Lower airway microbiota compositions differ between influenza, COVID-19 and bacteria-related acute respiratory distress syndromes.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is responsible for 400,000 deaths annually worldwide. Few improvements have been made despite five decades of research, partially because ARDS is a highly heterogeneous syndrome including various types of aetiologies. Lower airway microbiota is involved in chronic inflammatory diseases and recent data suggest that it could also play a role in ARDS. Nevertheless, whether the lower airway microbiota composition varies between the aetiologies of ARDS remain unknown. The aim of this study is to compare lower airway microbiota composition between ARDS aetiologies, i.e. pulmonary ARDS due to influenza, SARS-CoV-2 or bacterial infection. METHODS: Consecutive ARDS patients according to Berlin's classification requiring invasive ventilation with PCR-confirmed influenza or SARS-CoV-2 infections and bacterial infections (> 105 CFU/mL on endotracheal aspirate) were included. Endotracheal aspirate was collected at admission, V3-V4 and ITS2 regions amplified by PCR, deep-sequencing performed on MiSeq sequencer (Illumina®) and data analysed using DADA2 pipeline. RESULTS: Fifty-three patients were included, 24 COVID-19, 18 influenza, and 11 bacterial CAP-related ARDS. The lower airway bacteriobiota and mycobiota compositions (ß-diversity) were dissimilar between the three groups (p = 0.05 and p = 0.01, respectively). The bacterial α-diversity was significantly lower in the bacterial CAP-related ARDS group compared to the COVID-19 ARDS group (p = 0.04). In contrast, influenza-related ARDS patients had higher lung mycobiota α-diversity than the COVID-19-related ARDS (p = 0 < 01). CONCLUSION: Composition of lower airway microbiota (both microbiota and mycobiota) differs between influenza, COVID-19 and bacterial CAP-related ARDS. Future studies investigating the role of lung microbiota in ARDS pathophysiology should take aetiology into account.

Impact of dexamethasone in severe COVID-19-induced acute kidney injury: a multicenter cohort study.

BACKGROUND: Acute kidney injury (AKI) in intensive care unit (ICU) patients with severe COVID-19 is common (> 50%). A specific inflammatory process has been suggested in the pathogenesis of AKI, which could be improved by dexamethasone (DXM). In a small monocenter study (n = 100 patients), we reported a potential protective effect of DXM on the risk of AKI. This study aimed to investigate the preventive impact of DXM on AKI in a multicenter study of patients with severe COVID-19. METHODS: We conducted a multicenter study in three French ICUs from March 2020 to August 2021. All patients admitted to ICU for severe COVID-19 were included. Individuals with preexistent AKI or DXM administration before admission to ICU were excluded. While never used during the first wave, DXM was used subsequently at ICU entry, providing two treatment groups. Multivariate Cause-specific Cox models taking into account changes in ICU practices over time, were utilized to determine the association between DXM and occurrence of AKI. RESULTS: Seven hundred and ninety-eight patients were included. Mean age was 62.6 ± 12.1 years, 402/798 (50%) patients had hypertension, and 46/798 (6%) had previous chronic kidney disease. Median SOFA was 4 [3-6] and 420/798 (53%) required invasive mechanical ventilation. ICU mortality was 208/798 (26%). AKI was present in 598/798 (75%) patients: 266/598 (38%), 163/598 (27%), and 210/598 (35%) had, respectively, AKI KDIGO 1, 2, 3, and 61/598 (10%) patients required renal replacement therapy. Patients receiving DXM had a significantly decreased hazard of AKI occurrence compared to patients without DXM (HR 0.67; 95CI 0.55-0.81). These results were consistent in analyses that (1) excluded patients with DXM administration to AKI onset delay of less than 12 h, (2) incorporating the different 'waves' of the COVID-19 pandemic. CONCLUSIONS: DXM was associated with a decrease in the risk of AKI in severe COVID-19 patients admitted to ICU. This supports the hypothesis that the inflammatory injury of AKI may be preventable.

Critically ill patients with infective endocarditis, neurological complications and indication for cardiac surgery: a multicenter propensity-adjusted study.

