Effectiveness of exercise training on the dyspnoea of individuals with long COVID: A randomised controlled multicentre trial.

BACKGROUND: COVID-19-related acute respiratory distress syndrome (CARDS) is a severe evolution of the Sars-Cov-2 infection and necessitates intensive care. COVID-19 may subsequently be associated with long COVID, whose symptoms can include persistent respiratory symptoms up to 1 year later. Rehabilitation is currently recommended by most guidelines for people with this condition. OBJECTIVES: To evaluate the effects of exercise training rehabilitation (ETR) on dyspnoea and health-related quality of life measures in people with continuing respiratory discomfort following CARDS. METHODS: In this multicentre, two-arm, parallel, open, assessor-blinded, randomised controlled trial, we enroled adults previously admitted with CARDS to 3 French intensive care units who had been discharged at least 3 months earlier and who presented with an mMRC dyspnoea scale score > 1. Participants received either ETR or standard physiotherapy (SP) for 90 days. The primary outcome was dyspnoea, as measured by the Multidimensional Dyspnoea Profile (MDP), at day 0 (inclusion) and after 90 days of physiotherapy. Secondary outcomes were the mMRC and 12-item Short-Form Survey scores. RESULTS: Between August 7, 2020, and January 26, 2022, 487 participants with CARDS were screened for inclusion, of whom 60 were randomly assigned to receive either ETR (n = 27) or SP (n = 33). Mean MDP following ETR was 42% lower than after SP (26.15 vs. 44.76); a difference of -18.61 (95% CI -27.78 to -9.44; p<10-4). CONCLUSION: People who were still suffering from breathlessness three months after being discharged from hospital with CARDS had significantly improved dyspnoea scores when treated with ETR therapy for 90 days unlike those who only received SP. Study registered 29/09/2020 on Clinicaltrials.gov (NCT04569266).

Early shoulder-girdle MRI findings in severe COVID-19-related intensive care unit-acquired weakness: a prospective cohort study.

OBJECTIVE: To describe clinical and early shoulder-girdle MR imaging findings in severe COVID-19-related intensive care unit-acquired weakness (ICU-AW) after ICU discharge. METHODS: A single-center prospective cohort study of all consecutive patients with COVID-19-related ICU-AW from November 2020 to June 2021. All patients underwent similar clinical evaluations and shoulder-girdle MRI within the first month and then 3 months (± 1 month) after ICU discharge. RESULTS: We included 25 patients (14 males; mean [SD] age 62.4 [12.5]). Within the first month after ICU discharge, all patients showed severe proximal predominant bilateral muscular weakness (mean Medical Research Council total score = 46.5/60 [10.1]) associated with bilateral, peripheral muscular edema-like MRI signals of the shoulder girdle in 23/25 (92%) patients. At 3 months, 21/25 (84%) patients showed complete or quasi-complete resolution of proximal muscular weakness (mean Medical Research Council total score > 48/60) and 23/25 (92%) complete resolution of MRI signals of the shoulder girdle, but 12/20 (60%) patients experienced shoulder pain and/or shoulder dysfunction. CONCLUSIONS: Early shoulder-girdle MRI findings in COVID-19-related ICU-AW included muscular edema-like peripheral signal intensities, without fatty muscle involution or muscle necrosis, with favorable evolution at 3 months. Precocious MRI can help clinicians distinguish critical illness myopathy from alternative, more severe diagnoses and can be useful in the care of patients discharged from intensive care with ICU-AW. KEY POINTS: • We describe the clinical and shoulder-girdle MRI findings of COVID-19-related severe intensive care unit-acquired weakness. • This information can be used by clinicians to achieve a nearly specific diagnosis, distinguish alternative diagnoses, assess functional prognosis, and select the more appropriate health care rehabilitation and shoulder impairment treatment.

Remdesivir for Patients Hospitalized with COVID-19 Severe Pneumonia: A National Cohort Study (Remdeco-19).

