intention-to-treat population (at least one treatment administered). RESULTS: Of the 1222 participants who underwent randomisation, 1184 (96.9%) were included in the modified intention-to-treat population. 14 days after surgery, 101 of 595 participants (17.0%) in the dexamethasone group and 117 of 589 (19.9%) in the placebo group had complications or died (adjusted odds ratio 0.81, 95% confidence interval 0.60 to 1.08; P=0.15). In the stratum of participants who underwent non-thoracic surgery (n=1038), the primary outcome occurred in 69 of 520 participants (13.3%) in the dexamethasone group and 93 of 518 (18%) in the placebo group (adjusted odds ratio 0.70, 0.50 to 0.99). Adverse events were reported in 288 of 613 participants (47.0%) in the dexamethasone group and 296 of 609 (48.6%) in the placebo group (P=0.46). CONCLUSIONS: Dexamethasone was not found to significantly reduce the incidence of complications and death in patients 14 days after major non-cardiac surgery. The 95% confidence interval for the main result was, however, wide and suggests the possibility of important clinical effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov NCT03218553.

Circulating Regulatory T Cells Expressing Tumor Necrosis Factor Receptor Type 2 Contribute to Sepsis-Induced Immunosuppression in Patients During Septic Shock.

BACKGROUND: Septic shock remains a major cause of death that can be complicated by long-term impairment in immune function. Among regulatory T (Treg) cells, the tumor necrosis factor receptor 2 positive (TNFR2pos) Treg-cell subset endorses significant immunosuppressive functions in human tumors and a sepsis mouse model but has not been investigated during septic shock in humans. METHODS: We prospectively enrolled patients with septic shock hospitalized in intensive care units (ICU). We performed immunophenotyping and functional tests of CD4+ T cells, Treg cells, and TNFR2pos Treg cells on blood samples collected 1, 4, and 7 days after admission to ICU. RESULTS: We investigated 10 patients with septic shock compared to 10 healthy controls. Although the proportions of circulating Treg cells and TNFR2pos Treg-cell subsets were not increased, their CTLA4 expression and suppressive functions in vitro were increased at 4 days of septic shock. Peripheral blood mononuclear cells from healthy donors cultured with serum from septic shock patients had increased CTLA4 expression in TNFR2pos Treg cells compared to TNFR2neg Treg cells. CONCLUSIONS: In patients with septic shock, CTLA4 expression and suppressive function were increased in circulating TNFR2pos Treg cells. We identify TNFR2pos Treg cells as a potential attractive target for therapeutic intervention.

Digital ischaemia aetiologies and mid-term follow-up: A cohort study of 323 patients.

ABSTRACT: Upper extremity digital ischaemia (UEDI) is a rare heterogeneous condition whose frequency is 40 times less than that of toe ischaemia. Using a large cohort, the aim of this study was to evaluate aetiologies, prognosis and midterm clinical outcomes of UEDI.All patients with UEDI with or without cutaneous necrosis in a university hospital setting between January 2000 to December 2016 were included. Aetiologies, recurrence of UEDI, digital amputation and survival were analyzed retrospectively.Three hundred twenty three patients were included. UEDI due to cardio-embolic disease (DICE) was the highest occurring aetiology with 59 patients (18.3%), followed by DI due to Systemic Sclerosis (SSc) (16.1%), idiopathic causes (11.7%), Thromboangiitis obliterans (TAO) (9.3%), iatrogenic causes (9.3%), and cancer (6.2%). DICE patients tended to be older and featured more cases with arterial hypertension whereas TAO patients smoked more tobacco and cannabis. During follow-up, recurrences were significantly more frequent in SSc than in all other tested groups (P < .0001 vs idiopathic and DICE, P = .003 vs TAO) and among TAO patients when compared to DICE patients (P = .005). The cumulated rate of digital amputation was higher in the SSc group (n = 18) (P = .02) and the TAO group (n = 7) (P = .03) than in DICE (n = 2).This retrospective study suggests that main aetiologies of UEDI are DICE, SSc and idiopathic. This study highlights higher frequency of iatrogenic UEDI than previous studies. UEDI associated with SSc has a poor local prognosis (amputations and recurrences) and DICE a poor survival. UEDI with SSc and TAO are frequently recurrent.

Could Azithromycin Be Part of Pseudomonas aeruginosa Acute Pneumonia Treatment?

