Potential for recovery after extremely prolonged VV-ECMO support in well-selected severe COVID-19 patients: a retrospective cohort study.

BACKGROUND: VenoVenous ExtraCorporeal Membrane Oxygenation (VV-ECMO) has been widely used as supportive therapy for severe respiratory failure related to Acute Respiratory Distress Syndrome (ARDS) due to coronavirus 2019 (COVID-19). Only a few data describe the maximum time under VV-ECMO during which pulmonary recovery remains possible. The main objective of this study is to describe the outcomes of prolonged VV-ECMO in patients with COVID-19-related ARDS. METHODS: This retrospective study was conducted at a tertiary ECMO center in Brussels, Belgium, between March 2020 and April 2022. All adult patients with ARDS due to COVID-19 who were managed with ECMO therapy for more than 50 days as a bridge to recovery were included. RESULTS: Fourteen patients met the inclusion criteria. The mean duration of VV-ECMO was 87 ± 29 days. Ten (71%) patients were discharged alive from the hospital. The 90-day survival was 86%, and the one-year survival was 71%. The evolution of the patients was characterized by very impaired pulmonary compliance that started to improve slowly and progressively on day 53 (± 25) after the start of ECMO. Of note, four patients improved substantially after a second course of steroids. CONCLUSIONS: There is potential for recovery in patients with very severe ARDS due to COVID-19 supported by VV-ECMO for up to 151 days.

Dual antiplatelet therapy is associated with high α-tubulin acetylation in circulating platelets from coronary artery disease patients.

Platelet inhibition is the main treatment strategy to prevent atherothrombotic complications after acute coronary syndrome or percutaneous coronary intervention. Despite dual antiplatelet therapy (DAPT) combining aspirin and a P2Y12 receptor inhibitor, high on-treatment platelet reactivity (HPR) persists in some patients due to poor response to treatment and is associated with ischemic risk. Tubulin acetylation has been pointed out as a hallmark of stable microtubules responsible for the discoid shape of resting platelets. However, the impact of antiplatelet treatments on this post-translational modification has never been studied. This study investigated whether tubulin acetylation differs according to antiplatelet therapy and on-treatment platelet reactivity. Platelets were isolated from arterial blood samples of 240 patients admitted for coronary angiography, and levels of α-tubulin acetylation on lysine 40 (α-tubulin K40 acetylation) were assessed by western blot. We show that platelet α-tubulin K40 acetylation was significantly increased in DAPT-treated patients. In addition, the proportion of patients with high levels of α-tubulin K40 acetylation was drastically reduced among DAPT-treated patients with HPR. Multivariate logistic regression confirmed that DAPT resulting in adequate platelet inhibition was strongly associated with elevated α-tubulin K40 acetylation. In conclusion, our study highlights the role of elevated platelet α-tubulin K40 acetylation as a marker of platelet inhibition in response to DAPT.Clinical trial registration: https://clinicaltrials.gov - NCT03034148.

What is the context? High on-treatment platelet reactivity due to dual antiplatelet therapy poor response is associated with thrombotic risk.Acetylation of α-tubulin K40 plays a crucial role in regulating platelet shape.High α-tubulin K40 acetylation is a hallmark of stable microtubules.What is new? α-tubulin K40 acetylation is increased in platelets from dual antiplatelet therapy-treated patients.High platelet α-tubulin K40 acetylation is mainly observed in clopidogrel-responsive patients.What is the impact? Elevated acetylated K40 α-tubulin could be used as a readout of adequate platelet inhibition in response to dual antiplatelet therapy.High α-tubulin K40 acetylation could contribute to maintaining the resting morphology of circulating platelets and therefore modify their capacity to be involved in thrombotic events.

Dexamethasone Modulates the Cytokine Response but Not COVID-19-Induced Coagulopathy in Critically Ill.

