NEUT-SFL in Patients with COVID-ARDS: A Novel Biomarker for Thrombotic Events?

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped RNA virus first identified in December 2019 in Wuhan, China, and responsible for coronavirus disease 2019 (COVID-19). The ongoing COVID-19 pandemic is impacting healthcare worldwide. Patients who develop coagulopathy have worse outcomes. The pathophysiology of COVID-19 suggests a strong interplay between hemostasis and immune cells, especially neutrophils. Our purpose was to assess neutrophil fluorescence as a potential biomarker of deep vein thrombosis (DVT) in patients with COVID-acute respiratory distress syndrome (COVID-ARDS). Sixty-one patients with COVID-ARDS admitted to the four intensive care units (ICUs) of a French general hospital were included in this prospective study. Neutrophil activation was assessed by measuring neutrophil fluorescence (NEUT-Side Fluorescence Light, NEUT-SFL) with a specific fluorescent dye staining analyzed by a routine automated flow cytometer Sysmex XN-3000™ (Sysmex, Kobe, Japan). DVT was diagnosed by complete duplex ultrasound (CDU). We found that NEUT-SFL was elevated on admission in patients with COVID-ARDS (49.76 AU, reference value 46.40 AU, p < 0.001), but did not differ between patients with DVT (49.99 AU) and those without (49.52 AU, p = 0.555). NEUT-SFL is elevated in patients with COVID-ARDS, reflecting neutrophil activation, but cannot be used as a marker of thrombosis. Because neutrophils are at interface between immune response and hemostasis through release of neutrophil extracellular traps, monitoring their activation could be an interesting approach to improve our management of coagulopathy during COVID-ARDS. Further research is needed to better understand the pathophysiology of COVID-19 and identify high-performance biomarkers.

Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort.

The drivers of critical coronavirus disease 2019 (COVID-19) remain unknown. Given major confounding factors such as age and comorbidities, true mediators of this condition have remained elusive. We used a multi-omics analysis combined with artificial intelligence in a young patient cohort where major comorbidities were excluded at the onset. The cohort included 47 "critical" (in the intensive care unit under mechanical ventilation) and 25 "non-critical" (in a non-critical care ward) patients with COVID-19 and 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cell proteomics, cytokine profiling, and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing, and structural causal modeling were used. Patients with critical COVID-19 were characterized by exacerbated inflammation, perturbed lymphoid and myeloid compartments, increased coagulation, and viral cell biology. Among differentially expressed genes, we observed up-regulation of the metalloprotease ADAM9. This gene signature was validated in a second independent cohort of 81 critical and 73 recovered patients with COVID-19 and was further confirmed at the transcriptional and protein level and by proteolytic activity. Ex vivo ADAM9 inhibition decreased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uptake and replication in human lung epithelial cells. In conclusion, within a young, otherwise healthy, cohort of individuals with COVID-19, we provide the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients. We further identified ADAM9 as a driver of disease severity and a candidate therapeutic target.

Mental health and stress among ICU healthcare professionals in France according to intensity of the COVID-19 epidemic.

BACKGROUND: We investigated the impact of the COVID-19 crisis on mental health of professionals working in the intensive care unit (ICU) according to the intensity of the epidemic in France. METHODS: This cross-sectional survey was conducted in 77 French hospitals from April 22 to May 13 2020. All ICU frontline healthcare workers were eligible. The primary endpoint was the mental health, assessed using the 12-item General Health Questionnaire. Sources of stress during the crisis were assessed using the Perceived Stressors in Intensive Care Units (PS-ICU) scale. Epidemic intensity was defined as high or low for each region based on publicly available data from Santé Publique France. Effects were assessed using linear mixed models, moderation and mediation analyses. RESULTS: In total, 2643 health professionals participated; 64.36% in high-intensity zones. Professionals in areas with greater epidemic intensity were at higher risk of mental health issues (p < 0.001), and higher levels of overall perceived stress (p < 0.001), compared to low-intensity zones. Factors associated with higher overall perceived stress were female sex (B = 0.13; 95% confidence interval [CI] = 0.08-0.17), having a relative at risk of COVID-19 (B = 0.14; 95%-CI = 0.09-0.18) and working in high-intensity zones (B = 0.11; 95%-CI = 0.02-0.20). Perceived stress mediated the impact of the crisis context on mental health (B = 0.23, 95%-CI = 0.05, 0.41) and the impact of stress on mental health was moderated by positive thinking, b = - 0.32, 95% CI = - 0.54, - 0.11. CONCLUSION: COVID-19 negatively impacted the mental health of ICU professionals. Professionals working in zones where the epidemic was of high intensity were significantly more affected, with higher levels of perceived stress. This study is supported by a grant from the French Ministry of Health (PHRC-COVID 2020).

