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Abstract Background Activation of innate immunity is a first line of host defense during acute critical illness (ACI) that aims to contain injury and avoid tissue damages. Aberrant activation of innate immunity may also participate in the occurrence of organ failures during critical illness. This review aims to provide a narrative overview of recent advances in the field of innate immunity in critical illness, and to consider future potential therapeutic strategies. Main text Understanding the underlying biological concepts supporting therapeutic strategies modulating immune response is essential in decision-making. We will develop the multiple facets of innate immune response, especially its cellular aspects, and its interaction with other defense mechanisms. We will first describe the pathophysiological mechanisms of initiation of innate immune response and its implication during ACI. We will then develop the amplification of innate immunity mediated by multiple effectors. Our review will mainly focus on myeloid and lymphoid cellular effectors, the major actors involved in innate immune-mediated organ failure. We will third discuss the interaction and integration of innate immune response in a global view of host defense, thus considering interaction with non-immune cells through immunothrombosis, immunometabolism and long-term reprogramming via trained immunity. The last part of this review will focus on the specificities of the immune response in children and the older population. Conclusions Recent understanding of the innate immune response integrates immunity in a highly dynamic global vision of host response. A better knowledge of the implicated mechanisms and their tissue-compartmentalization allows to characterize the individual immune profile, and one day eventually, to develop individualized bench-to-bedside immunomodulation approaches as an adjuvant resuscitation strategy.

Abstract Background The STROMA-CoV-2 study was a French phase 2b, multicenter, double-blind, randomized, placebo-controlled clinical trial that did not identify a significant efficacy of umbilical cord-derived mesenchymal stromal cells in patients with SARS-CoV-2-induced acute respiratory distress syndrome. Safety on day 28 was found to be good. The aim of our extended study was to assess the 6- and 12-month safety of UC-MSCs administration in the STROMA-CoV-2 cohort. Methods A detailed multi-domain assessment was conducted at 6 and 12 months following hospital discharge focusing on adverse events, lung computed tomography-scan, pulmonary and muscular functional status, and quality of life in the STROMA-CoV-2 cohort including SARS–CoV-2-related early (

Background: The risk of SARS-CoV-2 transmission to health care workers in intensive care units (ICU) and the contribution of airborne and fomites to SARS-CoV-2 transmission remain unclear. To assess the rate of air and surface contamination and identify risk factors associated with this contamination in patients admitted to the ICU for acute respiratory failure due to SARS-CoV-2 pneumonia. Methods: Prospective multicentric non-interventional study conducted from June 2020 to November 2020 in 3 French ICUs. For each enrolled patient, 3 predefined surfaces were swabbed, 2 air samples at 1 m and 3 m from the patient’s mouth and face masks of 3 health care workers (HCW) were collected within the first 48 h of SARS-CoV-2 positive PCR in a respiratory sample. Droplet digital PCR and quantitative PCR were performed on different samples, respectively. Results: Among 150 included patients, 5 (3.6%, 95%CI: 1.2% to 8.2%) had positive ddPCR on air samples at 1 m or 3 m. Seventy-one patients (53.3%, CI95%: 44.5% to 62.0%) had at least one surface positive. Face masks worn by HCW were positive in 6 patients (4.4%, CI: 1.6% to 9.4%). The threshold of RT-qPCR of the respiratory sample performed at inclusion (odds ratio, OR= 0.88, 95%CI: 0.83 to 0.93, p

Background: Human metapneumovirus (hMPV) is one of the leading respiratory viruses. This prospective observational study aimed to describe the clinical features and the outcomes of hMPV-associated lower respiratory tract infections in adult inpatients. Methods: Consecutive adult patients admitted to one of the 31 participating centers with an acute lower respiratory tract infection and a respiratory multiplex PCR positive for hMPV were included. A primary composite end point of complicated course (hospital death and/or the need for invasive mechanical ventilation) was used. Results: Between March 2018 and May 2019, 208 patients were included. The median age was 74 [62–84] years. Ninety-seven (47 %) patients were men, 187 (90 %) had at least one coexisting illness, and 67 (31 %) were immunocompromised. Median time between first symptoms and hospital admission was 3 [2–7] days. The two most frequent symptoms were dyspnea (86 %) and cough (85 %). The three most frequent clinical diagnoses were pneumonia (42 %), acute bronchitis (20 %) and acute exacerbation of chronic obstructive pulmonary disease (16 %). Among the 52 (25 %) patients who had a lung CT-scan, the most frequent abnormality was ground glass opacity (41 %). While over four-fifths of patients (81 %) received empirical antibiotic therapy, a bacterial coinfection was diagnosed in 61 (29 %) patients. Mixed flora (16 %) and enterobacteria (5 %) were the predominant documentations. The composite criterion of complicated course was assessable in 202 (97 %) patients, and present in 37 (18 %) of them. In the subpopulation of pneumonia patients (42 %), we observed a more complicated course in those with a bacterial coinfection (8/24, 33 %) as compared to those without (5/60, 8 %) (p = 0.02). Sixty (29 %) patients were admitted to the intensive care unit. Among them, 23 (38 %) patients required invasive mechanical ventilation. In multivariable analysis, tachycardia and alteration of consciousness were identified as risk factors for complicated course. Conclusion: hMPV-associated lower respiratory tract infections in adult inpatients mostly involved elderly people with pre-existing conditions. Bacterial coinfection was present in nearly 30 % of the patients. The need for mechanical ventilation and/or the hospital death were observed in almost 20 % of the patients.

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Abstract Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is one of the leading causes of admission to the intensive care unit, often triggered by a respiratory tract infection of bacterial or viral aetiology. Managing antibiotic therapy in this context remains a challenge. Respiratory panel molecular tests allow identifying viral aetiologies of AECOPD. We hypothesized that the systematic use of a respiratory multiplex PCR (mPCR) would help antibiotics saving in severe AECOPD. Our objectives were to describe the spectrum of infectious aetiologies of severe AECOPD, using a diagnostic approach combining conventional diagnostic tests and mPCR, and to measure antibiotics exposure. The study was bicentric, prospective, observational, and included 105 critically ill patients with a severe AECOPD of presumed infectious aetiology, in whom a respiratory mPCR with a viral panel was performed in addition to conventional microbiological tests. Altogether, the microbiological documentation rate was 50%, including bacteria alone (19%), respiratory viruses alone (16%), and mixed viruses and bacterial species (16%). The duration of antibiotic therapy was shorter in patients without documented bacterial infection (5.6 vs. 9 days; P = 0.0006). This pilot study suggests that molecular tests may help for the proper use of anti-infective treatments in critically ill patients with severe AECOPD.