BACKGROUND: Given the rapidly evolving pandemic of COVID-19 in 2020, authorities focused on the repurposing of available drugs to develop timely and cost-effective therapeutic strategies. Evidence suggested the potential utility of remdesivir in the framework of an early access program. REMDECO-19 is a multicenter national cohort study assessing the ability of remdesivir to improve the outcome of patients hospitalized with COVID-19. METHODS: We conducted a retrospective real-life study that included all patients from the early access program of remdesivir in France. The primary endpoint was the clinical course evolution of critically ill and hospitalized COVID-19 patients treated with remdesivir. Secondary endpoints were the SOFA score evolution within 29 days following the admission and mortality at 29 and 90 days. RESULTS: Eighty-five patients were enrolled in 22 sites from January to April 2020. The median WHO and SOFA scores were respectively reduced by two and six points between days 1 and 29. Improvement in the WHO-CPS and the SOFA score were observed in 83.5% and 79.3% of patients, respectively, from day 10. However, there was no effect of remdesivir on the 90-day survival based on the control cohort for hospitalized COVID-19 patients with invasive ventilation. CONCLUSIONS: SOFA score appeared to be an attractive approach to assess remdesivir efficacy and stratify its utilization or not in critically ill patients with COVID-19. This study brings a new clinical benchmark for therapeutic decision making and supports the use of remdesivir for some hospitalized COVID-19 patients.

Clinical phenotypes and outcomes associated with SARS-CoV-2 variant Omicron in critically ill French patients with COVID-19.

Infection with SARS-CoV-2 variant Omicron is considered to be less severe than infection with variant Delta, with rarer occurrence of severe disease requiring intensive care. Little information is available on comorbid factors, clinical conditions and specific viral mutational patterns associated with the severity of variant Omicron infection. In this multicenter prospective cohort study, patients consecutively admitted for severe COVID-19 in 20 intensive care units in France between December 7th 2021 and May 1st 2022 were included. Among 259 patients, we show that the clinical phenotype of patients infected with variant Omicron (n = 148) is different from that in those infected with variant Delta (n = 111). We observe no significant relationship between Delta and Omicron variant lineages/sublineages and 28-day mortality (adjusted odds ratio [95% confidence interval] = 0.68 [0.35-1.32]; p = 0.253). Among Omicron-infected patients, 43.2% are immunocompromised, most of whom have received two doses of vaccine or more (85.9%) but display a poor humoral response to vaccination. The mortality rate of immunocompromised patients infected with variant Omicron is significantly higher than that of non-immunocompromised patients (46.9% vs 26.2%; p = 0.009). In patients infected with variant Omicron, there is no association between specific sublineages (BA.1/BA.1.1 (n = 109) and BA.2 (n = 21)) or any viral genome polymorphisms/mutational profile and 28-day mortality.

Plasma Endocan as a Biomarker of Thrombotic Events in COVID-19 Patients.

(1) Background: Endocan is a marker of endothelial dysfunction that may be associated with thrombotic events. The aim of the study was to investigate the performance of endocan as a marker of thrombotic events in COVID-19 patients. (2) Methods: We measured endocan in plasma from 79 documented COVID-19 patients classified according to disease severity (from mild to critical). Thrombotic events were recorded. (3) Results: Endocan concentrations at admission were significantly increased according to COVID-19 severity. Levels of endocan were significantly increased in patients experiencing thrombotic events in comparison with those without (16.2 (5.5-26.7) vs. 1.81 (0.71-10.5) ng/mL, p < 0.001). However, endocan concentrations were not different between pulmonary embolism and other thrombotic events. The Receiver Operating Characteristic (ROC) analysis for the identification of thrombotic events showed an area under the ROC curve (AUC) of 0.776 with an optimal threshold at 2.83 ng/mL (93.8% sensitivity and 54.7% specificity). When combining an endocan measurement with D-dimers, the AUC increased to 0.853. When considering both biomarkers, the Kaplan-Meier survival curves showed that the combination of endocan and D-dimers better discriminated patients with thrombotic events than those without. The combination of D-dimers and endocan was independently associated with thrombotic events. (4) Conclusions: Endocan might be a useful and informative biomarker to better identify thrombotic events in COVID-19 patients.