BACKGROUND: The benefit-risk balance and optimal timing of surgery for severe infective endocarditis (IE) with ischemic or hemorrhagic strokes is unknown. The study aim was to compare the neurological outcome between patients receiving surgery or not. METHODS: In a prospective register-based multicenter ICU study, patients were included if they met the following criteria: (i) left-sided IE with an indication for heart surgery; (ii) with cerebral complications documented by cerebral imaging before cardiac surgery; (iii) with Sequential Organ Failure Assessment score ≥ 3. Exclusion criteria were isolated right-sided IE, in-hospital acquired IE and patients with cerebral complications only after cardiac surgery. In the primary analysis, the prognostic value of surgery in term of disability at 6 month was assessed by using a propensity score-adjusted logistic regression. RESULTS: 192 patients were included including ischemic stroke (74.5%) and hemorrhagic lesion (15.6%): 67 (35%) had medical treatment and 125 (65%) cardiac surgery. In the propensity score-adjusted logistic regression, a favorable 6-month neurological outcome was associated with surgery (odds ratio 13.8 (95% CI 6.2-33.7). The 1-year mortality was strongly reduced with surgery in the fixed-effect propensity-adjusted Cox model (hazard ratio 0.18; 95% CI 0.11-0.27; p < 0.001). These effects remained whether the patients received delayed surgery (n = 62/125) or not and whether they were deeply comatose (Glasgow Coma Scale ≤ 10) or not. CONCLUSIONS: In critically ill IE patients with an indication for surgery and previous cerebral events, a better propensity-adjusted neurological outcome was associated with surgery compared with medical treatment.

Effects of mechanical in-exsufflation in preventing postextubation acute respiratory failure in intensive care acquired weakness patients: a randomized controlled trial.

OBJECTIVE: We hypothesized that the use of mechanical insufflation-exsufflation can reduce the incidence of acute respiratory failure within the 48-hour post-extubation period in intensive care unit-acquired weakness patients. METHODS: This was a prospective randomized controlled open-label trial. Patients diagnosed with intensive care unit-acquired weakness were consecutively enrolled based on a Medical Research Council score ≤ 48/60. The patients randomly received two daily sessions; in the control group, conventional chest physiotherapy was performed, while in the intervention group, chest physiotherapy was associated with mechanical insufflation-exsufflation. The incidence of acute respiratory failure within 48 hours of extubation was evaluated. Similarly, the reintubation rate, intensive care unit length of stay, mortality at 28 days, and survival probability at 90 days were assessed. The study was stopped after futility results in the interim analysis. RESULTS: We included 122 consecutive patients (n = 61 per group). There was no significant difference in the incidence of acute respiratory failure between treatments (11.5% control group versus 16.4%, intervention group; p = 0.60), the need for reintubation (3.6% versus 10.7%; p = 0.27), mean length of stay (3 versus 4 days; p = 0.33), mortality at Day 28 (9.8% versus 15.0%; p = 0.42), or survival probability at Day 90 (21.3% versus 28.3%; p = 0.41). CONCLUSION: Mechanical insufflation-exsufflation combined with chest physiotherapy seems to have no impact in preventing postextubation acute respiratory failure in intensive care unit-acquired weakness patients. Similarly, mortality and survival probability were similar in both groups. Nevertheless, given the early termination of the trial, further clinical investigation is strongly recommended. CLINICAL TRIALS REGISTER: NCT01931228.

The gut microbiota composition is linked to subsequent occurrence of ventilator-associated pneumonia in critically ill patients.

Ventilator-associated pneumonia (VAP) is the most frequent nosocomial infection in critically ill-ventilated patients. Oropharyngeal and lung microbiota have been demonstrated to be associated with VAP occurrence, but the involvement of gut microbiota has not been investigated so far. Therefore, the aim of this study is to compare the composition of the gut microbiota between patients who subsequently develop VAP and those who do not. A rectal swab was performed at admission of every consecutive patient into the intensive care unit (ICU) from October 2019 to March 2020. After DNA extraction, V3-V4 and internal transcribed spacer 2 regions deep-sequencing was performed on MiSeq sequencer (Illumina) and data were analyzed using Divisive Amplicon Denoising Algorithm 2 (DADA2) pipeline. Among 255 patients screened, 42 (16%) patients with invasive mechanical ventilation for more than 48 h were included, 18 (43%) with definite VAP and 24 without (57%). Patients who later developed VAP had similar gut bacteriobiota and mycobiota α-diversities compared to those who did not develop VAP. However, gut mycobiota was dissimilar (ß-diversity) between these two groups. The presence of Megasphaera massiliensis was associated with the absence of VAP occurrence, whereas the presence of the fungal genus Alternaria sp. was associated with the occurrence of VAP. The composition of the gut microbiota, but not α-diversity, differs between critically ill patients who subsequently develop VAP and those who do not. This study encourages large multicenter cohort studies investigating the role of gut-lung axis and oropharyngeal colonization in the development of VAP in ICU patients. Trial registration number: NCT04131569, date of registration: 18 October 2019. IMPORTANCE The composition of the gut microbiota, but not α-diversity, differs between critically ill patients who subsequently develop ventilator-associated pneumonia (VAP) and those who do not. Investigating gut microbiota composition could help to tailor probiotics to provide protection against VAP.