Azithromycin (AZM) is a 15-membered-ring macrolide that presents a broad-spectrum antimicrobial activity against Gram-positive bacteria and atypical microorganisms but suffers from a poor diffusion across the outer-membrane of Gram-negative bacilli, including Pseudomonas aeruginosa (PA). However, AZM has demonstrated clinical benefits in patients suffering from chronic PA respiratory infections, especially cystic fibrosis patients. Since the rise of multidrug-resistant PA has led to a growing need for new therapeutic options, this macrolide has been proposed as an adjunctive therapy. Clinical trials assessing AZM in PA acute pneumonia are scarce. However, a careful examination of the available literature provides good rationales for its use in that context. In fact, 14- and 15-membered-ring macrolides have demonstrated immunomodulatory and immunosuppressive effects that could be of major interest in the management of acute illness. Furthermore, growing evidence supports a downregulation of PA virulence dependent on direct interaction with the ribosomes, and based on the modulation of several key regulators from the Quorum Sensing network. First highlighted in vitro, these interesting properties of AZM have subsequently been confirmed in the animal models. In this review, we systematically analyzed the literature regarding AZM immunomodulatory and anti-PA effects. In vitro and in vivo studies, as well as clinical trials were reviewed, looking for rationales for AZM use in PA acute pneumonia.

Perioperative hemodynamic optimization: from guidelines to implementation-an experts' opinion paper.

Despite a large body of evidence, the implementation of guidelines on hemodynamic optimization and goal-directed therapy remains limited in daily routine practice. To facilitate/accelerate this implementation, a panel of experts in the field proposes an approach based on six relevant questions/answers that are frequently mentioned by clinicians, using a critical appraisal of the literature and a modified Delphi process. The mean arterial pressure is a major determinant of organ perfusion, so that the authors unanimously recommend not to tolerate absolute values below 65 mmHg during surgery to reduce the risk of postoperative organ dysfunction. Despite well-identified limitations, the authors unanimously propose the use of dynamic indices to rationalize fluid therapy in a large number of patients undergoing non-cardiac surgery, pending the implementation of a "validity criteria checklist" before applying volume expansion. The authors recommend with a good agreement mini- or non-invasive stroke volume/cardiac output monitoring in moderate to high-risk surgical patients to optimize fluid therapy on an individual basis and avoid volume overload. The authors propose to use fluids and vasoconstrictors in combination to achieve optimal blood flow and maintain perfusion pressure above the thresholds considered at risk. Although purchase of disposable sensors and stand-alone monitors will result in additional costs, the authors unanimously acknowledge that there are data strongly suggesting this may be counterbalanced by a sustained reduction in postoperative morbidity and hospital lengths of stay. Beside existing guidelines, knowledge and explicit clinical reasoning tools followed by decision algorithms are mandatory to implement individualized hemodynamic optimization strategies and reduce postoperative morbidity and duration of hospital stay in high-risk surgical patients.

Balanced Opioid-free Anesthesia with Dexmedetomidine versus Balanced Anesthesia with Remifentanil for Major or Intermediate Noncardiac Surgery.

BACKGROUND: It is speculated that opioid-free anesthesia may provide adequate pain control while reducing postoperative opioid consumption. However, there is currently no evidence to support the speculation. The authors hypothesized that opioid-free balanced anesthetic with dexmedetomidine reduces postoperative opioid-related adverse events compared with balanced anesthetic with remifentanil. METHODS: Patients were randomized to receive a standard balanced anesthetic with either intraoperative remifentanil plus morphine (remifentanil group) or dexmedetomidine (opioid-free group). All patients received intraoperative propofol, desflurane, dexamethasone, lidocaine infusion, ketamine infusion, neuromuscular blockade, and postoperative lidocaine infusion, paracetamol, nefopam, and patient-controlled morphine. The primary outcome was a composite of postoperative opioid-related adverse events (hypoxemia, ileus, or cognitive dysfunction) within the first 48 h after extubation. The main secondary outcomes were episodes of postoperative pain, opioid consumption, and postoperative nausea and vomiting. RESULTS: The study was stopped prematurely because of five cases of severe bradycardia in the dexmedetomidine group. The primary composite outcome occurred in 122 of 156 (78%) dexmedetomidine group patients compared with 105 of 156 (67%) in the remifentanil group (relative risk, 1.16; 95% CI, 1.01 to 1.33; P = 0.031). Hypoxemia occurred 110 of 152 (72%) of dexmedetomidine group and 94 of 155 (61%) of remifentanil group patients (relative risk, 1.19; 95% CI, 1.02 to 1.40; P = 0.030). There were no differences in ileus or cognitive dysfunction. Cumulative 0 to 48 h postoperative morphine consumption (11 mg [5 to 21] versus 6 mg [0 to 17]) and postoperative nausea and vomiting (58 of 157 [37%] versus 37 of 157 [24%]; relative risk, 0.64; 95% CI, 0.45 to 0.90) were both less in the dexmedetomidine group, whereas measures of analgesia were similar in both groups. Dexmedetomidine patients had more delayed extubation and prolonged postanesthesia care unit stay. CONCLUSIONS: This trial refuted the hypothesis that balanced opioid-free anesthesia with dexmedetomidine, compared with remifentanil, would result in fewer postoperative opioid-related adverse events. Conversely, it did result in a greater incidence of serious adverse events, especially hypoxemia and bradycardia.

