Intravenous immunoglobulins in patients with COVID-19-associated moderate-to-severe acute respiratory distress syndrome (ICAR): multicentre, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a major complication of COVID-19 and is associated with high mortality and morbidity. We aimed to assess whether intravenous immunoglobulins (IVIG) could improve outcomes by reducing inflammation-mediated lung injury. METHODS: In this multicentre, double-blind, placebo-controlled trial, done at 43 centres in France, we randomly assigned patients (1:1) receiving invasive mechanical ventilation for up to 72 h with PCR confirmed COVID-19 and associated moderate-to-severe ARDS to receive either IVIG (2 g/kg over 4 days) or placebo. Random assignment was done with a web-based system and was stratified according to the participating centre and the duration of invasive mechanical ventilation before inclusion in the trial (<12 h, 12-24 h, and >24-72 h), and treatment was administered within the first 96 h of invasive mechanical ventilation. To minimise the risk of adverse events, the IVIG administration was divided into four perfusions of 0·5 g/kg each administered over at least 8 hours. Patients in the placebo group received an equivalent volume of sodium chloride 0·9% (10 mL/kg) over the same period. The primary outcome was the number of ventilation-free days by day 28, assessed according to the intention-to-treat principle. This trial was registered on ClinicalTrials.gov, NCT04350580. FINDINGS: Between April 3, and October 20, 2020, 146 patients (43 [29%] women) were eligible for inclusion and randomly assigned: 69 (47%) patients to the IVIG group and 77 (53%) to the placebo group. The intention-to-treat analysis showed no statistical difference in the median number of ventilation-free days at day 28 between the IVIG group (0·0 [IQR 0·0-8·0]) and the placebo group (0·0 [0·0-6·0]; difference estimate 0·0 [0·0-0·0]; p=0·21). Serious adverse events were more frequent in the IVIG group (78 events in 22 [32%] patients) than in the placebo group (47 events in 15 [20%] patients; p=0·089). INTERPRETATION: In patients with COVID-19 who received invasive mechanical ventilation for moderate-to-severe ARDS, IVIG did not improve clinical outcomes at day 28 and tended to be associated with an increased frequency of serious adverse events, although not significant. The effect of IVIGs on earlier disease stages of COVID-19 should be assessed in future trials. FUNDING: Programme Hospitalier de Recherche Clinique.

The prognostic value of the neutrophil-to-lymphocyte ratio in critically ill cirrhotic patients.

BACKGROUND: Hospital death rates following ICU admission of cirrhotic patients remain high. Identifying patients at high risk of mortality after few days of aggressive management is imperative for providing adequate interventions. Herein, we aimed to evaluate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) combined with usual organ failure scores in the outcome prediction of cirrhotic patients hospitalized more than 3 days in ICU. METHODS: We conducted a retrospective bicentric study in two cohorts of cirrhotic patients hospitalized more than 3 days in French university hospital ICUs. At admission and day 3, we calculated several clinico-biological scores grading liver disease and organ failure severity and calculated the NLR. The primary outcome was 28-day mortality. RESULTS: The test cohort included 116 patients. At day 28, 43 (37.1%) patients had died. Variations of MELD score (ΔMELD), SOFA score (ΔSOFA), CLIF-SOFA score (ΔCLIF-SOFA) and NLR (ΔNRL) between admission and day 3 were significantly associated with 28-day mortality in univariate analysis. When included in bivariate analysis ΔNLR remained a significant predictor of 28-day mortality independently of these severity scores. Kaplan-Meier curves and statistics using reclassification methods showed a better 28-day mortality risk prediction using ΔNRL in association with ΔSOFA in comparison to ΔSOFA alone. These results were confirmed in an external validation cohort, including 101 critically ill cirrhotic patients. CONCLUSIONS: ΔNLR is an independent predictor of mortality in the critically ill cirrhotic patients' population who requires intensive care supportive treatment and should be used in association with ΔSOFA as a prognostic biomarker.

Primary bacterial ventriculitis in adults, an emergent diagnosis challenge: report of a meningoccal case and review of the literature.

