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BackgroundSARS coronavirus 2 (SARS-CoV-2) is responsible for high morbidity and mortality worldwide, mostly due to the exacerbated inflammatory response observed in critically ill patients. However, little is known about the kinetics of the systemic immune response and its association with survival in SARS-CoV-2+ patients admitted in ICU. We aimed to compare the immuno-inflammatory features according to organ failure severity and in-ICU mortality.MethodsSix-week multicentre study (N = 3) including SARS-CoV-2+ patients admitted in ICU. Analysis of plasma biomarkers at days 0 and 3–4 according to organ failure worsening (increase in SOFA score) and 60-day mortality.Results101 patients were included. Patients had severe respiratory diseases with PaO2/FiO2 of 155 [111–251] mmHg), SAPS II of 37 [31–45] and SOFA score of 4 [3–7]. Eighty-three patients (83%) required endotracheal intubation/mechanical ventilation and among them, 64% were treated with prone position. IL-1β was barely detectable. Baseline IL-6 levels positively correlated with organ failure severity. Baseline IL-6 and CRP levels were significantly higher in patients in the worsening group than in the non-worsening group (278 [70–622] vs. 71 [29–153] pg/mL, P < 0.01; and 178 [100–295] vs. 100 [37–213] mg/L, P < 0.05, respectively). Baseline IL-6 and CRP levels were significantly higher in non-survivors compared to survivors but fibrinogen levels and lymphocyte counts were not different between groups. After adjustment on SOFA score and time from symptom onset to first dosage, IL-6 and CRP remained significantly associated with mortality. IL-6 changes between Day 0 and Day 3–4 were not different according to the outcome. A contrario, kinetics of CRP and lymphocyte count were different between survivors and non-survivors.ConclusionsIn SARS-CoV-2+ patients admitted in ICU, a systemic pro-inflammatory signature was associated with clinical worsening and 60-day mortality.

The human pathogen Neisseria meningitidis can cause meningitis and fatal systemic disease. The bacteria colonize blood vessels and rapidly cause vascular damage, despite a neutrophil-rich inflammatory infiltrate. Here, we use a humanized mouse model to show that vascular colonization leads to the recruitment of neutrophils, which partially reduce bacterial burden and vascular damage. This partial effect is due to the ability of bacteria to colonize capillaries, venules and arterioles, as observed in human samples. In venules, potent neutrophil recruitment allows efficient bacterial phagocytosis. In contrast, in infected capillaries and arterioles, adhesion molecules such as E-Selectin are not expressed on the endothelium, and intravascular neutrophil recruitment is minimal. Our results indicate that the colonization of capillaries and arterioles by N. meningitidis creates an intravascular niche that precludes the action of neutrophils, resulting in immune escape and progression of the infection. The human pathogen Neisseria meningitidis colonizes blood vessels and causes vascular damage, despite a neutrophil-rich inflammatory infiltrate. Here, Manriquez et al. use a humanized mouse model to show that pathogen colonization of capillaries and arterioles creates an intravascular niche that precludes an effective action of neutrophils.

Sepsis is one of the main reasons for intensive care unit admission and is responsible for high morbidity and mortality. The usual hemodynamic targets for resuscitation of patients with septic shock use macro-hemodynamic parameters (hearth rate, mean arterial pressure, central venous pressure). However, persistent alterations of microcirculatory blood flow despite restoration of macro-hemodynamic parameters can lead to organ failure. This dissociation between macro- and microcirculatory compartments brings a need to assess end organs tissue perfusion in patients with septic shock. Traditional markers of tissue perfusion may not be readily available (lactate) or may take time to assess (urine output). The skin, an easily accessible organ, allows clinicians to quickly evaluate the peripheral tissue perfusion with noninvasive bedside parameters such as the skin temperatures gradient, the capillary refill time, the extent of mottling and the peripheral perfusion index.