Severe forms of coronavirus 2019 (COVID-19) disease are caused by an exaggerated systemic inflammatory response and subsequent inflammation-related coagulopathy. Anti-inflammatory treatment with low dose dexamethasone has been shown to reduce mortality in COVID-19 patients requiring oxygen therapy. However, the mechanisms of action of corticosteroids have not been extensively studied in critically ill patients in the context of COVID-19. Plasma biomarkers of inflammatory and immune responses, endothelial and platelet activation, neutrophil extracellular trap formation, and coagulopathy were compared between patients treated or not by systemic dexamethasone for severe forms of COVID-19. Dexamethasone treatment significantly reduced the inflammatory and lymphoid immune response in critical COVID-19 patients but had little effect on the myeloid immune response and no effect on endothelial activation, platelet activation, neutrophil extracellular trap formation, and coagulopathy. The benefits of low dose dexamethasone on outcome in critical COVID-19 can be partially explained by a modulation of the inflammatory response but not by reduction of coagulopathy. Future studies should explore the impact of combining dexamethasone with other immunomodulatory or anticoagulant drugs in severe COVID-19.

Preoperative frailty screening, assessment and management.

PURPOSE OF REVIEW: To highlight the importance of frailty assessment in thoracic surgery patients. RECENT FINDINGS: Frailty results from an accelerated loss of functional reserve associated with ageing and leads to increased vulnerability following surgery. It is a complex and multidimensional syndrome involving physiological and psychosocial systems. Frailty is a separate entity from comorbidities and disabilities. Frailty is associated with an increased risk of complications and a higher mortality rate after thoracic surgery. Patients can easily be screened for frailty and frail patients can benefit from further assessment of all areas of frailty secondarily. Prehabilitation and rehabilitation can help limit frailty-related complications after thoracic surgery. SUMMARY: Frailty should be part of the routine preoperative evaluation for thoracic surgery. Frailty must be considered in assessing eligibility for surgery and in planning prehabilitation and rehabilitation if necessary.

HELIOS-expressing human CD8 T cells exhibit limited effector functions.

Introduction: The transcription factor HELIOS is primarily known for its expression in CD4 regulatory T cells, both in humans and mice. In mice, HELIOS is found in exhausted CD8 T cells. However, information on human HELIOS+ CD8 T cells is limited and conflicting. Methods: In this study, we characterized by flow cytometry and transcriptomic analyses human HELIOS+ CD8 T cells. Results: These T cells primarily consist of memory cells and constitute approximately 21% of blood CD8 T cells. In comparison with memory HELIOS- T-BEThigh CD8 T cells that displayed robust effector functions, the memory HELIOS+ T-BEThigh CD8 T cells produce lower amounts of IFN-γ and TNF-α and have a lower cytotoxic potential. We wondered if these cells participate in the immune response against viral antigens, but did not find HELIOS+ cells among CD8 T cells recognizing CMV peptides presented by HLA-A2 and HLA-B7. However, we found HELIOS+ CD8 T cells that recognize a CMV peptide presented by MHC class Ib molecule HLA-E. Additionally, a portion of HELIOS+ CD8 T cells is characterized by the expression of CD161, often used as a surface marker for identifying TC17 cells. These CD8 T cells express TH17/TC17-related genes encoding RORgt, RORa, PLZF, and CCL20. Discussion: Our findings emphasize that HELIOS is expressed across various CD8 T cell populations, highlighting its significance beyond its role as a transcription factor for Treg or exhausted murine CD8 T cells. The significance of the connection between HELIOS and HLA-E restriction is yet to be understood.

NETosis and Nucleosome Biomarkers in Septic Shock and Critical COVID-19 Patients: An Observational Study.

Background: Neutrophil extracellular traps' (NETs') formation is a mechanism of defense that neutrophils deploy as an alternative to phagocytosis, to constrain the spread of microorganisms. Aim: The aim was to evaluate biomarkers of NETs' formation in a patient cohort admitted to intensive care unit (ICU) due to infection. Methods: Forty-six septic shock patients, 22 critical COVID-19 patients and 48 matched control subjects were recruited. Intact nucleosomes containing histone 3.1 (Nu.H3.1), or citrullinated histone H3R8 (Nu.Cit-H3R8), free citrullinated histone (Cit-H3), neutrophil elastase (NE) and myeloperoxidase (MPO) were measured. Results: Significant differences in Nu.H3.1 and NE levels were observed between septic shock and critical COVID-19 subjects as well as with controls (p-values < 0.05). The normalization of nucleosome levels according to the neutrophil count improved the discrimination between septic shock and critical COVID-19 patients. The ratio of Nu.Cit-H3R8 to Nu.H3.1 allowed the determination of nucleosome citrullination degree, presumably by PAD4. Conclusions: H3.1 and Cit-H3R8 nucleosomes appear to be interesting markers of global cell death and neutrophil activation when combined. Nu.H3.1 permits the evaluation of disease severity and differs between septic shock and critical COVID-19 patients, reflecting two distinct potential pathological processes in these conditions.