Impact of treating iron deficiency, diagnosed according to hepcidin quantification, on outcomes after a prolonged ICU stay compared to standard care: a multicenter, randomized, single-blinded trial.

BACKGROUND: Anemia is a significant problem in patients on ICU. Its commonest cause, iron deficiency (ID), is difficult to diagnose in the context of inflammation. Hepcidin is a new marker of ID. We aimed to assess whether hepcidin levels would accurately guide treatment of ID in critically ill anemic patients after a prolonged ICU stay and affect the post-ICU outcomes. METHODS: In a controlled, single-blinded, multicenter study, anemic (WHO definition) critically ill patients with an ICU stay ≥ 5 days were randomized when discharge was expected to either intervention by hepcidin treatment protocol or control. In the intervention arm, patients were treated with intravenous iron (1 g of ferric carboxymaltose) when hepcidin was < 20 µg/l and with intravenous iron and erythropoietin for 20 ≤ hepcidin < 41 µg/l. Control patients were treated according to standard care (hepcidin quantification remained blinded). Primary endpoint was the number of days spent in hospital 90 days after ICU discharge (post-ICU LOS). Secondary endpoints were day 15 anemia, day 30 fatigue, day 90 mortality and 1-year survival. RESULTS: Of 405 randomized patients, 399 were analyzed (201 in intervention and 198 in control arm). A total of 220 patients (55%) had ID at discharge (i.e., a hepcidin < 41 µg/l). Primary endpoint was not different (medians (IQR) post-ICU LOS 33(13;90) vs. 33(11;90) days for intervention and control, respectively, median difference - 1(- 3;1) days, p = 0.78). D90 mortality was significantly lower in intervention arm (16(8%) vs 33(16.6%) deaths, absolute risk difference - 8.7 (- 15.1 to - 2.3)%, p = 0.008, OR 95% IC, 0.46, 0.22-0.94, p = 0.035), and one-year survival was improved (p = 0.04). CONCLUSION: Treatment of ID diagnosed according to hepcidin levels did not reduce the post-ICU LOS, but was associated with a significant reduction in D90 mortality and with improved 1-year survival in critically ill patients about to be discharged after a prolonged stay. TRIAL REGISTRATION: www.clinicaltrial.gov NCT02276690 (October 28, 2014; retrospectively registered).

Risk factors for ventilator-associated pneumonia due to Staphylococcus aureus in patients with severe brain injury: A multicentre retrospective cohort study.

BACKGROUND: The present study aims at identifying the risk factors for ventilator-associated pneumonia (VAP) Staphylococcus aureus (S. aureus) in patients with severe brain injury (SBI). METHODS: In this multicentre, retrospective, observational study, patients ≥ 18 year old who had SBI (Glasgow coma scale GCS score < 9) who received mechanical ventilation for at least 48 h were analysed. The main objective was to identify risk factors for S. aureus VAP vs VAP due to other pathogens and to identify risk factors for S. aureus VAP vs patients who did not experience VAP. RESULTS: Eight hundred and forty-seven patients with SBI were admitted in ICU after severe traumatic brain injury (n = 489, 58%), aneurysmal SAH (n = 156, 18%), stroke (n = 27, 3%), spontaneous intracranial haemorrhage (n = 80, 9%), arteriovenous malformation rupture (n = 25, 3%), and other causes (n = 70, 8%). Three hundred fifty of 847 patients (41%) had VAP with S. aureus (n = 161) or other pathogens (n = 189). In patients with VAP, the multivariate analysis shows that age per 10 years of ageing (OR 0.80, 95% CI [0.70; 0.90]; p < 0.001) and tobacco use (OR 0.54, 95%CI [0.33;0.88]; p = 0.014) were protective factors against S. aureus. Age per 10 years of ageing remained a protective factor against S. aureus VAP vs no VAP (OR 0.80, 95%CI [0.73; 0.89], p < 0.001). CONCLUSIONS: In this retrospective study involving patients with SBI and who experienced VAP, increased age and tobacco use were protective factors against VAP due to S. aureus. Increased age remained protective against S. aureus in VAP vs no VAP analysis.

Monocytic Human Leukocyte Antigen DR Expression in Young Infants Undergoing Cardiopulmonary Bypass.