BACKGROUND: Defined by an infection of the ventricular system of the brain, ventriculitis is usually known as a health-care associated infection. In contrast, primary pyogenic ventriculitis complicating community-acquired meningitis is uncommon, and mainly described in infants. Only seven cases that have occured in adults have been found in the international literature. CASE PRESENTATION: We report here a new case due to Neisseria meningitidis occurring in an 85 year-old-man. The comparison with previous reports allows to drawn several conclusions: (i) cases occurred in relatively old adults (median age: 65 years); (ii) Streptococcus pneumoniae, N. meningitiditis and Staphylococcus aureus are the leading responsible pathogens; (iii) atypical clinical presentation seems the rule in which meningism often lacks; (iv) in absence of clinical or biological specific parameters, modern brain imaging such as magnetic resonance imaging with gadolinium enhancement is of utmost importance for the diagnosis, leading to anticipate an increase of the diagnosis in the near future, thanks to easier access to such exploration; (v) death or serious sequelae commonly occurred; (vi) prolonged antibiotic courses (6 weeks to 3 months) have been used, without strong rational. In the given case, the patient presented with a lack of meningeal irritation signs. The diagnosis was made by MRI considering a lasting confused state. A four-week antibiotic regimen was successful, combining two weeks of intravenous cefotaxime followed by two weeks of oral levofloxacin much easier to administrate and allowing early rehabilitation. CONCLUSION: Primary bacterial ventriculitis is a real diagnosis challenge. Larger indications of MRI for bacterial meningitis, particularly in cases with an atypical presentation or poor evolution would certainly increase the number of diagnosis.

Interferometric control of the absorption in optical patch antennas.

Optical patch nano-antennas possess unique absorption, field enhancement and concentration capabilities - but their crosssection, as well as their response outside of normal incidence are not well understood. Here we explain the large cross-section by considering that each patch nanoantenna is a cavity excited from both sides. Such a simple physical picture allows to fully understand the influence of the angle of incidence - that odd resonances have a very high absorption cross-section which decreases when the incidence angle increases, while even resonances cannot be excited in normal incidence. A direct application would be to use these structures as an optical nanometric set-square.

Targeting immunoproteasome and glutamine supplementation prevent intestinal hyperpermeability.

BACKGROUND: Intestinal hyperpermeability has been reported in several intestinal and non-intestinal disorders. We aimed to investigate the role of the ubiquitin proteasome system in gut barrier regulation in two mice models: the water avoidance stress model (WAS) and a post-inflammatory model (post-TNBS). METHODS: Both models were applied in C57BL/6 male mice (n=7-8/group); Proteasome was targeted by injection of a selective proteasome inhibitor or by using knock-out mice for ß2i proteasome subunit. Finally, glutamine supplementation was evaluated. RESULTS: In both models (WAS at day 10, post-TNBS at day 28), we observed an increase in proteasome trypsin-like activity and in inducible ß2/constitutive ß2 subunit protein expression ratio, associated with an increase in intestinal permeability. Moreover, intestinal hyperpermeability was blunted by intraperitoneal injection of selective proteasome inhibitor in WAS and post-TNBS mice. Of note, knock-out mice for the ß2i subunit exhibited a significant decrease in intestinal permeability and fecal pellet output during WAS. Glutamine supplementation also improved colonic permeability in both models. CONCLUSIONS: In conclusion, the proteasome system is altered in the colonic mucosa of WAS and post-TNBS mice with increased trypsin-like activity. Associated intestinal hyperpermeability was blunted by immunoproteasome inhibition.

Acute renal artery occlusion following infliximab infusion.

We report the case of a 44-year-old male patient who presented with acute renal artery occlusion, 3 d after first injection of infliximab for steroid refractory attack of ulcerative colitis. Extensive work-up provided no evidence of predisposing factors for arterial thrombosis. Infliximab was thus suspected in the genesis of thrombosis, based on both intrinsic and extrinsic criteria. At month 3 after thrombosis with ongoing anticoagulation, angio-tomodensitometry showed complete revascularization of the left renal artery with renal atrophy. Renal function remained normal and the patient was still in steroid free remission on mercaptopurin monotherapy at maximal follow-up. Few thromboembolic events have been described with anti- tumor necrosis factor (TNF) agents, but it is the first case reported of renal artery thrombosis after infliximab infusion. In addition, we review thrombosis associated with anti-TNF agents.