Tocilizumab plus dexamethasone versus dexamethasone in patients with moderate-to-severe COVID-19 pneumonia: A randomised clinical trial from the CORIMUNO-19 study group.

Background: In moderate-to-severe COVID-19 pneumonia, dexamethasone (DEX) and tocilizumab (TCZ) reduce the occurrence of death and ventilatory support. We investigated the efficacy and safety of DEX+TCZ in an open randomized clinical trial. Methods: From July 24, 2020, through May 18, 2021, patients with moderate-to-severe COVID-19 pneumonia requiring oxygen (>3 L/min) were randomly assigned to receive DEX (10 mg/d 5 days tapering up to 10 days) alone or combined with TCZ (8 mg/kg IV) at day 1, possibly repeated with a fixed dose of 400 mg i.v. at day 3. The primary outcome was time from randomization to mechanical ventilation support or death up to day 14, analysed on an intent-to-treat basis using a Bayesian approach. ClinicalTrials.gov number, NCT04476979. Findings: A total of 453 patients were randomized, 3 withdrew consent, 450 were analysed, of whom 226 and 224 patients were assigned to receive DEX or TCZ+DEX, respectively. At day 14, mechanical ventilation or death occurred in 32/226 (14%) and 27/224 (12%) in the DEX and TCZ+DEX arms, respectively (hazard ratio [HR] 0·85, 90% credible interval [CrI] 0·55 to 1·31). At day 14, the World health Organization (WHO) clinical progression scale (CPS) was significantly improved in the TCZ+DEX arm (OR 0·69, 95% CrI, 0·49 to 0.97). At day 28, the cumulative incidence of oxygen supply independency was 82% in the TCZ+DEX arms and 72% in the DEX arm (HR 1·36, 95% CI 1·11 to 1·67). On day 90, 24 deaths (11%) were observed in the DEX arm and 18 (8%) in the TCZ+DEX arm (HR 0·77, 95% CI 0·42-1·41). Serious adverse events were observed in 25% and 21% in DEX and TCZ+DEX arms, respectively. Interpretation: Mechanical ventilation need and mortality were not improved with TCZ+DEX compared with DEX alone. The safety of both treatments was similar. However, given the wide confidence intervals for the estimate of effect, definitive interpretation cannot be drawn. Funding: Programme Hospitalier de Recherche Clinique [PHRC COVID-19-20-0151, PHRC COVID-19-20-0029], Fondation de l'Assistance Publique - Hôpitaux de Paris (Alliance Tous Unis Contre le Virus) and from Fédération pour la Recherche Médicale" (FRM). Tocilizumab was provided by Roche.

Dynamics of circulating calprotectin accurately predict the outcome of moderate COVID-19 patients.

BACKGROUND: Severe COVID-19 is associated with a high circulating level of calprotectin, the S100A8/S100A9 alarmin heterodimer. Baseline calprotectin amount measured in peripheral blood at diagnosis correlates with disease severity. The optimal use of this biomarker along COVID-19 course remains to be delineated. METHODS: We focused on patients with a WHO-defined moderate COVID-19 requiring hospitalization in a medical ward. We collected plasma and serum from three independent cohorts (N = 626 patients) and measured calprotectin amount at admission. We performed longitudinal measures of calprotectin in 457 of these patients (1461 samples) and used a joint latent class mixture model in which classes were defined by age, body mass index and comorbidities to identify calprotectin trajectories predicting the risk of transfer into an intensive care unit or death. FINDINGS: After adjustment for age, sex, body mass index and comorbidities, the predictive value of baseline calprotectin in patients with moderate COVID19 could be refined by serial monitoring of the biomarker. We discriminated three calprotectin trajectories associated with low, moderate, and high risk of poor outcome, and we designed an algorithm available as online software (https://calpla.gustaveroussy.fr:8443/) to monitor the probability of a poor outcome in individual patients with moderate COVID-19. INTERPRETATION: These results emphasize the clinical interest of serial monitoring of calprotectin amount in the peripheral blood to anticipate the risk of poor outcomes in patients with moderate COVID-19 hospitalized in a standard care unit. FUNDING: The study received support (research grants) from ThermoFisher immunodiagnostics (France) and Gustave Roussy Foundation.