Cytokine profiles in adults with imported malaria.

The increase in worldwide travel is making imported malaria a growing health concern in non-endemic countries. Most data on the pathophysiology of malaria come from endemic areas. Little is known about cytokine profiles during imported malaria. This study aimed at deciphering the relationship between cytokine host response and malaria severity among imported cases in France. This study reports cytokine profiles in adults with Plasmodium falciparum malaria included in the PALUREA prospective study conducted between 2006 and 2010. The patients were classified as having uncomplicated malaria (UM) or severe malaria (SM), with this last further categorized as very severe malaria (VSM) or less severe malaria (LSM). At hospital admission, eight blood cytokines were assayed in duplicate using Luminex® technology: interleukin (IL)-1α, IL-1ß, IL-2, IL-4, IL-10, tumor necrosis factor (TNF)α, interferon (IFN)γ, and macrophage migration inhibitory factor (MIF). These assays were repeated on days 1 and 2 in the SM group. Of the 278 patients, 134 had UM and 144 SM. At hospital admission, over half the patients had undetectable levels of IL-1α, IL-1ß, IL-2, IL-4, IFNγ, and TNFα, while IL-10 and MIF were significantly higher in the SM vs. the UM group. Higher IL-10 was significantly associated with higher parasitemia (R = 0.32 [0.16-0.46]; P = 0.0001). In the SM group, IL-10 elevation persisting from admission to day 2 was significantly associated with subsequent nosocomial infection. Of eight tested cytokines, only MIF and IL-10 were associated with disease severity in adults with imported P. falciparum malaria. At admission, many patients had undetectable cytokine levels, suggesting that circulating cytokine assays may not be helpful as part of the routine evaluation of adults with imported malaria. Persisting high IL-10 concentration was associated with subsequent nosocomial infection, suggesting its possible interest in immune monitoring of most severe patients.

Bridging gut microbiota composition with extended-spectrum beta-lactamase Enterobacteriales faecal carriage in critically ill patients (microbe cohort study).

BACKGROUND: The worldwide dissemination of extended spectrum beta-lactamase producing Enterobacteriales (ESBL-E) is of major concern. Microbiota may play a role in the host resistance to colonization with ESBL-E, but the underlying mechanisms remain unknown. We aimed to compare the gut microbiota composition between ESBL-producing E. coli or K. pneumoniae carriers and ESBL-E non-carriers according to the bacterial species. RESULTS: Among 255 patients included, 11 (4,3%) were colonized with ESBL-producing E. coli and 6 (2,4%) with ESBL-producing K. pneumoniae, which were compared with age- and sex-matched ESBL-E non carriers. While no significant differences were found between ESBL-producing E. coli carriers and non-carriers, gut bacteriobiota α-diversity was decreased in ESBL-K. pneumoniae faecal carriers compared both with non-carriers (p = 0.05), and with ESBL-producing E. coli carriers. The presence of Sellimonas intestinalis was associated with the absence of ESBL-producing E. coli fecal carriage. Campylobacter ureolyticus, Campylobacter hominis, bacteria belonging to Clostridium cluster XI and Saccharomyces sp. were associated with the absence of ESBL-producing K. pneumoniae faecal carriage. CONCLUSIONS: The composition of the gut microbiota differs between ESBL-producing E. coli and K. pneumoniae faecal carriers suggesting that microbial species should be taken into account when investigating the role of gut microbiota in resistance to gut colonization with ESBL-E. TRIAL REGISTRATION NUMBER: NCT04131569, date of registration: October 18, 2019.