Abstract Background Despite current broad natural and vaccine-induced protection, a substantial number of patients infected with emerging SARS-CoV-2 variants (e.g., BF.7 and BQ.1.1) still experience severe COVID-19. Real-life studies investigating the impact of these variants on clinical outcomes of severe cases are currently not available. We performed a prospective multicenter observational cohort study. Adult patients with acute respiratory failure admitted between December 7, 2021 and December 15, 2022, in one of the 20 participating intensive care units (17 from the Greater Paris area and 3 from the North of France) were eligible for inclusion if they had SARS-CoV-2 infection confirmed by a positive reverse transcriptase-polymerase chain reaction (RT-PCR). Full-length SARS-CoV-2 genomes from all included patients were sequenced by means of next-generation sequencing. The primary endpoint of the study was day-28 mortality. Results The study included 158 patients infected with three groups of Omicron sublineages, including (i) BA.2 variants and their early sublineages referred as “BA.2” (n = 50), (ii) early BA.4 and BA.5 sublineages (including BA.5.1 and BA.5.2, n = 61) referred as “BA.4/BA.5”, and (iii) recent emerging BA.5 sublineages (including BQ.1, BQ.1.1, BF.7, BE.1 and CE.1, n = 47) referred as “BQ.1.1”. The clinical phenotype of BQ1.1-infected patients compared to earlier BA.2 and BA.4/BA.5 sublineages, showed more frequent obesity and less frequent immunosuppression. There was no significant difference between Omicron sublineage groups regarding the severity of the disease at ICU admission, need for organ failure support during ICU stay, nor day 28 mortality (21.7%, n = 10/47 in BQ.1.1 group vs 26.7%, n = 16/61 in BA.4/BA.5 vs 22.0%, n = 11/50 in BA.2, p = 0.791). No significant relationship was found between any SARS-CoV-2 substitution and/or deletion on the one hand and survival on the other hand over hospital follow-up. Conclusions Critically-ill patients with Omicron BQ.1.1 infection showed a different clinical phenotype than other patients infected with earlier Omicron sublineage but no day-28 mortality difference.

Abstract We aimed to explore the relationships between specific viral mutations/mutational patterns and ventilator-associated pneumonia (VAP) occurrence in COVID-19 patients admitted in intensive care units between October 1, 2020, and May 30, 2021. Full-length SARS-CoV-2 genomes were sequenced by means of next-generation sequencing. In this prospective multicentre cohort study, 259 patients were included. 222 patients (47%) had been infected with pre-existing ancestral variants, 116 (45%) with variant α, and 21 (8%) with other variants. 153 patients (59%) developed at least one VAP. There was no significant relationship between VAP occurrence and a specific SARS CoV-2 lineage/sublineage or mutational pattern.

Abstract Background Auto-antibodies (auto-Abs) neutralizing type I interferons (IFN) have been found in about 15% of critical cases COVID-19 pneumonia and less than 1% of mild or asymptomatic cases. Determining whether auto-Abs influence presentation and outcome of critically ill COVID-19 patients could lead to specific therapeutic interventions. Our objectives were to compare the severity at admission and the mortality of patients hospitalized for critical COVID-19 in ICU with versus without auto-Abs. Results We conducted a prospective multicentre cohort study including patients admitted in 11 intensive care units (ICUs) from Great Paris area hospitals with proven SARS-CoV-2 infection and acute respiratory failure. 925 critically ill COVID-19 patients were included. Auto-Abs neutralizing type I IFN-α2, β and/or ω were found in 96 patients (10.3%). Demographics and comorbidities did not differ between patients with versus without auto-Abs. At ICU admission, Auto-Abs positive patients required a higher FiO2 (100% (70–100) vs. 90% (60–100), p = 0.01), but were not different in other characteristics. Mortality at day 28 was not different between patients with and without auto-Abs (18.7 vs. 23.7%, p = 0.279). In multivariable analysis, 28-day mortality was associated with age (adjusted odds ratio (aOR) = 1.06 [1.04–1.08], p

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.

SARS-CoV-2 variant Omicron has been suggested to cause less severe disease. This prospective study shows that the clinical phenotype in patients infected with Omicron differs from patients infected with Delta but no association between Delta and Omicron including sublineages and mortality was observed.

Abstract Background Ventilator-associated pneumonia (VAP) is common in patients with severe SARS-CoV-2 pneumonia. The aim of this ancillary analysis of the coVAPid multicenter observational retrospective study is to assess the relationship between adjuvant corticosteroid use and the incidence of VAP. Methods Planned ancillary analysis of a multicenter retrospective European cohort in 36 ICUs. Adult patients receiving invasive mechanical ventilation for more than 48 h for SARS-CoV-2 pneumonia were consecutively included between February and May 2020. VAP diagnosis required strict definition with clinical, radiological and quantitative microbiological confirmation. We assessed the association of VAP with corticosteroid treatment using univariate and multivariate cause-specific Cox’s proportional hazard models with adjustment on pre-specified confounders. Results Among the 545 included patients, 191 (35%) received corticosteroids. The proportional hazard assumption for the effect of corticosteroids on the incidence of VAP could not be accepted, indicating that this effect varied during ICU stay. We found a non-significant lower risk of VAP for corticosteroid-treated patients during the first days in the ICU and an increased risk for longer ICU stay. By modeling the effect of corticosteroids with time-dependent coefficients, the association between corticosteroids and the incidence of VAP was not significant (overall effect p = 0.082), with time-dependent hazard ratios (95% confidence interval) of 0.47 (0.17–1.31) at day 2, 0.95 (0.63–1.42) at day 7, 1.48 (1.01–2.16) at day 14 and 1.94 (1.09–3.46) at day 21. Conclusions No significant association was found between adjuvant corticosteroid treatment and the incidence of VAP, although a time-varying effect of corticosteroids was identified along the 28-day follow-up.

