Determinants of Urine Output Using Advanced Hemodynamic Monitoring in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy.

INTRODUCTION: Low cardiac output and hypovolemia are candidate macrocirculatory mechanisms explanatory of de novo anuria in intensive care unit (ICU) patients undergoing continuous renal replacement therapy (CRRT). We aimed to determine the hemodynamic parameters and CRRT settings associated with the longitudinal course of UO during CRRT. METHODS: This is an ancillary analysis of the PRELOAD CRRT observational, single-center study (NCT03139123). Enrolled adult patients had severe acute kidney injury treated with CRRT for less than 24 h and were monitored with a calibrated continuous cardiac output monitoring device. Hemodynamics (including stroke volume index [SVI] and preload-dependence, identified by continuous cardiac index variation during postural maneuvers), net ultrafiltration (UFNET), and UO were reported 4-hourly, over 7 days. Two study groups were defined at inclusion: non-anuric participants if the cumulative 24 h UO at inclusion was ≥0.05 mL kg-1 h-1, and anuric otherwise. Quantitative data were reported by its median [interquartile range]. RESULTS: Forty-two patients (age 68 [58-76] years) were enrolled. At inclusion, 32 patients (76%) were not anuric. During follow-up, UO decreased significantly in non-anuric patients, with 25/32 (78%) progressing to anuria within 19 [10-50] hours. Mean arterial pressure (MAP) and UFNET did not significantly differ between study groups during follow-up, while SVI and preload-dependence were significantly associated with the interaction of study group and time since inclusion. Higher UFNET flow rates were significantly associated with higher systemic vascular resistances and lower cardiac output during follow-up. Multivariate analyses showed that (1) lower UO was significantly associated with lower SVI, lower MAP, and preload-independence; and (2) higher UFNET was significantly associated with lower UO. CONCLUSIONS: In ICU patients treated with CRRT, those without anuria showed a rapid loss of diuresis after CRRT initiation. Hemodynamic indicators of renal perfusion and effective volemia were the principal determinants of UO during follow-up, in relation with the hemodynamic impact of UFNET setting.

Safety of inter-facility transport strategies for patients referred for severe acute respiratory distress syndrome.

BACKGROUND: Inter-facility transport of patients with acute respiratory distress syndrome (ARDS) in the prone position (PP) is a high-risk situation, compared to other strategies. We aimed to quantify the prevalence of complications during transport in PP, compared to transports with veno-venous extracorporeal membrane oxygenation (VV-ECMO) or in the supine position (SP). METHODS: We performed a retrospective, single center cohort study in Lyon university hospital, France. We included patients ≥ 16 years with ARDS (Berlin definition) transported to an ARDS referral center between 01/12/2016 and 31/12/2021. We compared patients transported in PP, to those transported in SP without VV-ECMO, and those transported with VV-ECMO (in SP), by a multidisciplinary and specialized medical transport team, including an emergency physician and an intensivist. The primary outcome was the rate of transport-related complications (hypoxemia, hypotension, cardiac arrest, cannula or tube dislodgement) in each study groups, compared using a Fisher test. RESULTS: One hundred thirty-four patients were enrolled (median PaO2/FiO2 70 [58-82] mmHg), of which 11 (8%) were transported in PP, 44 (33%) with VV-ECMO, and 79 (59%) in SP. The most frequent risk factor for ARDS in the PP group was bacterial pneumonitis, and viral pneumonitis in the other 2 groups. Transport-related complications occurred in 36% (n = 4) of transports in PP, compared to 39% (n = 30) in SP and 14% (n = 6) with VV-ECMO, respectively (p = 0.33). VV-ECMO implantation after transport was not different between SP and PP patients (n = 7, 64% vs. n = 31, 39%, p = 0.19). CONCLUSIONS: In the context of a specialized multi-disciplinary ARDS transport team, transport-related complication rates were similar between patients transported in PP and SP, while there was a trend of lower rates in patients transported with VV-ECMO.

Type-I Interferon assessment in 45 minutes using the FilmArray® PCR platform in SARS-CoV-2 and other viral infections.

