Angiotensin II induces reactive oxygen species, DNA damage, and T-cell apoptosis in severe COVID-19.

BACKGROUND: Lymphopenia is predictive of survival in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: The aim of this study was to understand the cause of the lymphocyte count drop in severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: Monocytic production of reactive oxygen species (ROSs) and T-cell apoptosis were measured by flow cytometry, DNA damage in PBMCs was measured by immunofluorescence, and angiotensin II (AngII) was measured by ELISA in patients infected with SARS-CoV-2 at admission to an intensive care unit (ICU) (n = 29) or not admitted to an ICU (n = 29) and in age- and sex-matched healthy controls. RESULTS: We showed that the monocytes of certain patients with COVID-19 spontaneously released ROSs able to induce DNA damage and apoptosis in neighboring cells. Of note, high ROS production was predictive of death in ICU patients. Accordingly, in most patients, we observed the presence of DNA damage in up to 50% of their PBMCs and T-cell apoptosis. Moreover, the intensity of this DNA damage was linked to lymphopenia. SARS-CoV-2 is known to induce the internalization of its receptor, angiotensin-converting enzyme 2, which is a protease capable of catabolizing AngII. Accordingly, in certain patients with COVID-19 we observed high plasma levels of AngII. When looking for the stimulus responsible for their monocytic ROS production, we revealed that AngII triggers ROS production by monocytes via angiotensin receptor I. ROSs released by AngII-activated monocytes induced DNA damage and apoptosis in neighboring lymphocytes. CONCLUSION: We conclude that T-cell apoptosis provoked via DNA damage due to the release of monocytic ROSs could play a major role in COVID-19 pathogenesis.

Effect of Tocilizumab on Mortality in Patients with SARS-CoV-2 Pneumonia Caused by Delta or Omicron Variants: A Propensity-Matched Analysis in Nimes University Hospital, France.

We aimed to assess the factors associated with mortality in patients treated with tocilizumab for a SARS-CoV-2 pneumonia due to the delta or omicron variants of concern (VOC) and detect an effect of tocilizumab on mortality. We conducted a prospective cohort study in a tertiary hospital from 1 August 2021 to 31 March 2022 including patients with severe COVID-19, treated with tocilizumab. Factors associated with mortality were assessed in a Cox model; then, the 60-day mortality rates of COVID-19 patients treated with standard of care (SoC) +/- tocilizumab were compared after 1:1 propensity score matching. The mortality rate was 22% (N = 26/118) and was similar between delta and omicron cases (p = 0.6). The factors independently associated with mortality were age (HR 1.06; 95% CI (1.02-1.11), p = 0.002), Charlson index (HR 1.33; 95% CI (1.11-1.6), p = 0.002), WHO-CPS (HR 2.56; 95% CI (1.07-6.22) p = 0.03), and tocilizumab infusion within the first 48 h following hospital admission (HR 0.37, 95% CI (0.14-0.97), p = 0.04). No significant differences in mortality between the tocilizumab plus SoC and SoC alone groups (p = 0.5) were highlighted. However, the patients treated with tocilizumab within the 48 h following hospital admission had better survival (p = 0.04). In conclusion, our results suggested a protective effect on mortality of the early administration of tocilizumab in patients with severe COVID-19 regardless of the VOC involved.

Prognostic value of an automated thrombin generation assay in COVID-19 patients entering hospital: A multicentric, prospective observational study.

INTRODUCTION: The prognostic significance of the thrombin generation assay (TGA) with a thrombomodulin (TM) challenge in patients entering hospital with severe COVID-19 is uncertain. METHODS: We prospectively evaluated an automated TGA (aTGA) using the ST-ThromboScreen® assay and ST-Genesia® analyser in 179 patients with severe COVID-19 during their admission to 2 university hospitals. The primary outcome was early survival at Day 28 (D28). Secondary outcomes were late survival at Day 90 (D90), later transfer to an intensive care unit (ICU), and occurrence of any thrombotic complications during hospitalisation. RESULTS: Among the 174 patients, 50 were initially admitted to ICUs. Forty-two were transferred to ICUs before D28. Fourteen patients, all in ICUs, died before D28, and 20 before D90, all but 1 in ICUs. None of the aTGA-derived results were associated with vital status either at D28 or D90. Nine patients had a thrombotic event with no association with the aTGA results. Later transfer to the ICU was associated with higher velocity index, thrombin peak height and endogenous thrombin potential (ETP) values of the aTGA performed with TM, and mainly with a lower TM-induced decrease in ETP (odds ratio 15.5 (2.15-132), p = 0.009). CONCLUSIONS: aTGA, a global assay supposed to evidence coagulopathy, could predict neither early or late survival, nor thrombotic events, in hospitalised COVID-19 patients. Its clinical justification in that setting is thus unlikely. A relative resistance of the ETP to TM was associated with later transfer to the ICU and deserves further investigation.