Lung Mycobiota α-Diversity Is Linked to Severity in Critically Ill Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) affects more than 200 million people worldwide. The chronic course of COPD is frequently worsened by acute exacerbations (AECOPD). Mortality in patients hospitalized for severe AECOPD remains dramatically high, and the underlying mechanisms are poorly understood. Lung microbiota is associated with COPD outcomes in nonsevere AECOPD, but no study specifically investigated severe AECOPD patients. The aim of this study is thus to compare lung microbiota composition between severe AECOPD survivors and nonsurvivors. Induced sputum or endotracheal aspirate was collected at admission from every consecutive severe AECOPD patient. After DNA extraction, the V3-V4 and ITS2 regions were amplified by PCR. Deep-sequencing was performed on a MiSeq sequencer (Illumina); the data were analyzed using DADA2 pipeline. Among 47 patients admitted for severe AECOPD, 25 (53%) with samples of sufficient quality were included: 21 of 25 (84%) survivors and 4 of 25 (16%) nonsurvivors. AECOPD nonsurvivors had lower α-diversities indices than survivors for lung mycobiota but not for lung bacteriobiota. Similar results were demonstrated comparing patients receiving invasive mechanical ventilation (n = 13 [52%]) with those receiving only noninvasive ventilation (n = 12 [48%]). Previous systemic antimicrobial therapy and long-term inhaled corticosteroid therapy could alter the lung microbiota composition in severe AECOPD patients. In acidemic AECOPD, lower lung mycobiota α-diversity is linked to the severity of the exacerbation, assessed by mortality and the requirement for invasive mechanical ventilation, whereas lung bacteriobiota α-diversity is not. This study encourages a multicenter cohort study investigating the role of lung microbiota, especially fungal kingdom, in severe AECOPD. IMPORTANCE In AECOPD with acidemia, more severe patients-i.e., nonsurvivors and patients requiring invasive mechanical ventilation-have lower lung mycobiota α-diversity than survivors and patients receiving only noninvasive ventilation, respectively. This study encourages a large multicenter cohort study investigating the role of lung microbiota in severe AECOPD and urges investigation of the role of the fungal kingdom in severe AECOPD.

Efficacy of carbapenem vs non carbapenem ß-lactam therapy as empiric antimicrobial therapy in patients with extended-spectrum ß-lactamase-producing Enterobacterales urinary septic shock: a propensity-weighted multicenter cohort study.

BACKGROUND: The rise in antimicrobial resistance is a global threat responsible for about 33,000 deaths in 2015 with a particular concern for extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) and has led to a major increase in the use of carbapenems, last-resort antibiotics. METHODS: In this retrospective propensity-weighted multicenter observational study conducted in 11 ICUs, the purpose was to assess the efficacy of non carbapenem regimen (piperacillin-tazobactam (PTZ) + aminoglycosides or 3rd-generation cephalosporin (3GC) + aminoglycosides) as empiric therapy in comparison with carbapenem in extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) urinary septic shock. The primary outcome was Day-30 mortality. RESULTS: Among 156 patients included in this study, 69 received a carbapenem and 87 received non carbapenem antibiotics as empiric treatment. Baseline clinical characteristics were similar between the two groups. Patients who received carbapenem had similar Day-30 mortality (10/69 (15%) vs 6/87 (7%), OR = 1.99 [0.55; 5.34] p = 0.16), illness severity, resolution of septic shock, and ESBL-E infection recurrence rates than patients who received an empiric non carbapenem therapy. The rates of secondary infection with C. difficile were comparable. CONCLUSIONS: In ESBL-E urinary septic shock, empiric treatment with a non carbapenem regimen, including systematically aminoglycosides, was not associated with higher mortality, compared to a carbapenem regimen.

Clinical trajectories and impact of acute kidney disease after acute kidney injury in the intensive care unit: a 5-year single-centre cohort study.

BACKGROUND: Patients suffering from acute kidney injury(AKI) in the intensive care unit (ICU) can have various renal trajectories and outcomes. Aims were to assess the various clinical trajectories after AKI in the ICU and to determine risk factors for developing chronic kidney disease (CKD). METHODS: We conducted a prospective 5-year follow-up study in a medical ICU at Bordeaux University Hospital (France). The patients who received invasive mechanical ventilation, catecholamine infusion or both and developed an AKI from September 2013 to May 2015 were included. In the Cox analysis, the violation of the proportional hazard assumption for AKD was handled using appropriate interaction terms with time, resulting in a time-dependent hazard ratio (HR). RESULTS: A total of 232 patients were enrolled, with an age of 62 ± 16 years and a median follow-up of 52 days (interquartile range 6-1553). On day 7, 109/232 (47%) patients progressed to acute kidney disease (AKD) and 66/232 (28%) recovered. A linear trajectory (AKI, AKD to CKD) was followed by 44/63 (70%) of the CKD patients. The cumulative incidence of CKD was 30% [95% confidence interval (CI) 24-36] at the 5-year follow-up. In a multivariable Cox model, in the 6 months following AKI, the HR for CKD was higher in AKD patients [HR 29.2 (95% CI 8.5-100.7); P < 0.0001). After 6 months, the HR for CKD was 2.2 (95% CI 0.6-7.9; P = 0.21; n = 172 patients). CONCLUSION: There were several clinical trajectories of kidney disease after ICU-acquired AKI. CKD risk was higher in AKD patients only in the first 6 months. Lack of renal recovery rather than AKD per se was associated with the risk of CKD.