Low concentrations of type-I interferon (IFN) in blood seem to be associated with more severe forms of Coronavirus disease 2019 (COVID-19). However, following the type-I interferon response (IR) in early stage disease is a major challenge. We evaluated detection of a molecular interferon signature on a FilmArray® system, which includes PCR assays for four interferon stimulated genes. We analyzed three types of patient populations: (i) children admitted to a pediatric emergency unit for fever and suspected infection, (ii) ICU-admitted patients with severe COVID-19, and (iii) healthcare workers with mild COVID-19. The results were compared to the reference tools, that is, molecular signature assessed with Nanostring® and IFN-α2 quantification by SIMOA® (Single MOlecule Array). A strong correlation was observed between the IR measured by the FilmArray®, Nanostring®, and SIMOA® platforms (r-Spearman 0.996 and 0.838, respectively). The FilmArray® panel could be used in the COVID-19 pandemic to evaluate the IR in 45-min with 2 min hand-on-time at hospitalization and to monitor the IR in future clinical trials.

Response to PEEP in COVID-19 ARDS patients with and without extracorporeal membrane oxygenation. A multicenter case-control computed tomography study.

BACKGROUND: PEEP selection in severe COVID-19 patients under extracorporeal membrane oxygenation (ECMO) is challenging as no study has assessed the alveolar recruitability in this setting. The aim of the study was to compare lung recruitability and the impact of PEEP on lung aeration in moderate and severe ARDS patients with or without ECMO, using computed tomography (CT). METHODS: We conducted a two-center prospective observational case-control study in adult COVID-19-related patients who had an indication for CT within 72 h of ARDS onset in non-ECMO patients or within 72  h after ECMO onset. Ninety-nine patients were included, of whom 24 had severe ARDS under ECMO, 59 severe ARDS without ECMO and 16 moderate ARDS. RESULTS: Non-inflated lung at PEEP 5 cmH2O was significantly greater in ECMO than in non-ECMO patients. Recruitment induced by increasing PEEP from 5 to 15 cmH2O was not significantly different between ECMO and non-ECMO patients, while PEEP-induced hyperinflation was significantly lower in the ECMO group and virtually nonexistent. The median [IQR] fraction of recruitable lung mass between PEEP 5 and 15 cmH2O was 6 [4-10]%. Total superimposed pressure at PEEP 5 cmH2O was significantly higher in ECMO patients and amounted to 12 [11-13] cmH2O. The hyperinflation-to-recruitment ratio (i.e., a trade-off index of the adverse effects and benefits of PEEP) was significantly lower in ECMO patients and was lower than one in 23 (96%) ECMO patients, 41 (69%) severe non-ECMO patients and 8 (50%) moderate ARDS patients. Compliance of the aerated lung at PEEP 5 cmH2O corrected for PEEP-induced recruitment (CBABY LUNG) was significantly lower in ECMO patients than in non-ECMO patients and was linearly related to the logarithm of the hyperinflation-to-recruitment ratio. CONCLUSIONS: Lung recruitability of COVID-19 pneumonia is not significantly different between ECMO and non-ECMO patients, with substantial interindividual variations. The balance between hyperinflation and recruitment induced by PEEP increase from 5 to 15 cmH2O appears favorable in virtually all ECMO patients, while this PEEP level is required to counteract compressive forces leading to lung collapse. CBABY LUNG is significantly lower in ECMO patients, independently of lung recruitability.

Fluid balance neutralization secured by hemodynamic monitoring versus protocolized standard of care in patients with acute circulatory failure requiring continuous renal replacement therapy: results of the GO NEUTRAL randomized controlled trial.