Introduction Delirium is a severe complication that is associated with short-term adverse events, prolonged hospital stay and neurological sequelae in survivors. Automated pupillometry is an easy-to-use device that allows for accurate objective assessment of the pupillary light responses in comatose patients in the intensive care unit (ICU). Whether automated pupillometry might predict delirium in critically ill patients is not known. We hypothesise that automated pupillometry could predict the occurrence of delirium in critically ill patients without primary brain injury, requiring more than 48 hours of invasive mechanical ventilation in the ICU.Methods and analysis The PupillOmetry for preDIction of DeliriUM in ICU (PODIUM) study is a prospective cohort study, which will be conducted in eight French ICUs in the Paris area. We aim to recruit 213 adult patients requiring invasive mechanical ventilation for more than 48 hours. Automated pupillometry (Neurological Pupil Index; NPi-200, Neuroptics) will be assessed two times per day for 7 days. Delirium will be assessed using the Confusion Assessment Method in ICU two times per day over 14 days in non-comatose patients (Richmond Agitation and Sedation Scale ≥−3).The predictive performances of the seven automated pupillometry parameters (ie, pupillary diameter, variation of the pupillary diameter, pupillary constriction speed, pupillary dilatation speed, photomotor reflex latency, NPi and symmetry of pupillary responses) measured to detect the delirium occurrence within 14 days will be the main outcomes. Secondary outcomes will be the predictive performances of the seven automated pupillometry parameters to detect complications related to delirium, ICU length of stay, mortality, functional and cognitive outcomes at 90 days.Ethics and dissemination The PODIUM study has been approved by an independent ethics committee, the Comité de Protection des Personnes (CPP) OUEST IV—NANTES (CPP21.02.15.45239 32/21_3) on 06 April 2021). Participant recruitment started on 15 April 2022. Results will be published in international peer-reviewed medical journals and presented at conferences.Trial registration number NCT05248035; clinicaltrials.gov.

Abstract Background Post‐intensive care syndrome (PICS) encompasses physical, cognition, and mental impairments persisting after intensive care unit (ICU) discharge. Ultimately it significantly impacts the long‐term prognosis, both in functional outcomes and survival. Thus, survivors often develop permanent disabilities, consume a lot of healthcare resources, and may experience prolonged suffering. This review aims to present the multiple facets of the PICS, decipher its underlying mechanisms, and highlight future research directions. Main text This review abridges the translational data underlying the multiple facets of chronic critical illness (CCI) and PICS. We focus first on ICU-acquired weakness, a syndrome characterized by impaired contractility, muscle wasting, and persisting muscle atrophy during the recovery phase, which involves anabolic resistance, impaired capacity of regeneration, mitochondrial dysfunction, and abnormalities in calcium homeostasis. Second, we discuss the clinical relevance of post-ICU cognitive impairment and neuropsychological disability, its association with delirium during the ICU stay, and the putative role of low-grade long-lasting inflammation. Third, we describe the profound and persistent qualitative and quantitative alteration of the innate and adaptive response. Fourth, we discuss the biological mechanisms of the progression from acute to chronic kidney injury, opening the field for renoprotective strategies. Fifth, we report long-lasting pulmonary consequences of ARDS and prolonged mechanical ventilation. Finally, we discuss several specificities in children, including the influence of the child’s pre-ICU condition, development, and maturation. Conclusions Recent understandings of the biological substratum of the PICS’ distinct features highlight the need to rethink our patient trajectories in the long term. A better knowledge of this syndrome and precipitating factors is necessary to develop protocols and strategies to alleviate the CCI and PICS and ultimately improve patient recovery.

Abstract The local immune-inflammatory response elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still poorly described, as well as the extent to which its characteristics may be associated with the outcome of critical Coronavirus disease 2019 (COVID-19). In this prospective monocenter study, all consecutive COVID-19 critically ill patients admitted from February to December 2020 and explored by fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) were included. Biological assays, including digital ELISA cytokine profiling and targeted eicosanoid metabolomic analysis, were performed on paired blood and BAL fluid (BALF). Clinical outcome was assessed through the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) at the 28th day (D28) following the admission to intensive care unit. A D28-WHO-CPS value higher than 5 defined a poor outcome. Seventy-six patients were included, 45 (59%) had a poor day-28 outcome. As compared to their counterparts, patients with D28-WHO-CPS > 5 exhibited a neutrophil-predominant bronchoalveolar phenotype, with a higher BALF neutrophil/lymphocyte ratio, a blunted local type I interferon response, a decompartimentalized immune-inflammatory response illustrated by lower BALF/blood ratio of concentrations of IL-6 (1.68 [0.30–4.41] vs. 9.53 [2.56–19.1]; p = 0.001), IL-10, IL-5, IL-22 and IFN-γ, and a biological profile of vascular endothelial injury illustrated by a higher blood concentration of VEGF and higher blood and/or BALF concentrations of several vasoactive eicosanoids. In critically ill COVID-19 patients, we identified bronchoalveolar and blood immune-inflammatory biomarker signature associated with poor 28-day outcome.

Abstract 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

In some patients, SARS-CoV-2 infection induces cytokine storm, hypercoagulability and endothelial cell activation leading to worsening of COVID-19, intubation and death. Prompt identification of patients at risk of intubation is an urgent need. Objectives. To derive a prognostic score for the risk of intubation or death in patients with COVID-19 admitted in intensive care unit (ICU), by assessing biomarkers of hypercoagulability, endothelial cell activation and inflammation and a large panel of clinical analytes. Design, Setting and Participants. A prospective, observational study enrolled 118 patients with COVID-19 admitted in the ICU. On the first day of ICU admission, all patients were assessed for biomarkers (protein C, protein S, antithrombin, D-Dimer, fibrin monomers, FVIIa, FV, FXII, FXII, FVIII, FvW antigen, fibrinogen, procoagulant phospholipid dependent clotting time, TFPI, thrombomodulin, P-selectin, heparinase, microparticles exposing TF, IL-6, complement C3a, C5a, thrombin generation, PT, aPTT, hemogram, platelet count) and clinical predictors. Main Outcomes and Measures. The clinical outcomes were intubation and mortality during hospitalization in ICU. Results: The intubation and mortality rates were 70% and 18%, respectively. The COMPASS-COVID-19-ICU score composed of P-Selectin, D-Dimer, free TFPI, TF activity, IL-6 and FXII, age and duration of hospitalization predicted the risk of intubation or death with high sensitivity and specificity (0.90 and 0.92, respectively). Conclusions and Relevance. COVID-19 is related to severe endothelial cell activation and hypercoagulability orchestrated in the context of inflammation. The COMPASS-COVID-19-ICU risk assessment model is accurate for the evaluation of the risk of mechanical ventilation and death in patients with critical COVID-19. The COMPASS-COVID-19-ICU score is feasible in tertiary hospitals and could be placed in the diagnostic procedure of personalized medical management and prompt therapeutic intervention.