Effects of Prone Positioning on Respiratory Mechanics and Oxygenation in Critically Ill Patients With COVID-19 Requiring Venovenous Extracorporeal Membrane Oxygenation.

BACKGROUND: The effect of prone positioning (PP) on respiratory mechanics remains uncertain in patients with severe acute respiratory distress syndrome (ARDS) requiring venovenous extracorporeal membrane oxygenation (VV-ECMO). METHODS: We prospectively analyzed the effects of PP on respiratory mechanics from continuous data with over a thousand time points during 16-h PP sessions in patients with COVID-19 and ARDS under VV-ECMO conditions. The evolution of respiratory mechanical and oxygenation parameters during the PP sessions was evaluated by dividing each PP session into four time quartiles: first quartile: 0-4 h, second quartile: 4-8 h, third quartile: 8-12 h, and fourth quartile: 12-16 h. RESULTS: Overall, 38 PP sessions were performed in 10 patients, with 3 [2-5] PP sessions per patient. Seven (70%) patients were responders to at least one PP session. PP significantly increased the PaO2/FiO2 ratio by 14 ± 21% and compliance by 8 ± 15%, and significantly decreased the oxygenation index by 13 ± 18% and driving pressure by 8 ± 12%. The effects of PP on respiratory mechanics but not on oxygenation persisted after supine repositioning. PP-induced changes in different respiratory mechanical parameters and oxygenation started as early as the first-time quartile, without any difference in PP-induced changes among the different time quartiles. PP-induced changes in driving pressure (-14 ± 14 vs. -6 ± 10%, p = 0.04) and mechanical power (-11 ± 13 vs. -0.1 ± 12%, p = 0.02) were significantly higher in responders (increase in PaO2/FiO2 ratio > 20%) than in non-responder patients. CONCLUSIONS: In patients with COVID-19 and severe ARDS, PP under VV-ECMO conditions improved the respiratory mechanical and oxygenation parameters, and the effects of PP on respiratory mechanics persisted after supine repositioning.

Early Clinical and Electrophysiological Brain Dysfunction Is Associated With ICU Outcomes in COVID-19 Critically Ill Patients With Acute Respiratory Distress Syndrome: A Prospective Bicentric Observational Study.

OBJECTIVES: Describe the prevalence of acute cerebral dysfunction and assess the prognostic value of an early clinical and electroencephalography (EEG) assessment in ICU COVID-19 patients. DESIGN: Prospective observational study. SETTING: Two tertiary critical care units in Paris, France, between April and December 2020. PATIENTS: Adult critically ill patients with COVID-19 acute respiratory distress syndrome. INTERVENTIONS: Neurologic examination and EEG at two time points during the ICU stay, first under sedation and second 4-7 days after sedation discontinuation. MEASUREMENTS AND MAIN RESULTS: Association of EEG abnormalities (background reactivity, continuity, dominant frequency, and presence of paroxystic discharges) with day-28 mortality and neurologic outcomes (coma and delirium recovery). Fifty-two patients were included, mostly male (81%), median (interquartile range) age 68 years (56-74 yr). Delayed awakening was present in 68% of patients (median awakening time of 5 d [2-16 d]) and delirium in 74% of patients who awoke from coma (62% of mixed delirium, median duration of 5 d [3-8 d]). First, EEG background was slowed in the theta-delta range in 48 (93%) patients, discontinuous in 25 patients (48%), and nonreactive in 17 patients (33%). Bifrontal slow waves were observed in 17 patients (33%). Early nonreactive EEG was associated with lower day-28 ventilator-free days (0 vs 16; p = 0.025), coma-free days (6 vs 22; p = 0.006), delirium-free days (0 vs 17; p = 0.006), and higher mortality (41% vs 11%; p = 0.027), whereas discontinuous background was associated with lower ventilator-free days (0 vs 17; p = 0.010), coma-free days (1 vs 22; p < 0.001), delirium-free days (0 vs 17; p = 0.001), and higher mortality (40% vs 4%; p = 0.001), independently of sedation and analgesia. CONCLUSIONS: Clinical and neurophysiologic cerebral dysfunction is frequent in COVID-19 ARDS patients. Early severe EEG abnormalities with nonreactive and/or discontinuous background activity are associated with delayed awakening, delirium, and day-28 mortality.