Effects of mechanical in-exsufflation in preventing postextubation acute respiratory failure in intensive care acquired weakness patients: a randomized controlled trial / Efeitos da insuflação-exsuflação mecânica na prevenção da insuficiência respiratória aguda pós-extubação em pacientes com fraqueza adquirida em terapia intensiva: um estudo controlado e randomizado

ABSTRACT Objective: We hypothesized that the use of mechanical insufflation-exsufflation can reduce the incidence of acute respiratory failure within the 48-hour post-extubation period in intensive care unit-acquired weakness patients. Methods: This was a prospective randomized controlled open-label trial. Patients diagnosed with intensive care unit-acquired weakness were consecutively enrolled based on a Medical Research Council score ≤ 48/60. The patients randomly received two daily sessions; in the control group, conventional chest physiotherapy was performed, while in the intervention group, chest physiotherapy was associated with mechanical insufflation-exsufflation. The incidence of acute respiratory failure within 48 hours of extubation was evaluated. Similarly, the reintubation rate, intensive care unit length of stay, mortality at 28 days, and survival probability at 90 days were assessed. The study was stopped after futility results in the interim analysis. Results: We included 122 consecutive patients (n = 61 per group). There was no significant difference in the incidence of acute respiratory failure between treatments (11.5% control group versus 16.4%, intervention group; p = 0.60), the need for reintubation (3.6% versus 10.7%; p = 0.27), mean length of stay (3 versus 4 days; p = 0.33), mortality at Day 28 (9.8% versus 15.0%; p = 0.42), or survival probability at Day 90 (21.3% versus 28.3%; p = 0.41). Conclusion: Mechanical insufflation-exsufflation combined with chest physiotherapy seems to have no impact in preventing postextubation acute respiratory failure in intensive care unit-acquired weakness patients. Similarly, mortality and survival probability were similar in both groups. Nevertheless, given the early termination of the trial, further clinical investigation is strongly recommended. Clinical Trials Register: NCT 01931228

RESUMO Objetivo: Verificar se o uso de insuflação-exsuflação mecânica pode reduzir a incidência da insuficiência respiratória aguda no período de 48 horas pós-extubação em pacientes com fraqueza adquirida em unidades de terapia intensiva. Métodos: Estudo prospectivo, randomizado, controlado e aberto. Os pacientes diagnosticados com fraqueza adquirida em unidade de terapia intensiva foram incluídos consecutivamente, com base em uma pontuação do Medical Research Council ≤ 48/60. Os pacientes receberam aleatoriamente duas sessões diárias; no grupo controle, realizou-se fisioterapia torácica convencional, enquanto no grupo intervenção, combinou-se fisioterapia torácica com insuflação-exsuflação mecânica. Avaliou-se a incidência de insuficiência respiratória aguda dentro de 48 horas após a extubação. Da mesma forma, avaliaram-se a taxa de reintubação, o tempo de permanência na unidade de terapia intensiva, a mortalidade aos 28 dias e a probabilidade de sobrevida aos 90 dias. O estudo foi interrompido após resultados de futilidade na análise intermediária. Resultados: Incluímos 122 pacientes consecutivos (n = 61 por grupo). Não houve diferença significativa na incidência de insuficiência respiratória aguda entre os tratamentos (11,5% no grupo controle versus 16,4% no grupo intervenção; p = 0,60), na necessidade de reintubação (3,6% versus 10,7%; p = 0,27), no tempo médio de internação (3 versus 4 dias; p = 0,33), na mortalidade aos 28 dias (9,8% versus 15,0%; p = 0,42) ou na probabilidade de sobrevida aos 90 dias (21,3% versus 28,3%; p = 0,41). Conclusão: A insuflação-exsuflação mecânica associada à fisioterapia torácica parece não ter impacto na prevenção da insuficiência respiratória aguda pós-extubação em pacientes com fraqueza adquirida na unidade de terapia intensiva. Da mesma forma, a mortalidade e a probabilidade de sobrevida foram semelhantes em ambos os grupos. No entanto, devido ao término precoce do estudo, recomenda-se enfaticamente uma investigação clínica mais aprofundada. Registro Clinical Trials: NCT 01931228

Predictive factors for severe long-term chronic kidney disease after acute kidney injury requiring renal replacement therapy in critically ill patients: an ancillary study of the ELVIS randomized controlled trial.