PURPOSE: Net ultrafiltration (UFNET) during continuous renal replacement therapy (CRRT) can control fluid balance (FB), but is usually 0 ml·h-1 in patients with vasopressors due to the risk of hemodynamic instability associated with CRRT (HIRRT). We evaluated a UFNET strategy adjusted by functional hemodynamics to control the FB of patients with vasopressors, compared to the standard of care. METHODS: In this randomized, controlled, open-label, parallel-group, multicenter, proof-of-concept trial, adults receiving vasopressors, CRRT since ≤ 24 h and cardiac output monitoring were randomized (ratio 1:1) to receive during 72 h a UFNET ≥ 100 ml·h-1, adjusted using a functional hemodynamic protocol (intervention), or a UFNET ≤ 25 ml·h-1 (control). The primary outcome was the cumulative FB at 72 h and was analyzed in patients alive at 72 h and in whom monitoring and CRRT were continuously provided (modified intention-to-treat population [mITT]). Secondary outcomes were analyzed in the intention-to-treat (ITT) population. RESULTS: Between June 2021 and April 2023, 55 patients (age 69 [interquartile range, IQR: 62; 74], 35% female, Sequential Organ Failure Assessment (SOFA) 13 [11; 15]) were randomized (25 interventions, 30 controls). In the mITT population, (21 interventions, 24 controls), the 72 h FB was -2650 [-4574; -309] ml in the intervention arm, and 1841 [821; 5327] ml in controls (difference: 4942 [95% confidence interval: 2736-6902] ml, P < 0.01). Hemodynamics, oxygenation and the number of HIRRT at 72 h, and day-90 mortality did not statistically differ between arms. CONCLUSION: In patients with vasopressors, a UFNET fluid removal strategy secured by a hemodynamic protocol allowed active fluid balance control, compared to the standard of care.

Bias, trending ability and diagnostic performance of a non-calibrated multi-beat analysis continuous cardiac output monitor to identify fluid responsiveness in critically ill patients.

Objective: To evaluate the accuracy of non-calibrated multi-beat analysis continuous cardiac output (CCOMBA), against calibrated pulse-contour analysis continuous cardiac output (CCOPCA) during a passive leg raise (PLR) and/or a fluid challenge (FC). Design: Observational, single-centre, prospective study. Setting: Tertiary academic medical intensive care unit, Lyon, France. Participants: Adult patients receiving norepinephrine, monitored by CCOPCA, and in which a PLR and/or a FC was indicated. Main outcome measures: CCOMBA and CCOPCA were recorded prior to and during the PLR/FC to evaluate bias and evaluate changes in CCOMBA and CCOPCA (∆%CCOMBA and ∆%CCOPCA). Fluid responsiveness was identified by an increase >15% in calibrated cardiac output after FC, to identify the optimal ∆%CCOMBA threshold during PLR to predict fluid responsiveness. Results: 29 patients (median age 68 [IQR: 57-74]) performed 28 PLR and 16 FC. The bias between methods increased with higher CCOPCA values, with a percentage error of 64% (95%confidence interval: 52%-77%). ∆%CCOMBA adequately tracked changes in ∆%CCOPCA with an angular bias of 2 ± 29°. ∆%CCOMBA during PLR had an AUROC of 0.92 (P < 0.05), with an optimal threshold >14% to predict fluid responsiveness (sensitivity: 0.99, specificity: 0.87). Conclusions: CCOMBA showed a non-constant bias and a percentage error >30% against calibrated CCOPCA, but an adequate ability to track changes in CCOPCA and to predict fluid responsiveness.

Spontaneous breathing trial with pressure support on positive end-expiratory pressure and extensive use of non-invasive ventilation versus T-piece in difficult-to-wean patients from mechanical ventilation: a randomized controlled trial.