Impact of COVID-19 on the association between pulse oximetry and arterial oxygenation in patients with acute respiratory distress syndrome.

Managing patients with acute respiratory distress syndrome (ARDS) requires frequent changes in mechanical ventilator respiratory settings to optimize arterial oxygenation assessed by arterial oxygen partial pressure (PaO2) and saturation (SaO2). Pulse oxymetry (SpO2) has been suggested as a non-invasive surrogate for arterial oxygenation however its accuracy in COVID-19 patients is unknown. In this study, we aimed to investigate the influence of COVID-19 status on the association between SpO2 and arterial oxygenation. We prospectively included patients with ARDS and compared COVID-19 to non-COVID-19 patients, regarding SpO2 and concomitant arterial oxygenation (SaO2 and PaO2) measurements, and their association. Bias was defined as mean difference between SpO2 and SaO2 measurements. Occult hypoxemia was defined as a SpO2 ≥ 92% while concomitant SaO2 < 88%. Multiple linear regression models were built to account for confounders. We also assessed concordance between positive end-expiratory pressure (PEEP) trial-induced changes in SpO2 and in arterial oxygenation. We included 55 patients, among them 26 (47%) with COVID-19. Overall, SpO2 and SaO2 measurements were correlated (r = 0.70; p < 0.0001), however less so in COVID-19 than in non-COVID-19 patients (r = 0.55, p < 0.0001 vs. r = 0.84, p < 0.0001, p = 0.002 for intergroup comparison). Bias was + 1.1%, greater in COVID-19 than in non-COVID-19 patients (2.0 vs. 0.3%; p = 0.02). In multivariate analysis, bias was associated with COVID-19 status (unstandardized ß = 1.77, 95%CI = 0.38-3.15, p = 0.01), ethnic group and ARDS severity. Occult hypoxemia occurred in 5.5% of measurements (7.7% in COVID-19 patients vs. 3.4% in non-COVID-19 patients, p = 0.42). Concordance rate between PEEP trial-induced changes in SpO2 and SaO2 was 84%, however less so in COVID-19 than in non-COVID-19 patients (69% vs. 97%, respectively). Similar results were observed for PaO2 regarding correlations, bias, and concordance with SpO2 changes. In patients with ARDS, SpO2 was associated with arterial oxygenation, but COVID-19 status significantly altered this association.

Severe COVID-19 is associated with hyperactivation of the alternative complement pathway

Background Severe coronavirus disease 2019 (COVID-19) is characterized by impaired type I interferon activity and a state of hyperinflammation leading to acute respiratory distress syndrome. The complement system has recently emerged as a key player in triggering and maintaining the inflammatory state, but the role of this molecular cascade in severe COVID-19 is still poorly characterized. Objective We aimed at assessing the contribution of complement pathways at both protein and transcriptomic levels. Methods To this end, we systematically assessed RNA levels of 28 complement genes in circulating whole blood of COVID-19 patients and healthy controls, including genes of the alternative pathway, for which data remain scarce. Results We found differential expression of genes involved in the complement system, yet with various expression patterns: while patients displaying moderate disease had elevated expression of classical pathway genes, severe disease was associated with increased lectin and alternative pathway activation, which correlated with inflammation and coagulopathy markers. Additionally, properdin, a pivotal positive regulator of the alternative pathway, showed high RNA expression but was found at low protein concentrations in severe and critical patients, suggesting its deposition at the sites of complement activation. Notably, low properdin levels were significantly associated with the use of mechanical ventilation (AUC = 0.82, p = 0.002). Conclusion This study sheds light on the role of the alternative pathway in severe COVID-19 and provides additional rationale for the testing of drugs inhibiting the alternative pathway of the complement system. We show that activation of the alternative complement pathway characterizes COVID-19 severity. Specifically, low properdin levels were associated with use of mechanical ventilation. This work provides a rationale for the specific inhibition of the alternative complement pathway.