Abstract Background Severe acute respiratory syndrome coronavirus-2 (SARS–CoV-2)-induced acute respiratory distress syndrome (ARDS) causes high mortality. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have potentially relevant immune-modulatory properties, whose place in ARDS treatment is not established. This phase 2b trial was undertaken to assess the efficacy of UC-MSCs in patients with SARS–CoV-2-induced ARDS. Methods This multicentre, double-blind, randomized, placebo-controlled trial (STROMA–CoV-2) recruited adults (≥ 18 years) with SARS–CoV-2-induced early (

Abstract Background Recent multicenter studies identified COVID-19 as a risk factor for invasive pulmonary aspergillosis (IPA). However, no large multicenter study has compared the incidence of IPA between COVID-19 and influenza patients. Objectives To determine the incidence of putative IPA in critically ill SARS-CoV-2 patients, compared with influenza patients. Methods This study was a planned ancillary analysis of the coVAPid multicenter retrospective European cohort. Consecutive adult patients requiring invasive mechanical ventilation for > 48 h for SARS-CoV-2 pneumonia or influenza pneumonia were included. The 28-day cumulative incidence of putative IPA, based on Blot definition, was the primary outcome. IPA incidence was estimated using the Kalbfleisch and Prentice method, considering extubation (dead or alive) within 28 days as competing event. Results A total of 1047 patients were included (566 in the SARS-CoV-2 group and 481 in the influenza group). The incidence of putative IPA was lower in SARS-CoV-2 pneumonia group (14, 2.5%) than in influenza pneumonia group (29, 6%), adjusted cause-specific hazard ratio (cHR) 3.29 (95% CI 1.53–7.02, p = 0.0006). When putative IPA and Aspergillus respiratory tract colonization were combined, the incidence was also significantly lower in the SARS-CoV-2 group, as compared to influenza group (4.1% vs. 10.2%), adjusted cHR 3.21 (95% CI 1.88–5.46, p

Abstract Background Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-COV 2) and requiring intensive care unit (ICU) have a high incidence of hospital-acquired infections; however, data regarding hospital acquired bloodstream infections (BSI) are scarce. We aimed to investigate risk factors and outcome of BSI in critically ill coronavirus infectious disease-19 (COVID-19) patients. Patients and methods We performed an ancillary analysis of a multicenter prospective international cohort study (COVID-ICU study) that included 4010 COVID-19 ICU patients. For the present analysis, only those with data regarding primary outcome (death within 90 days from admission) or BSI status were included. Risk factors for BSI were analyzed using Fine and Gray competing risk model. Then, for outcome comparison, 537 BSI-patients were matched with 537 controls using propensity score matching. Results Among 4010 included patients, 780 (19.5%) acquired a total of 1066 BSI (10.3 BSI per 1000 patients days at risk) of whom 92% were acquired in the ICU. Higher SAPS II, male gender, longer time from hospital to ICU admission and antiviral drug before admission were independently associated with an increased risk of BSI, and interestingly, this risk decreased over time. BSI was independently associated with a shorter time to death in the overall population (adjusted hazard ratio (aHR) 1.28, 95% CI 1.05–1.56) and, in the propensity score matched data set, patients with BSI had a higher mortality rate (39% vs 33% p = 0.036). BSI accounted for 3.6% of the death of the overall population. Conclusion COVID-19 ICU patients have a high risk of BSI, especially early after ICU admission, risk that increases with severity but not with corticosteroids use. BSI is associated with an increased mortality rate.

Abstract Little is known about patients with sickle cell disease (SCD) who require intensive care unit (ICU) admission. The goals of this study were to assess outcomes in patients admitted to the ICU for acute complications of SCD and to identify factors associated with adverse outcomes. This multicenter retrospective study included consecutive adults with SCD admitted to one of 17 participating ICUs. An adverse outcome was defined as death or a need for life-sustaining therapies (non-invasive or invasive ventilation, vasoactive drugs, renal replacement therapy, and/or extracorporeal membrane oxygenation). Factors associated with adverse outcomes were identified by mixed multivariable logistic regression. We included 488 patients admitted in 2015–2017. The main reasons for ICU admission were acute chest syndrome (47.5%) and severely painful vaso-occlusive event (21.3%). Sixteen (3.3%) patients died in the ICU, mainly of multi-organ failure following a painful vaso-occlusive event or sepsis. An adverse outcome occurred in 81 (16.6%; 95% confidence interval [95% CI], 13.3%–19.9%) patients. Independent factors associated with adverse outcomes were low mean arterial blood pressure (adjusted odds ratio [aOR], 0.98; 95% CI 0.95–0.99; p = 0.027), faster respiratory rate (aOR, 1.09; 95% CI 1.05–1.14; p

Abstract Background Echocardiographic parameters have been poorly investigated for estimating cardiovascular risk in patients with sepsis and new-onset atrial fibrillation. We aim to assess the prevalence of transesophageal echocardiographic abnormalities and their relationship with cardiovascular events in mechanically ventilated patients with sepsis and new-onset atrial fibrillation. Methods In this prospective multicenter pilot study, left atrial/left atrial appendage (LA/LAA) dysfunction, severe aortic atheroma, and left ventricular systolic dysfunction were assessed using an initial transesophageal echocardiographic study, which was repeated after 48–72 h to detect LA/LAA thrombus formation. The study outcome was a composite of cardiovascular events at day 28, including arterial thromboembolic events (ischemic stroke, non-cerebrovascular arterial thromboembolism, LA/LAA thrombus), major bleeding, and all-cause death. Results The study population comprised 94 patients (septic shock 63%; 35% women; median age 69 years). LA/LAA dysfunction, severe aortic atheroma, and left ventricular systolic dysfunction were detected in 17 (19%), 22 (24%), and 27 (29%) patients, respectively. At day 28, the incidence of cardiovascular events was 46% (95% confidence interval [CI]: 35 to 56). Arterial thromboembolic events and major bleeding occurred in 7 (7%) patients (5 ischemic strokes, 1 non-cerebrovascular arterial thromboembolism, 2 left atrial appendage thrombi) and 18 (19%) patients, respectively. At day 28, 27 patients (29%) died. Septic shock (hazard ratio [HR]: 2.36; 95% CI 1.06 to 5.29) and left ventricular systolic dysfunction (HR: 2.06; 95% CI 1.05 to 4.05) were independently associated with cardiovascular events. Conclusions Transesophageal echocardiographic abnormalities are common in mechanically ventilated patients with sepsis and new-onset atrial fibrillation, but only left ventricular systolic dysfunction was associated with cardiovascular events at day 28.