Low perforin expression in CD8+ T lymphocytes during the acute phase of severe SARS-CoV-2 infection predicts long COVID.

T cell cytotoxicity plays a major role in antiviral immunity. Anti-SARS-CoV-2 immunity may determine acute disease severity, but also the potential persistence of symptoms (long COVID). We therefore measured the expression of perforin, a cytotoxic mediator, in T cells of patients recently hospitalized for SARS-CoV-2 infection. We recruited 54 volunteers confirmed as being SARS-CoV-2-infected by RT-PCR and admitted to Intensive Care Units (ICUs) or non-ICU, and 29 age- and sex-matched healthy controls (HCs). Amounts of intracellular perforin and granzyme-B, as well as cell surface expression of the degranulation marker CD107A were determined by flow cytometry. The levels of 15 cytokines in plasma were measured by Luminex. The frequency of perforin-positive T4 cells and T8 cells was higher in patients than in HCs (9.9 ± 10.1% versus 4.6 ± 6.4%, p = 0.006 and 46.7 ± 20.6% vs 33.3 ± 18.8%, p = 0.004, respectively). Perforin expression was neither correlated with clinical and biological markers of disease severity nor predictive of death. By contrast, the percentage of perforin-positive T8 cells in the acute phase of the disease predicted the onset of long COVID one year later. A low T8 cytotoxicity in the first days of SARS-CoV-2 infection might favor virus replication and persistence, autoimmunity, and/or reactivation of other viruses such as Epstein-Barr virus or cytomegalovirus, paving the way for long COVID. Under this hypothesis, boosting T cell cytotoxicity during the acute phase of the infection could prevent delayed sequelae.

Low quantity and quality of anti-spike humoral response is linked to CD4 T-cell apoptosis in COVID-19 patients.

In addition to an inflammatory reaction, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-infected patients present lymphopenia, which we recently reported as being related to abnormal programmed cell death. As an efficient humoral response requires CD4 T-cell help, we hypothesized that the propensity of CD4 T cells to die may impact the quantity and quality of the humoral response in acutely infected individuals. In addition to specific immunoglobulins (Ig)A, IgM, and IgG against SARS-CoV-2 nucleocapsid (N), membrane (M), and spike (S1) proteins, we assessed the quality of IgG response by measuring the avidity index. Because the S protein represents the main target for neutralization and antibody-dependent cellular cytotoxicity responses, we also analyzed anti-S-specific IgG using S-transfected cells (S-Flow). Our results demonstrated that most COVID-19 patients have a predominant IgA anti-N humoral response during the early phase of infection. This specific humoral response preceded the anti-S1 in time and magnitude. The avidity index of anti-S1 IgG was low in acutely infected individuals compared to convalescent patients. We showed that the percentage of apoptotic CD4 T cells is inversely correlated with the levels of specific IgG antibodies. These lower levels were also correlated positively with plasma levels of CXCL10, a marker of disease severity, and soluble Fas ligand that contributes to T-cell death. Finally, we found lower S-Flow responses in patients with higher CD4 T-cell apoptosis. Altogether, these results demonstrate that individuals with high levels of CD4 T-cell apoptosis and CXCL10 have a poor ability to build an efficient anti-S response. Consequently, preventing CD4 T-cell death might be a strategy for improving humoral response during the acute phase, thereby reducing COVID-19 pathogenicity.

Physical activity and sedentary behaviour patterns among French adults during the COVID-19 health crisis

Background The COVID-19 health crisis and the various restrictions (lockdowns) implemented may have impacted individuals' behaviours (e.g. physical activity [PA] and sedentary behaviour [SB]) and psychological health (e.g., self-esteem or adjustment strategies to cope with stressful events). The objective of this study was to identify PA and SB patterns and to investigate their associations with socioeconomic and psychological characteristics among French adults during the COVID-19 health crisis. Methods Cross-sectional data of French adults were collected during the COVID19 health crisis (between March 2020 and February 2021). PA and SB were measured using the International Physical Activity Questionnaire. The Rosenberg Self-Esteem Scale and the Brief Cope questionnaire were used to measure self-esteem and coping strategies, respectively. PA and SB cross-sectional patterns were identified using latent class analysis. Multivariable logistic regression models were used to investigate associations between identified patterns and adults' socioeconomic factors, self-esteem, and coping strategies. Results Among the 241 included adults (mean age ± standard deviation: 29.6 ± 13.1 years), three cross-sectional PA and SB patterns were identified: sedentary walker (n = 141;58.5%);varied PA practitioner (n = 68;28.2%);walker with intense PA (n = 32;13.3%);Compared to the sedentary walker pattern, the walker with intense PA one was overrepresented by socially less advantaged adults, using more planning and less religion as coping strategies to stressful events, and those in the varied PA practitioner pattern used more denial as coping strategy. Conclusions More than half of adults were in the least healthy pattern (sedentary walker). These results suggest using PA and SB as levers to cope with stressful life events.