Lupus Anticoagulant Single Positivity During the Acute Phase of COVID-19 Is Not Associated With Venous Thromboembolism or In-Hospital Mortality.

OBJECTIVE: The clinical relevance of antiphospholipid antibodies (aPLs) in COVID-19 is controversial. This study was undertaken to investigate the prevalence and prognostic value of conventional and nonconventional aPLs in patients with COVID-19. METHODS: This was a multicenter, prospective observational study in a French cohort of patients hospitalized with suspected COVID-19. RESULTS: Two hundred forty-nine patients were hospitalized with suspected COVID-19, in whom COVID-19 was confirmed in 154 and not confirmed in 95. We found a significant increase in lupus anticoagulant (LAC) positivity among patients with COVID-19 compared to patients without COVID-19 (60.9% versus 23.7%; P < 0.001), while prevalence of conventional aPLs (IgG and IgM anti-ß2 -glycoprotein I and IgG and IgM anticardiolipin isotypes) and nonconventional aPLs (IgA isotype of anticardiolipin, IgA isotype of anti-ß2 -glycoprotein I, IgG and IgM isotypes of anti-phosphatidylserine/prothrombin, and IgG and IgM isotypes of antiprothrombin) was low in both groups. Patients with COVID-19 who were positive for LAC, as compared to patients with COVID-19 who were negative for LAC, had higher levels of fibrinogen (median 6.0 gm/liter [interquartile range 5.0-7.0] versus 5.3 gm/liter [interquartile range 4.3-6.4]; P = 0.028) and C-reactive protein (CRP) (median 115.5 mg/liter [interquartile range 66.0-204.8] versus 91.8 mg/liter [interquartile range 27.0-155.1]; P = 0.019). Univariate analysis did not show any association between LAC positivity and higher risks of venous thromboembolism (VTE) (odds ratio 1.02 [95% confidence interval 0.44-2.43], P = 0.95) or in-hospital mortality (odds ratio 1.80 [95% confidence interval 0.70-5.05], P = 0.24). With and without adjustment for CRP level, age, and sex, Kaplan-Meier survival curves according to LAC positivity confirmed the absence of an association with VTE or in-hospital mortality (unadjusted P = 0.64 and P = 0.26, respectively; adjusted hazard ratio 1.13 [95% confidence interval 0.48-2.60] and 1.80 [95% confidence interval 0.67-5.01], respectively). CONCLUSION: Patients with COVID-19 have an increased prevalence of LAC positivity associated with biologic markers of inflammation. However, LAC positivity at the time of hospital admission is not associated with VTE risk and/or in-hospital mortality.

Regulation of the acetylcholine/α7nAChR anti-inflammatory pathway in COVID-19 patients.

The cholinergic system has been proposed as a potential regulator of COVID-19-induced hypercytokinemia. We investigated whole-blood expression of cholinergic system members and correlated it with COVID-19 severity. Patients with confirmed SARS-CoV-2 infection and healthy aged-matched controls were included in this non-interventional study. A whole blood sample was drawn between 9-11 days after symptoms onset, and peripheral leukocyte phenotyping, cytokines measurement, RNA expression and plasma viral load were determined. Additionally, whole-blood expression of native alpha-7 nicotinic subunit and its negative dominant duplicate (CHRFAM7A), choline acetyltransferase and acetylcholine esterase (AchE) were determined. Thirty-seven patients with COVID-19 (10 moderate, 11 severe and 16 with critical disease) and 14 controls were included. Expression of CHRFAM7A was significantly lower in critical COVID-19 patients compared to controls. COVID-19 patients not expressing CHRFAM7A had higher levels of CRP, more extended pulmonary lesions and displayed more pronounced lymphopenia. COVID-19 patients without CHRFAM7A expression also showed increased TNF pathway expression in whole blood. AchE was also expressed in 30 COVID-19 patients and in all controls. COVID-19-induced hypercytokinemia is associated with decreased expression of the pro-inflammatory dominant negative duplicate CHRFAM7A. Expression of this duplicate might be considered before targeting the cholinergic system in COVID-19 with nicotine.