Usually responsible for soft tissue infections, Clostridioides species can also cause bacteremia, life-threatening infections often requiring intensive care unit (ICU) admission. We conducted a multicenter retrospective study to investigate Clostridioides bacteremia in ICUs to describe the clinical and biologic characteristics and outcomes in critically ill patients. We identified 135 patients with Clostridioides bacteremia, which occurred almost exclusively (96%) in patients with underlying conditions. Septic shock and digestive symptoms were the hallmarks of Clostridioides bacteremia in the ICU. We identified 16 different species of Clostridioides, among which C. perfringens accounted for 31% of cases. Despite the high sensitivity of Clostridioides to common antimicrobial drugs, mortality rates were high: 52% for ICU patients and 71% overall at 3 months. In multivariate analysis, the most important factor associated with increased risk for death was the presence of hemolysis. Clostridioides bacteremia often leads to multiple organ failures, which have high mortality rates.

Abstract Background Growing 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 text Sepsis 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. Conclusions Recent 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.

Abstract Purpose At the critical care level, the flu surveillance system is limited in France, with heterogeneous regional modalities of implementation. Materials, patients and methods We aimed at assessing the relevance of the Assistance Publique-Hôpitaux de Paris (AP-HP) clinical data warehouse for estimating the burden of the influenza epidemic on medical adult critical care units of the AP-HP, and outcome of patients during the flu season 2017–2018. This exploratory multi-site epidemiological study comprised all consecutive adult stays (n = 320) in 18 medical intensive care units (ICU) or intermediate care wards (ICW) for probable or confirmed Influenza virus infection during the 2017–2018 flu season. Results Patients admitted to ICU/ICW had low vaccination coverage (21%), required life support in 60% of cases, stayed in the ICU for a median of 8 days, and had high 28-day mortality rate (19.7%; 95% confidence interval 15.5–24.5). Early prognostic factors included age, core temperature, the acute organ failures score, and the early administration of antiviral therapy. Conclusions Data directly extracted from the electronic medical records stored in the data warehouse provide detailed clinical, care pathway and prognosis information. The real-time availability should enable to detect and assess the burden of the most severe cases. By a firmer and more acute monitoring and adjustment of care and patient management, hospitals could generate more ICU/ICW capacities, sensitize their emergency department and contribute to the recommendations from health authorities. This pilot study is of particular relevance in the context of emerging epidemics of severe acute respiratory diseases.

Abstract Background Patients with SARS-CoV-2 infection are at higher risk for ventilator-associated pneumonia (VAP). No study has evaluated the relationship between VAP and mortality in this population, or compared this relationship between SARS-CoV-2 patients and other populations. The main objective of our study was to determine the relationship between VAP and mortality in SARS-CoV-2 patients. Methods Planned ancillary analysis of a multicenter retrospective European cohort. VAP was diagnosed using clinical, radiological and quantitative microbiological criteria. Univariable and multivariable marginal Cox’s regression models, with cause-specific hazard for duration of mechanical ventilation and ICU stay, were used to compare outcomes between study groups. Extubation, and ICU discharge alive were considered as events of interest, and mortality as competing event. Findings Of 1576 included patients, 568 were SARS-CoV-2 pneumonia, 482 influenza pneumonia, and 526 no evidence of viral infection at ICU admission. VAP was associated with significantly higher risk for 28-day mortality in SARS-CoV-2 (adjusted HR 1.70 (95% CI 1.16–2.47), p = 0.006), and influenza groups (1.75 (1.03–3.02), p = 0.045), but not in the no viral infection group (1.07 (0.64–1.78), p = 0.79). VAP was associated with significantly longer duration of mechanical ventilation in the SARS-CoV-2 group, but not in the influenza or no viral infection groups. VAP was associated with significantly longer duration of ICU stay in the 3 study groups. No significant difference was found in heterogeneity of outcomes related to VAP between the 3 groups, suggesting that the impact of VAP on mortality was not different between study groups. Interpretation VAP was associated with significantly increased 28-day mortality rate in SARS-CoV-2 patients. However, SARS-CoV-2 pneumonia, as compared to influenza pneumonia or no viral infection, did not significantly modify the relationship between VAP and 28-day mortality. Clinical trial registration The study was registered at ClinicalTrials.gov, number NCT04359693.

Abstract Background While acute kidney injury (AKI) is frequent in severe SARS-CoV2-related pneumonia ICU patients, few data are still available about its risk factors. Methods Retrospective observational study performed in four university affiliated hospitals in Paris. AKI was defined according to the KIDGO guidelines. Factors associated with AKI were picked up using multivariable mixed-effects logistic regression. Independent risk factors of day 28 mortality were assessed using Cox model. Results 379 patients (median age 62 [53,69], 77% of male) were included. Half of the patients had AKI (n = 195, 52%) including 58 patients (15%) with AKI stage 1, 44 patients (12%) with AKI stage 2, and 93 patients (25% with AKI stage 3). Chronic kidney disease (OR 7.41; 95% CI 2.98–18.4), need for invasive mechanical ventilation at day 1 (OR 4.83; 95% CI 2.26–10.3), need for vasopressors at day 1 (OR 2.1; 95% CI 1.05–4.21) were associated with increased risk of AKI. Day 28 mortality in the cohort was 26.4% and was higher in patients with AKI (37.4 vs. 14.7%, P

Abstract Acute chest syndrome (ACS) is the most serious complication of sickle cell disease. The pathophysiology of ACS may involve lower respiratory tract infection (LRTI), alveolar hypoventilation and atelectasis, bone infarcts-driven fat embolism, and in situ pulmonary artery thrombosis. One of the most challenging issues for the physicians is to diagnose LRTI as the cause of ACS. The use of a respiratory multiplex PCR (mPCR) for the diagnosis of LRTI has not been assessed in sickle-cell adult patients with ACS. To describe the spectrum of infectious aetiologies of severe ACS, using a diagnostic approach combining conventional tests and mPCR. A non-interventional monocenter prospective study involving all the consecutive sickle-cell adult patients with ACS admitted to the intensive care unit (ICU). Microbiological investigation included conventional tests and a nasopharyngeal swab for mPCR. Altogether, 36 patients were enrolled, of whom 30 (83%) had complete microbiological investigations. A bacterial microorganism, mostly Staphylococcus aureus (n = 8), was identified in 11 patients. There was no pneumonia-associated intracellular bacterial pathogen. A respiratory virus was identified in six patients. Using both conventional tests and nasopharyngeal mPCR, a microbiological documentation was obtained in half of adult ACS patients admitted to the ICU. Pyogenic bacteria, especially S. aureus, predominated.