BACKGROUND: Acute kidney injury (AKI) requiring renal replacement therapy (RRT) is a serious complication in the ICU that results in increased mortality and risk of chronic kidney disease (CKD). Some studies suggest RRT modality may have an impact on long-term renal recovery after AKI. However, other predictive factors of severe long-term CKD in ICU patients with AKI requiring RRT are unknown. METHODS: We performed an ancillary study of the multicenter ELVIS trial in the population with AKI requiring RRT. Patients alive 3 months after RRT initiation were eligible. Serum creatinine levels available at 3, 6 and 12 months and 3 and 5 years were recorded. CKD stage was determined according to the glomerular filtration rate as estimated by the CKD-EPI formula. At each timepoint, two groups of patients were compared, a no/mild CKD group with normal or mildly to moderately decreased renal function (stages 1, 2 and 3 of the international classification) and a severe CKD group (stages 4 and 5). Our objective was to identify predictive factors of severe long-term CKD. RESULTS: Of the 287 eligible patients, 183 had follow-up at 3 months, 136 (74.3%) from the no/mild CKD group and 47 (25.7%) from the severe CKD group, and 122 patients at 5 years comprising 96 (78.7%) from the no/mild CKD group and 26 (21.3%) from the severe CKD group. Multivariate analysis showed that a long RRT period was associated with severe CKD up to 12 months (ORM12 = 1.03 95% CI [1.02-1.05] per day) and that a high SOFA score at the initiation of RRT was not associated with severe CKD up to 5 years (ORM60 = 0.85 95% CI [0.77-0.93] per point). CONCLUSION: Severe long-term CKD was found in 21% of ICU survivors who underwent RRT for AKI. The duration of the RRT in AKI patients was identified as a new predictive factor for severe long-term CKD. This finding should be taken into consideration in future studies on the prognosis of ICU patients with AKI requiring RRT. Trial registration ELVIS trial was registered with ClinicalTrials.gov, number: NCT00875069 (June 16, 2014), and this ancillary study was registered with ClinicalTrials.gov, number: NCT03302624 (October 6, 2017).

Plasma Markers of Neutrophil Extracellular Trap Are Linked to Survival but Not to Pulmonary Embolism in COVID-19-Related ARDS Patients.

Introduction: Coronavirus disease 2019 (COVID-19) can cause life-threatening acute respiratory distress syndrome (ARDS). Recent data suggest a role for neutrophil extracellular traps (NETs) in COVID-19-related lung damage partly due to microthrombus formation. Besides, pulmonary embolism (PE) is frequent in severe COVID-19 patients, suggesting that immunothrombosis could also be responsible for increased PE occurrence in these patients. Here, we evaluate whether plasma levels of NET markers measured shorty after admission of hospitalized COVID-19 patients are associated with clinical outcomes in terms of clinical worsening, survival, and PE occurrence. Patients and Methods: Ninety-six hospitalized COVID-19 patients were included, 50 with ARDS (severe disease) and 46 with moderate disease. We collected plasma early after admission and measured 3 NET markers: total DNA, myeloperoxidase (MPO)-DNA complexes, and citrullinated histone H3. Comparisons between survivors and non-survivors and patients developing PE and those not developing PE were assessed by Mann-Whitney test. Results: Analysis in the whole population of hospitalized COVID-19 patients revealed increased circulating biomarkers of NETs in patients who will die from COVID-19 and in patients who will subsequently develop PE. Restriction of our analysis in the most severe patients, i.e., the ones who enter the hospital for COVID-19-related ARDS, confirmed the link between NET biomarker levels and survival but not PE occurrence. Conclusion: Our results strongly reinforce the hypothesis that NETosis is an attractive therapeutic target to prevent COVID-19 progression but that it does not seem to be linked to PE occurrence in patients hospitalized with COVID-19.

Gut bacteriobiota and mycobiota are both associated with Day-28 mortality among critically ill patients.