Platelet activation in critically ill COVID-19 patients.

BACKGROUND: Microvascular, arterial and venous thrombotic events have been largely described during severe coronavirus disease 19 (COVID-19). However, mechanisms underlying hemostasis dysregulation remain unclear. METHODS: We explored two independent cross-sectional cohorts to identify soluble markers and gene-expression signatures that discriminated COVID-19 severity and outcomes. RESULTS: We found that elevated soluble (s)P-selectin at admission was associated with disease severity. Elevated sP-selectin was predictive of intubation and death (ROC AUC = 0.67, p = 0.028 and AUC = 0.74, p = 0.0047, respectively). An optimal cutoff value was predictive of intubation with 66% negative predictive value (NPV) and 61% positive predictive value (PPV), and of death with 90% NPV and 55% PPV. An unbiased gene set enrichment analysis revealed that critically ill patients had increased expression of genes related to platelet activation. Hierarchical clustering identified ITG2AB, GP1BB, PPBP and SELPLG to be upregulated in a grade-dependent manner. ROC curve analysis for the prediction of intubation was significant for SELPLG and PPBP (AUC = 0.8, p = 0.046 for both). An optimal cutoff value for PBPP was predictive of intubation with 100% NPV and 45% PPV, and for SELPLG with 100% NPV and 50% PPV. CONCLUSION: We provide evidence that platelets contribute to COVID-19 severity. Plasma sP-selectin level was associated with severity and in-hospital mortality. Transcriptional analysis identified PPBP/CXCL7 and SELPLG as biomarkers for intubation. These findings provide additional evidence for platelet activation in driving critical COVID-19. Specific studies evaluating the performance of these biomarkers are required.

Oxidative Stress and Inflammatory Biomarkers for the Prediction of Severity and ICU Admission in Unselected Patients Hospitalized with COVID-19.

OBJECTIVE: We aimed to investigate the prognostic performances of oxidative stress (OS), inflammatory and cell activation biomarkers measured at admission in COVID-19 patients. DESIGN: retrospective monocentric study. SETTING: patients with suspected SARS-CoV-2 infection (COVID-19) admitted to the hospital. PATIENTS: One hundred and sixty documented and unselected COVID-19-patients. Disease severity (from mild to critical) was scored according to NIH's classification. INTERVENTIONS: none. MEASUREMENTS AND MAIN RESULTS: We measured OS biomarkers (thiol, advanced oxidation protein products (AOPP), ischemia-modified albumin (IMA)), inflammation biomarkers (interleukin-6 (IL-6), presepsin) and cellular activation biomarkers (calprotectin) in plasma at admission. Thiol concentrations decreased while IMA, IL-6, calprotectin and PSEP increased with disease severity in COVID-19 patients and were associated with increased O2 needs and ICU admission. The best area under the receiver-operating-characteristics curve (AUC) for the prediction of ICU admission was for thiol (AUC = 0.762). A thiol concentration <154 µmol/L was predictive for ICU admission (79.7% sensitivity, 64.6% specificity, 58.8% positive predictive value, 78.9% negative predictive value). In a stepwise logistic regression, we found that being overweight, having dyspnoea, and thiol and IL-6 plasmatic concentrations were independently associated with ICU admission. In contrast, calprotectin was the best biomarker to predict mortality (AUC = 0.792), with an optimal threshold at 24.1 mg/L (94.1% sensitivity, 64.9% specificity, 97.1% positive predictive value and 98.9% negative predictive value), and survival curves indicated that high IL-6 and calprotectin concentrations were associated with a significantly increased risk of mortality. CONCLUSIONS: Thiol measurement at admission is a promising tool to predict ICU admission in COVID-19-patients, whereas IL-6 and calprotectin measurements effectively predict mortality.