BACKGROUND: Monocytic human leukocyte antigen DR (mHLA-DR) expression levels have been reported to be a marker of immunosuppression and a predictor of sepsis and mortality. There are, however, scant data regarding mHLA-DR monitoring in young infants after cardiopulmonary bypass. Our objectives were to investigate the kinetics of mHLA-DR expression and to determine whether mHLA-DR levels are associated with healthcare-associated infection (HAI) after cardiopulmonary bypass in young infants. METHODS: mHLA-DR levels were analyzed by flow cytometry using a standardized method in 49 infants (<3 months old) with congenital heart disease before and after cardiopulmonary bypass. Results are expressed as the number of anti-HLA-DR antibodies per cell (AB/c). RESULTS: Postoperative mHLA-DR expression was reduced in all infants. Eleven patients (22%) developed HAI, and 4 patients (8%) died during the 30-day follow-up. mHLA-DR expression was significantly lower on postoperative day 4 in the HAI group compared with those who without HAI (3768 AB/c [range, 1938-6144] vs 13,230 AB/c [range, 6152-19,130], P = .014). Although mHLA-DR expression was associated with postoperative severity, mHLA-DR ≤4500 AB/c in the first 72 hours among patients with higher postoperative severity (extracorporeal membrane oxygenation and/or corticoids and/or delayed closure of sternum) was associated with occurrence of HAI in the univariate analysis (odds ratio, 6.3; 95% confidence interval, 1.0-38.7; P = .037). CONCLUSIONS: Cardiopulmonary bypass induces a profound decrease in mHLA-DR expression in young infants. Among patients with higher postoperative severity, low level of mHLA-DR in the early postoperative period is associated with the development of HAI.

Pseudomonas aeruginosa Infection Impairs NKG2D-Dependent NK Cell Cytotoxicity through Regulatory T-Cell Activation.

Natural killer (NK) cells play a key role in both antibacterial and antitumor immunity. Pseudomonas aeruginosa infection has already been reported to alter NK cell functions. We studied in vitro the effect of P. aeruginosa on NK cell cytotoxic response (CD107a membrane expression) to a lymphoma cell line. Through positive and negative cell sorting and adoptive transfer, we determined the influence of monocytes, lymphocytes, and regulatory T cells (Treg) on NK cell function during P. aeruginosa infection. We also studied the role of the activating receptor natural killer group 2D (NKG2D) in NK cell response to B221. We determined that P. aeruginosa significantly altered both cytotoxic response to B221 and NKG2D expression on NK cells in a Treg-dependent manner and that the NKG2D receptor was involved in NK cell cytotoxic response to B221. Our results also suggested that during P. aeruginosa infection, monocytes participated in Treg-mediated NK cell alteration. In conclusion, P. aeruginosa infection impairs NK cell cytotoxicity and alters antitumor immunity. These results highlight the strong interaction between bacterial infection and immunity against cancer.

Regulatory T Cells Expressing Tumor Necrosis Factor Receptor Type 2 Play a Major Role in CD4+ T-Cell Impairment During Sepsis.

Sepsis causes inflammation-induced immunosuppression with lymphopenia and alterations of CD4+ T-cell functions that renders the host prone to secondary infections. Whether and how regulatory T cells (Treg) are involved in this postseptic immunosuppression is unknown. We observed in vivo that early activation of Treg during Staphylococcus aureus sepsis induces CD4+ T-cell impairment and increases susceptibility to secondary pneumonia. The tumor necrosis factor receptor 2 positive (TNFR2pos) Treg subset endorsed the majority of effector immunosuppressive functions, and TNRF2 was particularly associated with activation of genes involved in cell cycle and replication in Treg, probably explaining their maintenance. Blocking or deleting TNFR2 during sepsis decreased the susceptibility to secondary infection. In humans, our data paralleled those in mice; the expression of CTLA-4 was dramatically increased in TNFR2pos Treg after culture in vitro with S. aureus. Our findings describe in vivo mechanisms underlying sepsis-induced immunosuppression and identify TNFR2pos Treg as targets for therapeutic intervention.

Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis.

Sepsis and trauma cause inflammation and elevated susceptibility to hospital-acquired pneumonia. As phagocytosis by macrophages plays a critical role in the control of bacteria, we investigated the phagocytic activity of macrophages after resolution of inflammation. After resolution of primary pneumonia, murine alveolar macrophages (AMs) exhibited poor phagocytic capacity for several weeks. These paralyzed AMs developed from resident AMs that underwent an epigenetic program of tolerogenic training. Such adaptation was not induced by direct encounter of the pathogen but by secondary immunosuppressive signals established locally upon resolution of primary infection. Signal-regulatory protein α (SIRPα) played a critical role in the establishment of the microenvironment that induced tolerogenic training. In humans with systemic inflammation, AMs and also circulating monocytes still displayed alterations consistent with reprogramming six months after resolution of inflammation. Antibody blockade of SIRPα restored phagocytosis in monocytes of critically ill patients in vitro, which suggests a potential strategy to prevent hospital-acquired pneumonia.