INTRODUCTION: Gut microbiota is associated with host characteristics such as age, sex, immune condition or frailty and is thought to be a key player in numerous human diseases. Nevertheless, its association with outcome in critically ill patients has been poorly investigated. The aim of this study is to assess the association between gut microbiota composition and Day-28 mortality in critically ill patients. METHODS: Rectal swab at admission of every patient admitted to intensive care unit (ICU) between October and November 2019 was frozen at - 80 °C. DNA extraction was performed thanks to QIAamp® PowerFecal® Pro DNA kit (QIAgen®). V3-V4 regions of 16SRNA and ITS2 coding genes were amplified by PCR. Sequencing (2x250 bp paired-end) was performed on MiSeq sequencer (Illumina®). DADA2 pipeline on R software was used for bioinformatics analyses. Risk factors for Day-28 mortality were investigated by logistic regression. RESULTS: Fifty-seven patients were consecutively admitted to ICU of whom 13/57 (23%) deceased and 44/57 (77%) survived. Bacteriobiota α-diversity was lower among non-survivors than survivors (Shannon and Simpson index respectively, p < 0.001 and p = 0.001) as was mycobiota α-diversity (respectively p = 0.03 and p = 0.03). Both gut bacteriobiota and mycobiota Shannon index were independently associated with Day-28 mortality in multivariate analysis (respectively OR: 0.19, 97.5 CI [0.04-0.60], p < 0.01 and OR: 0.29, 97.5 CI [0.09-0.75], p = 0.02). Bacteriobiota ß-diversity was significantly different between survivors and non-survivors (p = 0.05) but not mycobiota ß-diversity (p = 0.57). Non-survivors had a higher abundance of Staphylococcus haemolyticus, Clostridiales sp., Campylobacter ureolyticus, Akkermansia sp., Malassezia sympodialis, Malassezia dermatis and Saccharomyces cerevisiae, whereas survivors had a higher abundance of Collinsella aerofaciens, Blautia sp., Streptococcus sp., Faecalibacterium prausnitzii and Bifidobacterium sp. CONCLUSION: The gut bacteriobiota and mycobiota α diversities are independently associated with Day-28 mortality in critically ill patients. The causal nature of this interference and, if so, the underlying mechanisms should be further investigated to assess if gut microbiota modulation could be a future therapeutic approach.

Urine Protein/Creatinine Ratio in Thrombotic Microangiopathies: A Simple Test to Facilitate Thrombotic Thrombocytopenic Purpura and Hemolytic and Uremic Syndrome Diagnosis.

BACKGROUND: Early diagnosis of thrombotic thrombocytopenic purpura (TTP) versus hemolytic and uremic syndrome (HUS) is critical for the prompt initiation of specific therapies. OBJECTIVE: To evaluate the diagnostic performance of the proteinuria/creatininuria ratio (PU/CU) for TTP versus HUS. PATIENTS/METHODS: In a retrospective study, in association with the "French Score" (FS) (platelets < 30 G/L and serum creatinine level < 200 µmol/L), we assessed PU/CU for the diagnosis of TTP in patients above the age of 15 with thrombotic microangiopathy (TMA). Patients with a history of kidney disease or with on-going cancer, allograft or pregnancy were excluded from the analysis. RESULTS: Between February 2011 and April 2019, we identified 124 TMA. Fifty-six TMA patients for whom PU/CU were available, including 35 TTP and 21 HUS cases, were considered. Using receiver-operating characteristic curves (ROC), those with a threshold of 1.5 g/g for the PU/CU had a 77% sensitivity (95% CI (63, 94)) and a 90% specificity (95% CI (71, 100)) for TTP diagnosis compared with those having an 80% sensitivity (95% CI (66, 92)) and a 90% specificity (95% CI (76, 100) with a FS of 2. In comparison, a composite score, defined as a FS of 2 or a PU/CU ≤ 1.5 g/g, improved sensitivity to 99.6% (95% CI (93, 100)) for TTP diagnosis and enabled us to reclassify seven false-negative TTP patients. CONCLUSIONS: The addition of urinary PU/CU upon admission of patients with TMA is a fast and readily available test that can aid in the differential diagnosis of TTP versus HUS alongside traditional scoring.

Complement Blockade Is a Promising Therapeutic Approach in a Subset of Critically Ill Adult Patients with Complement-Mediated Hemolytic Uremic Syndromes.

Thrombotic microangiopathy (TMA) gathers consumptive thrombocytopenia, mechanical haemolytic anemia, and organ damage. Hemolytic uremic syndromes (HUS) are historically classified as primary or secondary to another disease once thrombotic thrombocytopenic purpura (TTP), Shiga-toxin HUS, and cobalamin C-related HUS have been ruled out. Complement genetics studies reinforced the link between complement dysregulation and primary HUS, contributing to reclassifying some pregnancy- and/or post-partum-associated HUS and to revealing complement involvement in severe and/or refractory hypertensive emergencies. By contrast, no firm evidence allows a plausible association to be drawn between complement dysregulation and Shiga-toxin HUS or other secondary HUS. Nevertheless, rare complement gene variants are prevalent in healthy individuals, thus providing an indication that an investigation into complement dysregulation should be carefully balanced and that the results should be cautiously interpreted with the help of a trained geneticist. Several authors have suggested reclassifying HUS in two entities, regardless of they are complement-mediated or not, since the use of eculizumab, an anti-C5 antibody, dramatically lowers the proportion of patients who die or suffer from end-stage renal disease within the year following diagnosis. Safety and the ideal timing of eculizumab discontinuation is currently under investigation, and the long-term consequences of HUS should be closely monitored over time once patients exit emergency departments.