Abstract Background SARS 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. Methods Six-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. Results 101 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

Abstract Background Sickle-cell anaemia is a widespread genetic disease prevalent worldwide among African and African-American populations. The pathogenesis is most often revealed by pulmonary conditions, including acute thoracic syndrome, which is affecting the life expectancy of these populations. The global spread of CoV2-SARS infection with a respiratory tropism, endothelial damages and procoagulant status endangers the SCD population. However, with only a few case reports, consequences of the Covid-19 pandemic on SCD population remain poorly known. Case presentation We report a case of a 33-year-old man with a history of homozygous SS homozygous sickle cell anemia who consulted on March 24, 2020 for febrile dyspnea 11 days after the onset of symptoms. A nasopharyngeal swab was positive for SARS-CoV-2. His respiratory status worsened rapidly in the emergency room and then in ICU leading to severe ARDS requiring intubation, curarization, and venovenous ECMO. Hematologically, severe hemolysis associated with major thrombocytopenia without documented spinal cord injury was noted. Several transfusion exchanges are performed. The evolution was finally slowly favorable and led to discharge from the intensive care unit and then from the hospital. Conclusions This case recalls the importance of an increased prevention policy against COVID-19among the SCD population. In addition, from a therapeutic point of view, it advocates (1) a high preventive anticoagulation from the outset according to the level of D-dimers (2) the use of venovenous ECMO in this particular case, whereas this technique has had rather disappointing results in acute chest syndromes. (3) Unexpectedly, our patient did not develop pulmonary arterial hypertension (PAH) and acute cor pulmonale (ACP), whereas this is a common feature of ARDS during SCD. These last two observations suggest a different pathophysiology of pulmonary disorders in SCD patients in the case of SARS COv2. It could be associated with marked hypoxemia secondary to pulmonary vascular vasodilation.

Introduction COVID-19 induces venous, arterial and microvascular thrombosis, involving several pathophysiological processes. In patients with severe COVID-19 without macrovascular thrombosis, escalating into high-dose prophylactic anticoagulation (HD-PA) or therapeutic anticoagulation (TA) could be beneficial in limiting the extension of microvascular thrombosis and forestalling the evolution of lung and multiorgan microcirculatory dysfunction. In the absence of data from randomised trials, clinical practice varies widely.Methods and analysis This is a French multicentre, parallel-group, open-label, randomised controlled superiority trial to compare the efficacy and safety of three anticoagulation strategies in patients with COVID-19. Patients with oxygen-treated COVID-19 showing no pulmonary artery thrombosis on computed tomography with pulmonary angiogram will be randomised to receive either low-dose PA, HD-PA or TA for 14 days. Patients attaining the extremes of weight and those with severe renal failure will not be included. We will recruit 353 patients. Patients will be randomised on a 1:1:1 basis, and stratified by centre, use of invasive mechanical ventilation, D-dimer levels and body mass index. The primary endpoint is a hierarchical criterion at day 28 including all-cause mortality, followed by the time to clinical improvement defined as the time from randomisation to an improvement of at least two points on the ordinal clinical scale. Secondary outcomes include thrombotic and major bleeding events at day 28, individual components of the primary endpoint, number of oxygen-free, ventilator-free and vasopressor-free days at day 28, D-dimer and sepsis-induced coagulopathy score at day 7, intensive care unit and hospital stay at day 28 and day 90, and all-cause death and quality of life at day 90.Ethics and dissemination The study has been approved by an ethical committee (Ethics Committee, Ile de France VII, Paris, France; reference 2020-A03531-38). Patients will be included after obtaining their signed informed consent. The results will be submitted for publication in peer-reviewed journals.Trial registration number NCT04808882.

Abstract Introduction Acute respiratory failure is the main reason for admission to the intensive care unit (ICU) in HIV-infected adults. There is little data about the epidemiology of respiratory viruses in this population. Methods HIV-infected adults admitted to two intensive care units over a 6-year period for an acute respiratory failure and explored for respiratory viruses with multiplex polymerase chain reaction (mPCR) were retrospectively selected. Objectives were to describe the prevalence of respiratory viruses, coinfections with non-viral pathogens, and hospital outcome. Results A total of 123 episodes were included. An HIV infection was newly diagnosed in 9% of cases and 72% of the population were on antiretroviral therapy. Real-time mPCR tests identified at least one respiratory virus in the respiratory tract of 33 (27%) patients, but with a non-viral copathogen in two-thirds of cases. Rhinovirus was predominant, documented in 15 patients, followed by Influenza and Respiratory Syncytial Viruses (both n = 6). The prevalence of respiratory virus-associated infection did not vary along with the level of the CD4 T-cell deficiency, except for Rhinovirus which was more prevalent in patients with a CD4 lymphocyte count below 200 cells/µL (n = 13 (20%) vs. n = 2 (4%), p

Community-acquired Pseudomonas aeruginosa infections are rare. Most cases involve patients either with underlying immunosuppression or structural chronic lung diseases. We report here an atypical case of a severe community-acquired invasive infection due to a hypervirulent ExoU-producing strain, in an immunocompetent patient.

Abstract Background Mucormycosis is an invasive fungal infection, with an increasing incidence especially in patients with hematological malignancies. Its prognosis is poor because of its high invasive power and its intrinsic low susceptibility to antifungal agents. We aimed to describe the epidemiology of mucormycosis in intensive care units (ICU) and evaluate the outcomes. We performed a retrospective multi-center study in 16 French ICUs between 2008 and 2017. We compared the patients who survived in ICU and the patients who did not to identify factors associated with ICU survival. Then, we focused on the subgroup of patients with hematological malignancies. Results Mucormycosis was diagnosed in 74 patients during the study period. Among them, 60 patients (81%) were immunocompromised: 41 had hematological malignancies, 9 were solid organ transplant recipients, 31 received long-term steroids, 11 had diabetes, 24 had malnutrition. Only 21 patients survived to ICU stay (28.4%) with a median survival of 22 days (Q1–Q3 = 9–106) and a survival rate at day 28 and day 90, respectively, of 35.1% and 26.4%. Survivors were significantly younger (p = 0.001), with less frequently hematological malignancies (p = 0.02), and less malnutrition (p = 0.05). Median survival in patients with hematological malignancies (n = 41) was 15 days (Q1–Q3 = 5–23.5 days). In this subgroup, curative surgery was a major factor associated with survival in multivariate analysis (odds ratio = 0.71, [0.45–0.97], p

Purpose To compare the characteristics, management, and prognosis of patients admitted to intensive care units (ICU) for coronavirus disease (COVID)-19 during the first two waves of the outbreak and to evaluate the relationship between ICU strain (ICU demand due to COVID-19 admissions) and mortality. Methods In a multicentre retrospective study, 1166 COVID-19 patients admitted to five ICUs in France between 20 February and 31 December 2020 were included. Data were collected at each ICU from medical records. A Cox proportional-hazards model identified factors associated with 28-day mortality. Results 640 patients (55%) were admitted during the first wave (February to June 2020) and 526 (45%) during the second wave (July to December 2020). ICU strain was lower during the second wave (-0.81 [-1.04 –-0.31] vs. 1.18 [-0.34–1.29] SD when compared to mean COVID-19 admission in each center during study period, PConclusion The characteristics and the management of patients varied between the first and the second wave of the pandemic. Rather than the wave, ICU strain was independently associated with 28-day mortality, but not with hospital mortality.