Background A dysregulated immune response is emerging as a key feature of critical illness in COVID-19. Neutrophils are key components of early innate immunity that, if not tightly regulated, contribute to uncontrolled systemic inflammation. We sought to decipher the role of neutrophil phenotypes, functions, and homeostasis in COVID-19 disease severity and outcome. Methods By using flow cytometry, this longitudinal study compares peripheral whole-blood neutrophils from 90 COVID-19 ICU patients with those of 22 SARS-CoV-2-negative patients hospitalized for severe community-acquired pneumonia (CAP) and 38 healthy controls. We also assessed correlations between these phenotypic and functional indicators and markers of endothelial damage as well as disease severity. Results At ICU admission, the circulating neutrophils of the COVID-19 patients showed continuous basal hyperactivation not seen in CAP patients, associated with higher circulating levels of soluble E- and P-selectin, which reflect platelet and endothelial activation. Furthermore, COVID-19 patients had expanded aged-angiogenic and reverse transmigrated neutrophil subsets—both involved in endothelial dysfunction and vascular inflammation. Simultaneously, COVID-19 patients had significantly lower levels of neutrophil oxidative burst in response to bacterial formyl peptide. Moreover patients dying of COVID-19 had significantly higher expansion of aged-angiogenic neutrophil subset and greater impairment of oxidative burst response than survivors. Conclusions These data suggest that neutrophil exhaustion may be involved in the pathogenesis of severe COVID-19 and identify angiogenic neutrophils as a potentially harmful subset involved in fatal outcome. Graphic Abstract

Spontaneous pneumomediastinum (SP) has been described early during the COVID-19 pandemic in large series of patients with severe pneumonia, but most patients were receiving invasive mechanical ventilation (IMV) at the time of SP diagnosis. In this retrospective multicenter observational study, we aimed at describing the prevalence and outcomes of SP during severe COVID-19 with pneumonia before any IMV, to rule out mechanisms induced by IMV in the development of pneumomediastinum. Among 549 patients, 21 patients (4%) developed a SP while receiving non-invasive respiratory support, after a median of 6 days [4–12] from ICU admission. The proportion of patients requiring IMV was similar. However, the time to tracheal intubation was longer in patients with SP (6 days [5–13] vs. 2 days [1–4]; P  = 0.00002), with a higher first-line use of non-invasive ventilation ( n  = 11; 52% vs. n  = 150; 28%; P  = 0.02). The 21 patients who developed a SP had persisting signs of severe lung disease and respiratory failure with lower ROX index between ICU admission and occurrence of SP (3.94 [3.15–5.55] at admission vs. 3.25 [2.73–4.02] the day preceding SP; P  = 0.1), which may underline potential indirect signals of Patient-self inflicted lung injury (P-SILI). In this series of critically ill COVID-19 patients, the prevalence of SP without IMV was not uncommon, affecting 4% of patients. They received more often vasopressors and had a longer ICU length of stay, as compared with their counterparts. One pathophysiological mechanism may potentially be carried out by P-SILI related to a prolonged respiratory failure, as underlined by a delayed use of IMV and the evolution of the ROX index between ICU admission and the day preceding SP.

Background Vitamin C has potential protective effects through antioxidant and anti-inflammatory properties. However, the effect of vitamin C supplementation on microvascular function and peripheral tissue perfusion in human sepsis remains unknown. We aimed to determine vitamin C effect on microvascular endothelial dysfunction and peripheral tissue perfusion in septic shock patients. Methods Patients with septic shock were prospectively included after initial resuscitation. Bedside peripheral tissue perfusion and skin microvascular reactivity in response to acetylcholine iontophoresis in the forearm area were measured before and 1 h after intravenous vitamin C supplementation (40 mg/kg). Norepinephrine dose was not modified during the studied period. Results We included 30 patients with septic shock. SOFA score was 11 [8–14], SAPS II was 66 [54–79], and in-hospital mortality was 33%. Half of these patients had vitamin C deficiency at inclusion. Vitamin C supplementation strongly improved microvascular reactivity (AUC 2263 [430–4246] vs 5362 [1744–10585] UI, p  = 0.0004). In addition, vitamin C supplementation improved mottling score ( p  = 0.06), finger-tip ( p  = 0.0003) and knee capillary refill time (3.7 [2.6–5.5] vs 2.9 [1.9–4.7] s, p  < 0.0001), as well as and central-to-periphery temperature gradient (6.1 [4.9–7.4] vs 4.6 [3.4–7.0] °C, p  < 0.0001). The beneficial effects of vitamin C were observed both in patients with or without vitamin C deficiency. Conclusion In septic shock patients being resuscitated, vitamin C supplementation improved peripheral tissue perfusion and microvascular reactivity whatever plasma levels of vitamin C. ClinicalTrials.gov Identifier: NCT04778605 registered 26 January 2021.