Uncoupling of IL-6 signaling and LC3-associated phagocytosis drives immunoparalysis during sepsis.

Immune deactivation of phagocytes is a central event in the pathogenesis of sepsis. Herein, we identify a master regulatory role of IL-6 signaling on LC3-associated phagocytosis (LAP) and reveal that uncoupling of these two processes during sepsis induces immunoparalysis in monocytes/macrophages. In particular, we demonstrate that activation of LAP by the human fungal pathogen Aspergillus fumigatus depends on ERK1/2-mediated phosphorylation of p47phox subunit of NADPH oxidase. Physiologically, autocrine IL-6/JAK2/Ninein axis orchestrates microtubule organization and dynamics regulating ERK recruitment to the phagosome and LC3+ phagosome (LAPosome) formation. In sepsis, loss of IL-6 signaling specifically abrogates microtubule-mediated trafficking of ERK, leading to defective activation of LAP and impaired killing of bacterial and fungal pathogens by monocytes/macrophages, which can be selectively restored by IL-6 supplementation. Our work uncovers a molecular pathway linking IL-6 signaling with LAP and provides insight into the mechanisms underlying immunoparalysis in sepsis.

Timing and causes of death in severe COVID-19 patients.

BACKGROUND: Previous studies reporting the causes of death in patients with severe COVID-19 have provided conflicting results. The objective of this study was to describe the causes and timing of death in patients with severe COVID-19 admitted to the intensive care unit (ICU). METHODS: We performed a retrospective study in eight ICUs across seven French hospitals. All consecutive adult patients (aged ≥ 18 years) admitted to the ICU with PCR-confirmed SARS-CoV-2 infection and acute respiratory failure were included in the analysis. The causes and timing of ICU deaths were reported based on medical records. RESULTS: From March 1, 2020, to April 28, 287 patients were admitted to the ICU for SARS-CoV-2 related acute respiratory failure. Among them, 93 patients died in the ICU (32%). COVID-19-related multiple organ dysfunction syndrome (MODS) was the leading cause of death (37%). Secondary infection-related MODS accounted for 26% of ICU deaths, with a majority of ventilator-associated pneumonia. Refractory hypoxemia/pulmonary fibrosis was responsible for death in 19% of the cases. Fatal ischemic events (venous or arterial) occurred in 13% of the cases. The median time from ICU admission to death was 15 days (25th-75th IQR, 7-27 days). COVID-19-related MODS had a median time from ICU admission to death of 14 days (25th-75th IQR: 7-19 days), while only one death had occurred during the first 3 days since ICU admission. CONCLUSIONS: In our multicenter observational study, COVID-19-related MODS and secondary infections were the two leading causes of death, among severe COVID-19 patients admitted to the ICU.

Single-cell RNA sequencing of blood antigen-presenting cells in severe COVID-19 reveals multi-process defects in antiviral immunity.

COVID-19 can lead to life-threatening respiratory failure, with increased inflammatory mediators and viral load. Here, we perform single-cell RNA-sequencing to establish a high-resolution map of blood antigen-presenting cells (APCs) in 15 patients with moderate or severe COVID-19 pneumonia, at day 1 and day 4 post admission to intensive care unit or pulmonology department, as well as in 4 healthy donors. We generated a unique dataset of 81,643 APCs, including monocytes and rare dendritic cell (DC) subsets. We uncovered multi-process defects in antiviral immune defence in specific APCs from patients with severe disease: (1) increased pro-apoptotic pathways in plasmacytoid DCs (pDCs, key effectors of antiviral immunity), (2) a decrease of the innate sensors TLR9 and DHX36 in pDCs and CLEC9a+ DCs, respectively, (3) downregulation of antiviral interferon-stimulated genes in monocyte subsets and (4) a decrease of major histocompatibility complex (MHC) class II-related genes and MHC class II transactivator activity in cDC1c+ DCs, suggesting viral inhibition of antigen presentation. These novel mechanisms may explain patient aggravation and suggest strategies to restore the defective immune defence.