Little is known about the immuno-inflammatory response to Tocilizumab and its association with outcome in critically-ill SARS-CoV2 pneumonia. In this multicenter retrospective cohort of SARS-CoV-2 patients admitted to three intensive care units between March and April 2020, we matched on gender and SAPS II 21 Tocilizumab-treated patients to 42 non-treated patients. Need for mechanical ventilation was 76% versus 79%. IL-6, C-reactive protein, and fibrinogen had been collected within the first days of admission (T1), 3 d (T2) and 7 d (T3) later. Tocilizumab-treated patients had persistently higher IL-6 plasma levels and persistently lower C-Reactive protein and fibrinogen levels. Among Tocilizumab-treated patients, baseline levels of inflammatory biomarkers were not different according to outcome. Conversely, C-reactive protein and fibrinogen decrease was delayed in non-survivors. C-Reactive protein decreased at T1 in survivors (45 [30–98] vs 170 [69–204] mg/l, P

Rationale Acute pulmonary hypertension (PH) may develop during sickle-cell acute chest syndrome (ACS), and is associated with an increased mortality. Its mechanisms remain poorly known. We questioned whether there is endothelial dysfunction and hypercoagulability in severe ACS, with and without acute PH. Methods In a prospective monocentre cohort follow-up study, all sickle-cell adult patients with ACS admitted to the intensive care unit underwent transthoracic echocardiography and measurement of biomarkers of coagulation, endothelial activation and platelet and erythrocyte activation. Acute PH was defined as a high echocardiographic probability of PH. The biological profiles of sickle-cell patients were analysed at the time of ACS, contrasting with the existence of acute PH, and compared with steady-state and with non-sickle-cell controls (healthy subjects and community-acquired pneumonia). Results Most patients (36 patients with 39 ACS episodes; 23 males; median age 27 years) had thoracic pain, dyspnoea and computed tomography scan lung consolidation. Acute PH was diagnosed in seven (19%) patients. Erythrocyte- and platelet-derived microparticles and the pro-coagulant activity of microparticles were higher in ACS patients with acute PH, compared with their counterparts. Compared with healthy controls, ACS patients had higher levels of tissue factor, fibrin monomers, D-dimer, release of pro-coagulant microparticles and erythrocyte- and platelet-derived microparticles. Compared with community-acquired pneumonia patients, ACS patients had increased levels of fibrin monomers and erythrocyte- and platelet-derived microparticles. Conclusions Severe ACS is characterised by endothelial dysfunction and hypercoagulability, with a marked pro-coagulant profile in cases of associated PH.

Background Whereas first-line bronchial artery embolisation (BAE) is considered standard of care for the management of severe haemoptysis, it is unknown whether this approach is warranted for non-severe haemoptysis.Research question To assess the efficacy on bleeding control and the safety of first-line BAE in non-severe haemoptysis of mild abundance.Study design and methods This multicentre, randomised controlled open-label trial enrolled adult patients without major comorbid condition and having mild haemoptysis (onset

Introduction At the time of the worrying emergence and spread of bacterial resistance, reducing the selection pressure by reducing the exposure to antibiotics in patients with community-acquired pneumonia (CAP) is a public health issue. In this context, the combined use of molecular tests and biomarkers for guiding antibiotics discontinuation is attractive. Therefore, we have designed a trial comparing an integrated approach of diagnosis and treatment of severe CAP to usual care.Methods and analysis The multiplex PCR and procalcitonin to reduce duration of antibiotics exposure in patients with severe-CAP (MULTI-CAP) trial is a multicentre (n=20), parallel-group, superiority, open-label, randomised trial. Patients are included if adult admitted to intensive care unit for a CAP. Diagnosis of pneumonia is based on clinical criteria and a newly appeared parenchymal infiltrate. Immunocompromised patients are excluded. Subjects are randomised (1:1 ratio) to either the intervention arm (experimental strategy) or the control arm (usual strategy). In the intervention arm, the microbiological diagnosis combines a respiratory multiplex PCR (mPCR) and conventional microbiological investigations. An algorithm of early antibiotic de-escalation or discontinuation is recommended, based on mPCR results and the procalcitonin value. In the control arm, only conventional microbiological investigations are performed and antibiotics de-escalation remains at the clinician’s discretion. The primary endpoint is the number of days alive without any antibiotic from the randomisation to day 28. Based on our hypothesis of 2 days gain in the intervention arm, we aim to enrol a total of 450 patients over a 30-month period.Ethics and dissemination The MULTI-CAP trial is conducted according to the principles of the Declaration of Helsinki, is registered in Clinical Trials and has been approved by the Committee for Protection of Persons and the National French Drug Safety Agency. Written informed consents are obtained from all the patients (or representatives). The results will be disseminated through educational institutions, submitted to peer-reviewed journals for publication and presented at medical congresses.Trial registration number NCT03452826; Pre-results.

Abstract Background Since the beginning of SARS-CoV-2 outbreak in China, severe acute respiratory syndrome has been widely descripted. Hemoptysis has rarely been observed in SARS-CoV-2 infection. We report here a case of severe hemoptysis in post-tuberculosis bronchiectasis precipitated by SARS-CoV-2 infection and managed in a referral center. Case presentation A 58-year-old man was admitted to our intensive care unit for severe hemoptysis with history of post-tuberculosis bronchiectasis. At ICU admission the patient had fever and severe acute respiratory failure requiring high flow oxygen therapy. Respiratory tract sampling was positive for SARS-CoV-2. Multi-detector computed tomography angiography pointed out localized bronchiectasis on the left lower lobe and enlarged left bronchial and phrenic arteries; bronchial arteriography with distal embolization was performed with favorable outcome and no bleeding recurrence. Conclusions To our knowledge, this is the first case of acute exacerbation of bronchiectasis related to SARS-CoV-2 infection and complicated by severe hemoptysis. Whether the virus may play a role in the dysregulation of airway haemostasis, and contribute to episodes of hemoptysis in patients with chronic pulmonary diseases and predisposing factors might be investigated.