High-resolution Free-breathing late gadolinium enhancement Cardiovascular magnetic resonance to diagnose myocardial injuries following COVID-19 infection.

PURPOSE: High-resolution free-breathing late gadolinium enhancement (HR-LGE) was shown valuable for the diagnosis of acute coronary syndromes with non-obstructed coronary arteries. The method may be useful to detect COVID-related myocardial injuries but is hampered by prolonged acquisition times. We aimed to introduce an accelerated HR-LGE technique for the diagnosis of COVID-related myocardial injuries. METHOD: An undersampled navigator-gated HR-LGE (acquired resolution of 1.25 mm3) sequence combined with advanced patch-based low-rank reconstruction was developed and validated in a phantom and in 23 patients with structural heart disease (test cohort; 15 men; 55 ± 16 years). Twenty patients with laboratory-confirmed COVID-19 infection associated with troponin rise (COVID cohort; 15 men; 46 ± 24 years) prospectively underwent cardiovascular magnetic resonance (CMR) with the proposed sequence in our center. Image sharpness, quality, signal intensity differences and diagnostic value of free-breathing HR-LGE were compared against conventional breath-held low-resolution LGE (LR-LGE, voxel size 1.8x1.4x6mm). RESULTS: Structures sharpness in the phantom showed no differences with the fully sampled image up to an undersampling factor of x3.8 (P > 0.5). In patients (N = 43), this acceleration allowed for acquisition times of 7min21s ± 1min12s at 1.25 mm3 resolution. Compared with LR-LGE, HR-LGE showed higher image quality (P = 0.03) and comparable signal intensity differences (P > 0.5). In patients with structural heart disease, all LGE-positive segments on LR-LGE were also detected on HR-LGE (80/391) with 21 additional enhanced segments visible only on HR-LGE (101/391, P < 0.001). In 4 patients with COVID-19 history, HR-LGE was definitely positive while LR-LGE was either definitely negative (1 microinfarction and 1 myocarditis) or inconclusive (2 myocarditis). CONCLUSIONS: Undersampled free-breathing isotropic HR-LGE can detect additional areas of late enhancement as compared to conventional breath-held LR-LGE. In patients with history of COVID-19 infection associated with troponin rise, the method allows for detailed characterization of myocardial injuries in acceptable scan times and without the need for repeated breath holds.

High mean arterial pressure target to improve sepsis-associated acute kidney injury in patients with prior hypertension: a feasibility study.

BACKGROUND: The optimal mean arterial pressure (MAP) in cases of septic shock is still a matter of debate in patients with prior hypertension. An MAP between 75 and 85 mmHg can improve glomerular filtration rate (GFR) but its effect on tubular function is unknown. We assessed the effects of high MAP level on glomerular and tubular renal function in two intensive care units of a teaching hospital. Inclusion criteria were patients with a history of chronic hypertension and developing AKI in the first 24 h of septic shock. Data were collected during two 6 h periods of MAP regimen administered consecutively after haemodynamic stabilisation in an order depending on the patient's admission unit: a high-target period (80-85 mmHg) and a low-target period (65-70 mmHg). The primary endpoint was the creatinine clearance (CrCl) calculated from urine and serum samples at the end of each MAP period by the UV/P formula. RESULTS: 26 patients were included. Higher urine output (+0.2 (95%:0, 0.4) mL/kg/h; P = 0.04), urine sodium (+6 (95% CI 0.2, 13) mmol/L; P = 0.04) and lower serum creatinine (- 10 (95% CI - 17, - 3) µmol/L; P = 0.03) were observed during the high-MAP period as compared to the low-MAP period, resulting in a higher CrCl (+25 (95% CI 11, 39) mL/mn; P = 0.002). The urine creatinine, urine-plasma creatinine ratio, urine osmolality, fractional excretion of sodium and urea showed no significant variation. The KDIGO stage at inclusion only interacted with serum creatinine variation and low level of sodium excretion at inclusion did not interact with these results. CONCLUSIONS: In the early stage of sepsis-associated AKI, a high-MAP target in patients with a history of hypertension was associated with a higher CrCl, but did not affect the kidneys' ability to concentrate urine, which may reflect no effect on tubular function.