BACKGROUND: The aim of this study is to assess whether a strategy combining spontaneous breathing trial (SBT) with both pressure support (PS) and positive end-expiratory pressure (PEEP) and extended use of post-extubation non-invasive ventilation (NIV) (extensively-assisted weaning) would shorten the time until successful extubation as compared with SBT with T-piece (TP) and post-extubation NIV performed in selected patients as advocated by guidelines (standard weaning), in difficult-to-wean patients from mechanical ventilation. METHODS: The study is a single-center prospective open label, randomized controlled superiority trial with two parallel groups and balanced randomization with a 1:1 ratio. Eligible patients were intubated patients mechanically ventilated for more than 24 h who failed their first SBT using TP. In the extensively-assisted weaning group, SBT was performed with PS (7 cmH2O) and PEEP (5 cmH2O). In case of SBT success, an additional SBT with TP was performed. Failure of this SBT-TP was an additional criterion for post-extubation NIV in this group in addition to other recommended criteria. In the standard weaning group, SBT was performed with TP, and NIV was performed according to international guidelines. The primary outcome criterion was the time between inclusion and successful extubation evaluated with a Cox model with adjustment on randomization strata. RESULTS: From May 2019 to March 2023, 98 patients were included and randomized in the study (49 in each group). Four patients were excluded from the intention-to-treat population (2 in both groups); therefore, 47 patients were analyzed in each group. The extensively-assisted weaning group had a higher median age (68 [58-73] vs. 62 [55-71] yrs.) and similar sex ratio (62% male vs. 57%). Time until successful extubation was not significantly different between extensively-assisted and standard weaning groups (median, 172 [50-436] vs. 95 [47-232] hours, Cox hazard ratio for successful extubation, 0.88 [95% confidence interval: 0.55-1.42] using the standard weaning group as a reference; p = 0.60). All secondary outcomes were not significantly different between groups. CONCLUSION: An extensively-assisted weaning strategy did not lead to a shorter time to successful extubation than a standard weaning strategy. Trial registration The trial was registered on ClinicalTrials.gov (NCT03861117), on March 1, 2019, before the inclusion of the first patient. https://clinicaltrials.gov/study/NCT03861117 .

Precision of CT-derived alveolar recruitment assessed by human observers and a machine learning algorithm in moderate and severe ARDS.

BACKGROUND: Assessing measurement error in alveolar recruitment on computed tomography (CT) is of paramount importance to select a reliable threshold identifying patients with high potential for alveolar recruitment and to rationalize positive end-expiratory pressure (PEEP) setting in acute respiratory distress syndrome (ARDS). The aim of this study was to assess both intra- and inter-observer smallest real difference (SRD) exceeding measurement error of recruitment using both human and machine learning-made lung segmentation (i.e., delineation) on CT. This single-center observational study was performed on adult ARDS patients. CT were acquired at end-expiration and end-inspiration at the PEEP level selected by clinicians, and at end-expiration at PEEP 5 and 15 cmH2O. Two human observers and a machine learning algorithm performed lung segmentation. Recruitment was computed as the weight change of the non-aerated compartment on CT between PEEP 5 and 15 cmH2O. RESULTS: Thirteen patients were included, of whom 11 (85%) presented a severe ARDS. Intra- and inter-observer measurements of recruitment were virtually unbiased, with 95% confidence intervals (CI95%) encompassing zero. The intra-observer SRD of recruitment amounted to 3.5 [CI95% 2.4-5.2]% of lung weight. The human-human inter-observer SRD of recruitment was slightly higher amounting to 5.7 [CI95% 4.0-8.0]% of lung weight, as was the human-machine SRD (5.9 [CI95% 4.3-7.8]% of lung weight). Regarding other CT measurements, both intra-observer and inter-observer SRD were close to zero for the CT-measurements focusing on aerated lung (end-expiratory lung volume, hyperinflation), and higher for the CT-measurements relying on accurate segmentation of the non-aerated lung (lung weight, tidal recruitment…). The average symmetric surface distance between lung segmentation masks was significatively lower in intra-observer comparisons (0.8 mm [interquartile range (IQR) 0.6-0.9]) as compared to human-human (1.0 mm [IQR 0.8-1.3] and human-machine inter-observer comparisons (1.1 mm [IQR 0.9-1.3]). CONCLUSIONS: The SRD exceeding intra-observer experimental error in the measurement of alveolar recruitment may be conservatively set to 5% (i.e., the upper value of the CI95%). Human-machine and human-human inter-observer measurement errors with CT are of similar magnitude, suggesting that machine learning segmentation algorithms are credible alternative to humans for quantifying alveolar recruitment on CT.