Macrophage Activation in COVID-19 Patients in Intensive Care Unit.

We report six cases of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, admitted to intensive care unit (ICU), for whom bone marrow aspirate revealed hemophagocytosis. We compared their clinical presentation and laboratory findings to those that can be encountered during a hemophagocytic lymphohistiocytosis. These observations might evoke a macrophage activation mechanism different from the one encountered in the hemophagocytic lymphohistiocytosis (HLH).

Characterization of pulmonary impairment associated with COVID-19 in patients requiring mechanical ventilation. / Caracterização do comprometimento pulmonar associado à COVID-19 em pacientes com necessidade de ventilação mecânica.

OBJECTIVE: To detect early respiratory and hemodynamic instability to characterize pulmonary impairment in patients with severe COVID-19. METHODS: We retrospectively analyzed data collected from COVID-19 patients suffering from acute respiratory failure requiring intubation and mechanical ventilation. We used transpulmonary thermodilution assessment with a PiCCO™ device. We collected demographic, respiratory, hemodynamic and echocardiographic data within the first 48 hours after admission. Descriptive statistics were used to summarize the data. RESULTS: Fifty-three patients with severe COVID-19 were admitted between March 22nd and April 7th. Twelve of them (22.6%) were monitored with a PiCCO™ device. Upon admission, the global-end diastolic volume indexed was normal (mean 738.8mL ± 209.2) and moderately increased at H48 (879mL ± 179), and the cardiac index was subnormal (2.84 ± 0.65). All patients showed extravascular lung water over 8mL/kg on admission (17.9 ± 8.9). We did not identify any argument for cardiogenic failure. CONCLUSION: In the case of severe COVID-19 pneumonia, hemodynamic and respiratory presentation is consistent with pulmonary edema without evidence of cardiogenic origin, favoring the diagnosis of acute respiratory distress syndrome.

OBJETIVO: Detectar precocemente a instabilidade respiratória e hemodinâmica para caracterizar o comprometimento pulmonar em pacientes com COVID-19 grave. MÉTODOS: Analisamos retrospectivamente os dados colhidos de pacientes com COVID-19 que apresentaram insuficiência respiratória aguda com necessidade de intubação e ventilação mecânica. Utilizamos a avaliação da termodiluição transpulmonar por meio do dispositivo PiCCO™. Foram coletados os dados demográficos, respiratórios, hemodinâmicos e ecocardiográficos dentro das primeiras 48 horas após a admissão. Para resumir os dados, utilizamos estatística descritiva. RESULTADOS: Entre 22 de março e 7 de abril de 2020, foram admitidos 23 pacientes com COVID-19 grave. Foram monitorados com o dispositivo PiCCO™ 12 (22,6%) deles. Quando da admissão, o volume diastólico final global indexado era normal (média de 738,8mL ± 209,2) e, na hora 48, encontrava-se moderadamente aumentado (879mL ± 179), enquanto o índice cardíaco se achava abaixo do normal (2,84 ± 0,65). Todos os pacientes revelaram a presença de água extravascular pulmonar acima de 8mL/kg na admissão (17,9 ± 8,9). Não identificamos qualquer evidência de origem cardiogênica. CONCLUSÃO: No caso de pneumonia grave por COVID-19, o quadro hemodinâmico e respiratório é compatível com edema pulmonar sem evidência de origem cardiogênica, o que favorece o diagnóstico de síndrome do desconforto respiratório agudo.