Background Extubation failure is associated with increased mortality. Cough ineffectiveness may be associated with extubation failure, but its quantification for patients undergoing weaning from invasive mechanical ventilation (IMV) remains challenging. Methods Patients under IMV for more than 24 h completing a successful spontaneous T-tube breathing trial (SBT) were included. At the end of the SBT, we performed quantitative sonometric assessment of three successive coughing efforts using a sonometer. The mean of the 3-cough volume in decibels was named Sonoscore. Results During a 1-year period, 106 patients were included. Median age was 65 [51–75] years, mainly men (60%). Main reasons for IMV were acute respiratory failure (43%), coma (25%) and shock (17%). Median duration of IMV at enrollment was 4 [3–7] days. Extubation failure occurred in 15 (14%) patients. Baseline characteristics were similar between success and failure extubation groups, except percentage of simple weaning which was lower and MV duration which was longer in extubation failure patients. Sonoscore was significantly lower in patients who failed extubation (58 [52–64] vs. 75 [70–78] dB, P  < 0.001). After adjustment on MV duration and comorbidities, Sonoscore remained associated with extubation failure. Sonoscore was predictive of extubation failure with an area under the ROC curve of 0.91 (IC 95% [0.83–0.99], P  < 0.001). A threshold of Sonoscore < 67.1 dB predicted extubation failure with a sensitivity of 0.93 IC 95% [0.70–0.99] and a specificity of 0.82 IC 95% [0.73–0.90]. Conclusion Sonometric assessment of cough strength might be helpful to identify patients at risk of extubation failure in patients undergoing IMV.

Background Out-of-plane (OOP) approach is frequently used for ultrasound-guided insertion of central venous catheter (CVC) owing to its simplicity but does not avoid mechanical complication. In-plane (IP) approach might improve safety of insertion; however, it is less easy to master. We assessed, a homemade needle guide device aimed to improve CVC insertion using IP approach. Method We evaluated in a randomized simulation trial, the impact of a homemade needle guide on internal jugular, subclavian and femoral vein puncture, using three approaches: out-of-plane free hand (OOP-FH), in-plane free hand (IP-FH), and in-plane needle guided (IP-NG). Success at first pass, the number of needle redirections and arterial punctures was recorded. Time elapsed (i) from skin contact to first skin puncture, (ii) from skin puncture to successful venous puncture and (iii) from skin contact to venous return were measured. Results Thirty operators performed 270 punctures. IP-NG approach resulted in high success rate at first pass (jugular: 80%, subclavian: 95% and femoral: 100%) which was higher than success rate observed with OOP-FH and IP-FH regardless of the site ( p  = .01). Compared to IP-FH and OOP-FH, the IP-NG approach decreased the number of needle redirections at each site ( p  = .009) and arterial punctures ( p  = .001). Compared to IP-FH, the IP-NG approach decreased the total procedure duration for puncture at each site. Conclusion In this simulation study, IP approach using a homemade needle guide for ultrasound-guided central vein puncture improved success rate at first pass, reduced the number of punctures/redirections and shortened the procedure duration compared to OOP and IP free-hand approaches.