Ultra-low tidal volume ventilation for COVID-19-related ARDS in France (VT4COVID): a multicentre, open-label, parallel-group, randomised trial.

BACKGROUND: COVID-19-related acute respiratory distress syndrome (ARDS) is associated with a high mortality rate and longer mechanical ventilation. We aimed to assess the effectiveness of ventilation with ultra-low tidal volume (ULTV) compared with low tidal volume (LTV) in patients with COVID-19-related ARDS. METHODS: This study was a multicentre, open-label, parallel-group, randomised trial conducted in ten intensive care units in France. Eligible participants were aged 18 years or older, received invasive mechanical ventilation for COVID-19 (confirmed by RT-PCR), had ARDS according to the Berlin definition, a partial pressure of arterial oxygen to inspiratory oxygen fraction (PaO2/FiO2) ratio of 150 mm Hg or less, a tidal volume (VT) of 6·0 mL/kg predicted bodyweight or less, and received continuous intravenous sedation. Patients were randomly assigned (1:1) using randomisation blocks to receive ULTV (intervention group) aiming for VT of 4·0 mL/kg predicted bodyweight or LTV (control group) aiming for VT 6·0 mL/kg predicted bodyweight. Participants, investigators, and outcome assessors were not masked to group assignment. The primary outcome was a ranked composite score based on all-cause mortality at day 90 as the first criterion and ventilator-free days among patients alive at day 60 as the second criterion. Effect size was computed with the unmatched win ratio, on the basis of pairwise prioritised comparison of primary outcome components between every patient in the ULTV group and every patient in the LTV group. The unmatched win ratio was calculated as the ratio of the number of pairs with more favourable outcome in the ULTV group over the number of pairs with less favourable outcome in the ULTV group. Primary analysis was done in the modified intention-to-treat population, which included all participants who were randomly assigned and not lost to follow-up. This trial is registered with ClinicalTrials.gov, NCT04349618. FINDINGS: Between April 15, 2020, and April 13, 2021, 220 patients were included and five (2%) were excluded. 215 patients were randomly assigned (106 [49%] to the ULTV group and 109 [51%] to the LTV group). 58 (27%) patients were female and 157 (73%) were male. The median age was 68 years (IQR 60-74). 214 patients completed follow-up (one lost to follow-up in the ULTV group) and were included in the modified intention-to-treat analysis. The primary outcome was not significantly different between groups (unmatched win ratio in the ULTV group 0·85 [95% CI 0·60 to 1·19]; p=0·38). 46 (44%) of 105 patients in the ULTV group and 43 (39%) of 109 in the LTV group died by day 90 (absolute difference 4% [-9 to 18]; p=0·52). The rate of severe respiratory acidosis in the first 28 days was higher in the ULTV group than in the LTV group (35 [33%] vs 14 [13%]; absolute difference 20% [95% CI 9 to 31]; p=0·0004). INTERPRETATION: In patients with moderate-to-severe COVID-19-related ARDS, there was no significant difference with ULTV compared with LTV in the composite score based on mortality and ventilator-free days among patients alive at day 60. These findings do not support the systematic use of ULTV in patients with COVID-19-related ARDS. FUNDING: French Ministry of Solidarity and Health and Hospices Civils de Lyon.

Pressure support and positive end-expiratory pressure versus T-piece during spontaneous breathing trial in difficult weaning from mechanical ventilation: study protocol for the SBT-ICU study.