Improving the performance of a triage scale for chest pain patients admitted to emergency departments: combining cardiovascular risk factors and electrocardiogram.

BACKGROUND: The triage of patients presenting with chest pain on admission to the emergency department uses scales based on patient clinical presentation or an electrocardiogram (ECG). These scales have different sensitivity and specificity. Although a good sensitivity allows for the prompt identification of high-risk patients, specificity prevent ED overcrowding. Moreover, ECG at triage avoids missing ST elevation myocardial infarction, which requires urgent revascularization. Our study therefore aimed to investigate whether a scale combining ECG and cardiovascular risk factors (CVRF) improves the diagnostic performance of ED chest pain triage scale. METHODS AND RESULTS: In this prospective single-center observational study involving 505 patients, the standard ECG-based FRENCH scale was compared to a scale combining the ECG-based FRENCH scale and the patients CVRF. The new scale was called the "modified" FRENCH. The accuracy of patient CVRF collection was evaluated by comparing the results of triage nurses and ED physicians. Compared with the standard FRENCH scale, the modified FRENCH scale had an increased sensitivity (61% versus 75%) but a decrease in specificity (76% versus 64%) resulting in a similar diagnostic performance. Using CVRF collected by the ED physicians, the modified FRENCH scale had a sensitivity of 87% and a specificity of 56% with a significant improvement in his diagnostic performance compared with standard FRENCH scales. This improvement can be explained by an accurate collection of the CVRF by physicians compared with nurses, as suggested by the weak to moderate correlation between their respective data collection. CONCLUSION: In conclusion, combining ECG and accurately collected cardiovascular risks factor improves the diagnostic performance of the ECG based chest pain triage in the ED. TRIAL REGISTRATION: Trial registration number: NCT03913767 .

Development of SARS-CoV2 humoral response including neutralizing antibodies is not sufficient to protect patients against fatal infection.

More than a year after the start of the pandemic, COVID-19 remains a global health emergency. Although the immune response against SARS-CoV-2 has been extensively studied, some points remain controversial. One is the role of antibodies in viral clearance and modulation of disease severity. While passive transfer of neutralizing antibodies protects against SARS-CoV-2 infection in animal models, titers of anti-SARS-CoV-2 antibodies have been reported to be higher in patients suffering from more severe forms of the disease. A second key question for pandemic management and vaccine design is the persistence of the humoral response. Here, we characterized the antibody response in 187 COVID-19 patients, ranging from asymptomatic individuals to patients who died from COVID-19, and including patients who recovered. We developed in-house ELISAs to measure titers of IgG, IgM and IgA directed against the RBD or N regions in patient serum or plasma, and a spike-pseudotyped neutralization assay to analyse seroneutralization. Higher titers of virus-specific antibodies were detected in patients with severe COVID-19, including deceased patients, compared to asymptomatic patients. This demonstrates that fatal infection is not associated with defective humoral response. Finally, most of recovered patients still had anti-SARS-CoV-2 IgG more than 3 months after infection.

Oxidative stress-induced endothelial dysfunction and decreased vascular nitric oxide in COVID-19 patients.