Abstract In this survey endorsed by the European Society of Intensive Care Medicine (ESICM), we aimed to describe the practice patterns of intensivists worldwide, regarding their diagnosis and management of respiratory viruses in lower respiratory tract infections. There were 229 respondents from 53 countries, mainly in Europe (78%). Our main findings are that a majority of intensivists (i) searched for respiratory viruses in case of severe community-acquired LRTI in adults, whatever the season and the medical history and clinical presentation; (ii) had access to large-panel respiratory mPCR; (iii) used them as first-line diagnostic test in routine practice; (iv) had some knowledge about the panel of the mPCR that they use, but markedly less about the cost. However, we observed strong heterogeneity regarding how intensivists took into account mPCR results for infection control (confinement measures) and patient care (antiviral treatment and antibiotics management).

Abstract Background The French Emergency Medicine Society, the French Intensive Care Society and the Pediatric Intensive Care and Emergency Medicine French-Speaking Group edited guidelines on severe asthma exacerbation (SAE) in adult and pediatric patients. Results The guidelines were related to 5 areas: diagnosis, pharmacological treatment, oxygen therapy and ventilation, patients triage, specific considerations regarding pregnant women. The literature analysis and formulation of the guidelines were conducted according to the Grade of Recommendation Assessment, Development and Evaluation methodology. An extensive literature research was conducted based on publications indexed in PubMed™ and Cochrane™ databases. Of the 21 formalized guidelines, 4 had a high level of evidence (GRADE 1+/−) and 7 a low level of evidence (GRADE 2+/−). The GRADE method was inapplicable to 10 guidelines, which resulted in expert opinions. A strong agreement was reached for all guidelines. Conclusion The conjunct work of 36 experts from 3 scientific societies resulted in 21 formalized recommendations to help improving the emergency and intensive care management of adult and pediatric patients with SAE.

Abstract Background The objective of this study was to assess the cumulative incidence of invasive candidiasis (IC) in intensive care units (ICUs) in Europe. Methods A multinational, multicenter, retrospective study was conducted in 23 ICUs in 9 European countries, representing the first phase of the candidemia/intra-abdominal candidiasis in European ICU project (EUCANDICU). Results During the study period, 570 episodes of ICU-acquired IC were observed, with a cumulative incidence of 7.07 episodes per 1000 ICU admissions, with important between-center variability. Separated, non-mutually exclusive cumulative incidences of candidemia and IAC were 5.52 and 1.84 episodes per 1000 ICU admissions, respectively. Crude 30-day mortality was 42%. Age (odds ratio [OR] 1.04 per year, 95% CI 1.02–1.06, p

The SARS-CoV-2 variant of concern, α, spread worldwide at the beginning of 2021. It was suggested that this variant was associated with a higher risk of mortality than other variants. We aimed to characterize the genetic diversity of SARS-CoV-2 variants isolated from patients with severe COVID-19 and unravel the relationships between specific viral mutations/mutational patterns and clinical outcomes. This is a prospective multicenter observational cohort study. Patients aged ≥18 years admitted to 11 intensive care units (ICUs) in hospitals in the Greater Paris area for SARS-CoV-2 infection and acute respiratory failure between 1 October 2020 and 30 May 2021 were included. The primary clinical endpoint was day-28 mortality. Full-length SARS-CoV-2 genomes were sequenced by means of next-generation sequencing (Illumina COVIDSeq). In total, 413 patients were included, 183 (44.3%) were infected with pre-existing variants, 197 (47.7%) were infected with variant α, and 33 (8.0%) were infected with other variants. The patients infected with pre-existing variants were significantly older (64.9 ± 11.9 vs. 60.5 ± 11.8 years; p = 0.0005) and had more frequent COPD (11.5% vs. 4.1%; p = 0.009) and higher SOFA scores (4 [3–8] vs. 3 [2–4]; 0.0002). The day-28 mortality was no different between the patients infected with pre-existing, α, or other variants (31.1% vs. 26.2% vs. 30.3%; p = 0.550). There was no association between day-28 mortality and specific variants or the presence of specific mutations. At ICU admission, the patients infected with pre-existing variants had a different clinical presentation from those infected with variant α, but mortality did not differ between these groups. There was no association between specific variants or SARS-CoV-2 genome mutational pattern and day-28 mortality.

In this visual case of Strongyloides stercoralis disseminated infection with Enterobacteriaceae-related invasive infection, we demonstrated the in-host S. stercoralis circulation with DNA found in different fluids and specimens, but also in cerebrospinal fluid (CSF), supporting the role of migrant larvae in the Enterobacteriaceae-related invasive and central nervous system infection.

Abstract Background Anti-synthetase (AS) and dermato-pulmonary associated with anti-MDA-5 antibodies (aMDA-5) syndromes are near one of the other autoimmune inflammatory myopathies potentially responsible for severe acute interstitial lung disease. We undertook a 13-year retrospective multicenter study in 35 French ICUs in order to describe the clinical presentation and the outcome of patients admitted to the ICU for acute respiratory failure (ARF) revealing AS or aMDA-5 syndromes. Results From 2005 to 2017, 47 patients (23 males; median age 60 [1st–3rd quartiles 52–69] years, no comorbidity 85%) were admitted to the ICU for ARF revealing AS (n = 28, 60%) or aMDA-5 (n = 19, 40%) syndromes. Muscular, articular and cutaneous manifestations occurred in 11 patients (23%), 14 (30%) and 20 (43%) patients, respectively. Seventeen of them (36%) had no extra-pulmonary manifestations. C-reactive protein was increased (139 [40–208] mg/L), whereas procalcitonine was not (0.30 [0.12–0.56] ng/mL). Proportion of patients with creatine kinase ≥ 2N was 20% (n = 9/47). Forty-two patients (89%) had ARDS, which was severe in 86%, with a rate of 17% (n = 8/47) of extra-corporeal membrane oxygenation requirement. Proportion of patients who received corticosteroids, cyclophosphamide, rituximab, intravenous immunoglobulins and plasma exchange were 100%, 72%, 15%, 21% and 17%, respectively. ICU and hospital mortality rates were 45% (n = 21/47) and 51% (n = 24/47), respectively. Patients with aMDA-5 dermato-pulmonary syndrome had a higher hospital mortality than those with AS syndrome (n = 16/19, 84% vs. n = 8/28, 29%; p = 0.001). Conclusions Intensivists should consider inflammatory myopathies as a cause of ARF of unknown origin. Extra-pulmonary manifestations are commonly lacking. Mortality is high, especially in aMDA-5 dermato-pulmonary syndrome.