BACKGROUND: Spontaneous breathing trials are performed in critically ill intubated patients in order to assess readiness to be weaned from mechanical ventilation. In patients with difficult weaning (i.e. not extubated after their first SBT), performing SBT using pressure support with or without positive end-expiratory pressure or using T-piece is debated. As ventilatory support during SBT is greater on pressure support than on T-piece and as positive end-expiratory pressure can prevent weaning-induced pulmonary oedema, we hypothesized that their combination and large use of post-extubation non-invasive ventilation may shorten the time until successful extubation as compared with T-piece, without increasing the rate of reintubation. METHODS: SBT-ICU is a monocentric prospective open labelled, randomized controlled superiority trial comparing two mechanical ventilation weaning strategies; i.e. daily spontaneous breathing trials using pressure support with positive end-expiratory pressure or T-piece. The primary outcome will be time until successful extubation (defined by as extubation, without reintubation or death within the seven following days). DISCUSSION: This paper describes the protocol of the SBT-ICU trial. Enrolment of patients in the study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT03861117. Registered on March 1, 2019, before the beginning of inclusion.

Virological and clinical features of acute respiratory failure associated with COVID-19 in pregnancy: a case-control study.

Objective: Pregnancy is a risk factor for acute respiratory failure (ARF) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We hypothesised that SARS-CoV-2 viral load in the respiratory tract might be higher in pregnant intensive care unit (ICU) patients with ARF than in non-pregnant ICU patients with ARF as a consequence of immunological adaptation during pregnancy. Design: Single-centre, retrospective observational case-control study. Setting: Adult level 3 ICU in a French university hospital. Participants: Eligible participants were adults with ARF associated with coronavirus disease 2019 (COVID-19) pneumonia. Main outcome measure: The primary endpoint of the study was viral load in pregnant and non-pregnant patients. Results: 251 patients were included in the study, including 17 pregnant patients. Median gestational age at ICU admission amounted to 28 + 3/7 weeks (interquartile range [IQR], 26 + 1/7 to 31 + 5/7 weeks). Twelve patients (71%) had an emergency caesarean delivery due to maternal respiratory failure. Pregnancy was independently associated with higher viral load (-4.6 ± 1.9 cycle threshold; P < 0.05). No clustering or over-represented mutations were noted regarding SARS-CoV-2 sequences of pregnant women. Emergency caesarean delivery was independently associated with a modest but significant improvement in arterial oxygenation, amounting to 32 ± 12 mmHg in patients needing invasive mechanical ventilation. ICU mortality was significantly lower in pregnant patients (0 v 35%; P < 0.05). Age, Simplified Acute Physiology Score (SAPS) II score, and acute respiratory distress syndrome were independent risk factors for ICU mortality, while pregnancy status and virological variables were not. Conclusions: Viral load was substantially higher in pregnant ICU patients with COVID-19 and ARF compared with non-pregnant ICU patients with COVID-19 and ARF. Pregnancy was not independently associated with ICU mortality after adjustment for age and disease severity.

Prevalence and risk factors of hemodynamic instability associated with preload-dependence during continuous renal replacement therapy in a prospective observational cohort of critically ill patients.

BACKGROUND: Hemodynamic instability is a frequent complication of continuous renal replacement therapy (CRRT). Postural tests (i.e., passive leg raising in the supine position or Trendelenburg maneuver in the prone position) combined with measurement of cardiac output are highly reliable to identify preload-dependence and may provide new insights into the mechanisms involved in hemodynamic instability related to CRRT (HIRRT). We aimed to assess the prevalence and risk factors of HIRRT associated with preload-dependence in ICU patients. We conducted a single-center prospective observational cohort study in ICU patients with acute kidney injury KDIGO 3, started on CRRT in the last 24 h, and monitored with a PiCCO® device. The primary endpoint was the rate of HIRRT episodes associated with preload-dependence during the first 7 days after inclusion. HIRRT was defined as the occurrence of a mean arterial pressure below 65 mmHg requiring therapeutic intervention. Preload-dependence was assessed by postural tests every 4 h, and during each HIRRT episode. Data are expressed in median [1st quartile-3rd quartile], unless stated otherwise. RESULTS: 42 patients (62% male, age 69 [59-77] year, SAPS-2 65 [49-76]) were included 6 [1-16] h after CRRT initiation and studied continuously for 121 [60-147] h. A median of 5 [3-8] HIRRT episodes occurred per patient, for a pooled total of 243 episodes. 131 episodes (54% [CI95% 48-60%]) were associated with preload-dependence, 108 (44%, [CI95% 38-51%]) without preload-dependence, and 4 were unclassified. Multivariate analysis (using variables collected prior to HIRRT) identified the following variables as risk factors for the occurrence of HIRRT associated with preload-dependence: preload-dependence before HIRRT [odds ratio (OR) = 3.82, p < 0.001], delay since last HIRRT episode > 8 h (OR = 0.56, p < 0.05), lactate (OR = 1.21 per 1-mmol L-1 increase, p < 0.05), cardiac index (OR = 0.47 per 1-L min-1 m-2 increase, p < 0.001) and SOFA at ICU admission (OR = 0.91 per 1-point increase, p < 0.001). None of the CRRT settings was identified as risk factor for HIRRT. CONCLUSIONS: In this single-center study, HIRRT associated with preload-dependence was slightly more frequent than HIRRT without preload-dependence in ICU patients undergoing CRRT. Testing for preload-dependence could help avoiding unnecessary decrease of fluid removal in preload-independent HIRRT during CRRT.