BACKGROUND: SARS-CoV-2 targets endothelial cells through the angiotensin-converting enzyme 2 receptor. The resulting endothelial injury induces widespread thrombosis and microangiopathy. Nevertheless, early specific markers of endothelial dysfunction and vascular redox status in COVID-19 patients are currently missing. METHODS: Observational study including ICU and non-ICU adult COVID-19 patients admitted in hospital for acute respiratory failure, compared with control subjects matched for cardiovascular risk factors similar to ICU COVID-19 patients, and ICU septic shock patients unrelated to COVID-19. FINDINGS: Early SARS-CoV-2 infection was associated with an imbalance between an exacerbated oxidative stress (plasma peroxides levels in ICU patients vs. controls: 1456.0 ± 400.2 vs 436 ± 272.1 mmol/L; P < 0.05) and a reduced nitric oxide bioavailability proportional to disease severity (5-α-nitrosyl-hemoglobin, HbNO in ICU patients vs. controls: 116.1 ± 62.1 vs. 163.3 ± 46.7 nmol/L; P < 0.05). HbNO levels correlated with oxygenation parameters (PaO2/FiO2 ratio) in COVID-19 patients (R2 = 0.13; P < 0.05). Plasma levels of angiotensin II, aldosterone, renin or serum level of TREM-1 ruled out any hyper-activation of the renin-angiotensin-aldosterone system or leucocyte respiratory burst in ICU COVID-19 patients, contrary to septic patients. INTERPRETATION: Endothelial oxidative stress with ensuing decreased NO bioavailability appears as a likely pathogenic factor of endothelial dysfunction in ICU COVID-19 patients. A correlation between NO bioavailability and oxygenation parameters is observed in hospitalized COVID-19 patients. These results highlight an urgent need for oriented research leading to a better understanding of the specific endothelial oxidative stress that occurs during SARS-CoV-2. FUNDING: Stated in the acknowledgments section.

Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial α1AMPK.

Sepsis capillary leak syndrome (SCLS) is an independent prognostic factor for poor sepsis outcome. We previously demonstrated that α1AMP-activated protein kinase (α1AMPK) prevents sepsis-induced vascular hyperpermeability by mechanisms involving VE-cadherin (VE-Cad) stabilization and activation of p38 mitogen activated protein kinase/heat shock protein of 27 kDa (p38MAPK/HSP27) pathway. Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, has recently been proven to activate AMPK in endothelial cells. Therefore, we hypothesized that canagliflozin could be of therapeutic potential in patients suffering from SCLS. We herein report that canagliflozin, used at clinically relevant concentrations, counteracts lipopolysaccharide-induced vascular hyperpermeability and albumin leakage in wild-type, but not in endothelial-specific α1AMPK-knockout mice. In vitro, canagliflozin was demonstrated to activate α1AMPK/p38MAPK/HSP27 pathway and to preserve VE-Cad's integrity in human endothelial cells exposed to human septic plasma. In conclusion, our data demonstrate that canagliflozin protects against SCLS via an α1AMPK-dependent pathway, and lead us to consider novel therapeutic perspectives for this drug in SCLS.

COVID-19: an 'extraterrestrial' disease?

BACKGROUND: Since the beginning of the pandemic, COVID-19 has been regarded as an exceptional disease. Control measures have exclusively focused on 'the virus', while failing to account for other biological and social factors that determine severe forms of the disease. AIM: We argue that although COVID-19 was initially considered a new challenge, justifying extraordinary response measures, this situation has changed - and so should our response. MAIN ARGUMENTS: We now know that COVID-19 shares many features of common infectious respiratory diseases, and can now ascertain that SARS-CoV-2 has not suddenly presented new problems. Instead, it has exposed and exacerbated existing problems in health systems and the underlying health of the population. COVID-19 is evidently not an 'extraterrestrial' disease. It is a complex zoonotic disease, and it needs to be managed as such, following long-proven principles of medicine and public health. CONCLUSION: A complex disease cannot be solved through a simple, magic-bullet cure or vaccine. The heterogeneity of population profiles susceptible to developing a severe form of COVID-19 suggests the need to adopt varying, targeted measures that are able to address risk profiles in an appropriate way. The critical role of comorbidities in disease severity calls for short-term, virus-targeted interventions to be complemented with medium-term policies aimed at reducing the burden of comorbidities, as well as mitigating the risk of transition from infection to disease. Strategies required include upstream prevention, early treatment, and consolidation of the health system.

Inflammation-Induced Coagulopathy Substantially Differs Between COVID-19 and Septic Shock: A Prospective Observational Study.