Antibodies against type I interferon: detection and association with severe clinical outcome in COVID-19 patients.

OBJECTIVES: Impairment of type I interferon (IFN-I) immunity has been reported in critically ill COVID-19 patients. This defect can be explained in a subset of patients by the presence of circulating autoantibodies (auto-Abs) against IFN-I. We set out to improve the detection and the quantification of IFN-I auto-Abs in a cohort of critically ill COVID-19 patients, in order to better evaluate the prevalence of these Abs as the pandemic progresses, and how they correlate with the clinical course of the disease. METHODS: The concentration of anti-IFN-α2 Abs was determined in the serum of 84 critically ill COVID-19 patients who were admitted to ICU in Hospices Civils de Lyon, France, using a commercially available kit (Thermo Fisher, Catalog #BMS217). RESULTS: A total of 21 of 84 (25%) critically ill COVID-19 patients had circulating anti-IFN-α2 Abs above cut-off (> 34 ng mL-1). Among them, 15 of 21 had Abs with neutralising activity against IFN-α2, that is 15 of 84 (18%) critically ill patients. In addition, we noticed an impairment of the IFN-I response in the majority of patients with neutralising anti-IFN-α2 Abs. There was no significant difference in the clinical characteristics or outcome of with or without neutralising anti-IFN-α2 auto-Abs. We detected anti-IFN-α2 auto-Abs in COVID-19 patients' sera throughout their ICU stay. Finally, we also found auto-Abs against multiple subtypes of IFN-I including IFN-ω. CONCLUSIONS: We reported that 18% of critically ill COVID-19 patients were positive for IFN-I auto-Abs, whereas all mild COVID-19 patients were negative, confirming that the presence of these antibodies is associated with a higher risk of developing a critical COVID-19 form.

Open-label randomized controlled trial of ultra-low tidal ventilation without extracorporeal circulation in patients with COVID-19 pneumonia and moderate to severe ARDS: study protocol for the VT4COVID trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe complication of COVID-19 pneumonia, with a mortality rate amounting to 34-50% in moderate and severe ARDS, and is associated with prolonged duration of invasive mechanical ventilation. Such as in non-COVID ARDS, harmful mechanical ventilation settings might be associated with worse outcomes. Reducing the tidal volume down to 4 mL kg-1 of predicted body weight (PBW) to provide ultra-low tidal volume ventilation (ULTV) is an appealing technique to minimize ventilator-inducted lung injury. Furthermore, in the context of a worldwide pandemic, it does not require any additional material and consumables and may be applied in low- to middle-income countries. We hypothesized that ULTV without extracorporeal circulation is a credible option to reduce COVID-19-related ARDS mortality and duration of mechanical ventilation. METHODS: The VT4COVID study is a randomized, multi-centric prospective open-labeled, controlled superiority trial. Adult patients admitted in the intensive care unit with COVID-19-related mild to severe ARDS defined by a PaO2/FiO2 ratio ≤ 150 mmHg under invasive mechanical ventilation for less than 48 h, and consent to participate to the study will be eligible. Patients will be randomized into two balanced parallels groups, at a 1:1 ratio. The control group will be ventilated with protective ventilation settings (tidal volume 6 mL kg-1 PBW), and the intervention group will be ventilated with ULTV (tidal volume 4 mL kg-1 PBW). The primary outcome is a composite score based on 90-day all-cause mortality as a prioritized criterion and the number of ventilator-free days at day 60 after inclusion. The randomization list will be stratified by site of recruitment and generated using random blocks of sizes 4 and 6. Data will be analyzed using intention-to-treat principles. DISCUSSION: The purpose of this manuscript is to provide primary publication of study protocol to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. Enrollment of patients in the study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT04349618 . Registered on April 16, 2020.

Short- and long-term prognosis of acute critically ill patients with systemic rheumatic diseases: A retrospective multicentre study.

ABSTRACT: Patients with systemic rheumatic disease (SRD) share the risks of multi-organ flare-up, cardiovascular diseases, and immunosuppression. Such situations can lead to an acute critical illness. The present study describes the clinical features of SRD patients admitted to the intensive care unit (ICU) and their short- and long- term mortality.We performed a multicentre retrospective study in 10 French ICU in Lyon, France. Inclusion criteria were SRD diagnosis and admission for an acute organ failure. The primary endpoint was ICU mortality.A total of 271 patients were included. SRD included systemic lupus erythematosus (23.2% of included patients), vasculitis (10.7%), systemic sclerosis (10.7%), idiopathic inflammatory myopathy (6.3%), and other connective tissue disorders (rheumatoid arthritis, Sjögren and Sharp syndromes; 50.9%). Initial organ failure(s) were shock (43.5% of included patients), acute kidney injury (30.5%), and acute respiratory failure (23.2%). The cause(s) of ICU admission included sepsis (61.6%), cardiovascular events (33.9%), SRD-flare up (32.8%), and decompensations related to comorbidities (28%). The ICU mortality reached 14.3%. The factors associated with ICU mortality were chronic cardiac failure, invasive ventilation and admission in ICU for another reason than sepsis or SRD flare-up. The median follow-up after ICU discharge was 33.6 months. During follow-up, 109 patients died. The factors associated with long-term mortality included age, Charlson comorbidity index, and ICU admission for sepsis or SRD flare-up.The ICU mortality of patients with SRD was low. Sepsis was the first cause of admission. Cardiovascular events and comorbidities negatively impacted ICU mortality. Admission for sepsis or SRD flare-up exerted a negative effect on the long-term outcome.

Early nasal type I IFN immunity against SARS-CoV-2 is compromised in patients with autoantibodies against type I IFNs.

IFN-I and IFN-III immunity in the nasal mucosa is poorly characterized during SARS-CoV-2 infection. We analyze the nasal IFN-I/III signature, namely the expression of ISGF-3-dependent IFN-stimulated genes, in mildly symptomatic COVID-19 patients and show its correlation with serum IFN-α2 levels, which peak at symptom onset and return to baseline from day 10 onward. Moreover, the nasal IFN-I/III signature correlates with the nasopharyngeal viral load and is associated with the presence of infectious viruses. By contrast, we observe low nasal IFN-I/III scores despite high nasal viral loads in a subset of critically ill COVID-19 patients, which correlates with the presence of autoantibodies (auto-Abs) against IFN-I in both blood and nasopharyngeal mucosa. In addition, functional assays in a reconstituted human airway epithelium model of SARS-CoV-2 infection confirm the role of such auto-Abs in abrogating the antiviral effects of IFN-I, but not those of IFN-III. Thus, IFN-I auto-Abs may compromise not only systemic but also local antiviral IFN-I immunity at the early stages of SARS-CoV-2 infection.

Polyclonal expansion of TCR Vbeta 21.3+ CD4+ and CD8+ T cells is a hallmark of Multisystem Inflammatory Syndrome in Children.

Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vß21.3 T cell receptor ß chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vß21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vß21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS and acute COVID-19.