Critical COVID-19, like septic shock, is related to a dysregulated systemic inflammatory reaction and is associated with a high incidence of thrombosis and microthrombosis. Improving the understanding of the underlying pathophysiology of critical COVID-19 could help in finding new therapeutic targets already explored in the treatment of septic shock. The current study prospectively compared 48 patients with septic shock and 22 patients with critical COVID-19 regarding their clinical characteristics and outcomes, as well as key plasmatic soluble biomarkers of inflammation, coagulation, endothelial activation, platelet activation, and NETosis. Forty-eight patients with matched age, gender, and co-morbidities were used as controls. Critical COVID-19 patients exhibited less organ failure but a prolonged ICU length-of-stay due to a prolonged respiratory failure. Inflammatory reaction of critical COVID-19 was distinguished by very high levels of interleukin (IL)-1ß and T lymphocyte activation (including IL-7 and CD40L), whereas septic shock displays higher levels of IL-6, IL-8, and a more significant elevation of myeloid response biomarkers, including Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) and IL-1ra. Subsequent inflammation-induced coagulopathy of COVID-19 also differed from sepsis-induced coagulopathy (SIC) and was characterized by a marked increase in soluble tissue factor (TF) but less platelets, antithrombin, and fibrinogen consumption, and less fibrinolysis alteration. In conclusion, COVID-19 inflammation-induced coagulopathy substantially differs from SIC. Modulating TF release and activity should be evaluated in critical COVID-19 patients.

Cardiogenic Shock in a Hemodialyzed Patient on Flecainide: Treatment with Intravenous Fat Emulsion, Extracorporeal Cardiac Life Support, and CytoSorb® Hemoadsorption.

A 67-year-old woman with a history of end-stage renal disease on hemodialysis received a therapeutic dose (150 mg daily) of flecainide for three weeks. She was admitted to the Emergency Department for malaise and dizziness, and the electrocardiogram revealed ventricular tachycardia treated by amiodarone. Hemodynamic condition remained stable, and the toxicity of flecainide was initially not suspected until she developed within 8 hours a cardiogenic shock requiring vasopressors. The patient then received sodium bicarbonate (300 mmol) and dobutamine but experienced cardiac arrest two hours later. The administration of intravenous fat emulsion (IFE) was associated with return of spontaneous circulation, but there was a relapse of cardiovascular shock at the end of IFE infusion. The patient was placed on extracorporeal cardiac life support (ECLS), continuous hemofiltration, and hemoadsorption using the CytoSorb® cartridge. Serial determinations of serum flecainide concentration were obtained during the course of hemoadsorption, with a terminal half-life of 3.7 h during the first four hours and a global plasma clearance of 40.3 ml/min over the first 22 hours. The weaning of ECLS was possible on day 7. Intravenous fat emulsion infusion was followed by a significant increase in serum flecainide concentration. In addition, while conventional techniques of extrarenal epuration usually appear as poorly effective for flecainide removal, a mean plasma clearance of 40.3 ml/min was observed using the hemoadsorption technique based on CytoSorb® cartridge. However, the impact on the clinical course was probably extremely modest in comparison with ECLS.

Pneumomediastinum revisited: we should reconsider usual classification.

Pneumomediastinum work-up should focus on differentiating mediastinal organ injuries from alveolar rupture since these two causative mechanisms have a different management and prognosis. After an admission at our Emergency Department, we wanted to challenge the current classification into 'spontaneous' or 'secondary' pneumomediastinum, which reflects the clinical rather than the pathophysiological circumstances and is therefore confusing and inappropriate to our view. We propose a new work-up algorithm based on clinical risks factors and chest CT findings.

Comparison of clinical-based and ECG-based triage of acute chest pain in the Emergency Department.

In the Emergency Department, chest pain triage systems are based on either clinical features or ECG recording. In this prospective, single-center, observational study, we aimed to compare the diagnostic performance of these triage systems in distinguishing acute coronary syndromes (ACS) from diseases of mild severity. Patients were sorted into the triage systems based on collected data at admission and on a systematic 12-lead ECG performed at triage. The final diagnosis was determined after a 30-day follow-up. For ACS, we determined a high-acuity triage score (Level 1 or 2) as being adequate, and for mild severity diseases a low-acuity triage score (Level 3, 4 or 5) as being adequate. The diagnostic performance of all studied systems was moderate (AUC from 0.644 to 0.694), with no statistically significant difference found between them. However, characteristics of the systems differed because the clinical-based systems had a higher sensitivity (87-91%) but lower specificity (32-39%) compared with the ECG-based system (sensitivity 62% and specificity 64%). A higher sensitivity limits the risk of a patient with acute coronary syndrome staying unsafely in the waiting room, while a higher specificity prevents overcrowding. ECG at triage also ensures that no STEMIs or high-risk NSTEMIs are missed. Based on these findings, each Emergency Depatment could more accurately select the triage system that fits their local particularities.