Behavioral and Emotional Changes One Year after the First Lockdown Induced by COVID-19 in a French Adult Population.

(1) Background: The lockdown had various consequences on physical activity and food consumption behaviors. The post-lockdown has been much less studied. The aim of this study is to compare behaviors one year after the first lockdown in a group of normal-weight (NW) or overweight French adults (OW). (2) Methods: Over a period of 4 days, both at the beginning of May 2020 (lockdown) and in June 2021 (free living post-lockdown), the same French adults used the WellBeNet smartphone application to record their sedentary behavior, physical activity (PA), food consumption and emotions. (3) Results: One year post first lockdown, the weight and body mass index increased (+1.1 kg; +0.4 kg.m-2, p < 0.01), and sedentary behaviors increased (+5.5%, p < 0.01) to the detriment of light-intensity activities (-3.3%, p = 0.10) in the whole group. Some food categories, such as alcohol, tended to be consumed more (+0.15 portion/day, p = 0.09), while fatty, salty and sugary products decreased (-0.25 portion/d, p = 0.02) but without a change in the food balance score. A higher number of both positive and negative emotions were scored per day (+9.5, p < 0.0001; +2.9, p = 0.03), and the positive ones were perceived stronger (+0.23, p = 0.09). Simultaneously, the desire to eat was lower (-11.6/100, p < 0.0001), and the desire to move remained constant. Sedentary/active behaviors and the desire to eat changed differently in NW and OW adults after the lockdown. (4) Conclusions: In general, the post-lockdown period was less favorable for physical activity practice and resulted in a similar food balance score but was more conducive to mental wellbeing.

T cell apoptosis characterizes severe Covid-19 disease.

Severe SARS-CoV-2 infections are characterized by lymphopenia, but the mechanisms involved are still elusive. Based on our knowledge of HIV pathophysiology, we hypothesized that SARS-CoV-2 infection-mediated lymphopenia could also be related to T cell apoptosis. By comparing intensive care unit (ICU) and non-ICU COVID-19 patients with age-matched healthy donors, we found a strong positive correlation between plasma levels of soluble FasL (sFasL) and T cell surface expression of Fas/CD95 with the propensity of T cells to die and CD4 T cell counts. Plasma levels of sFasL and T cell death are correlated with CXCL10 which is part of the signature of 4 biomarkers of disease severity (ROC, 0.98). We also found that members of the Bcl-2 family had modulated in the T cells of COVID-19 patients. More importantly, we demonstrated that the pan-caspase inhibitor, Q-VD, prevents T cell death by apoptosis and enhances Th1 transcripts. Altogether, our results are compatible with a model in which T-cell apoptosis accounts for T lymphopenia in individuals with severe COVID-19. Therefore, a strategy aimed at blocking caspase activation could be beneficial for preventing immunodeficiency in COVID-19 patients.

French multicentre observational study on SARS-CoV-2 infections intensive care initial management: the FRENCH CORONA study.

AIM: Describing acute respiratory distress syndrome patterns, therapeutics management, and outcomes of ICU COVID-19 patients and indentifying risk factors of 28-day mortality. METHODS: Prospective multicentre, cohort study conducted in 29 French ICUs. Baseline characteristics, comorbidities, adjunctive therapies, ventilatory support at ICU admission and survival data were collected. RESULTS: From March to July 2020, 966 patients were enrolled with a median age of 66 (interquartile range 58-73) years and a median SAPS II of 37 (29-48). During the first 24 h of ICU admission, COVID-19 patients received one of the following respiratory supports: mechanical ventilation for 559 (58%), standard oxygen therapy for 228 (24%) and high-flow nasal cannula (HFNC) for 179 (19%) patients. Overall, 721 (75%) patients were mechanically ventilated during their ICU stay. Prone positioning and neuromuscular blocking agents were used in 494 (51%) and 460 (48%) patients, respectively. Bacterial co-infections and ventilator-associated pneumonia were diagnosed in 79 (3%) and 411 (43%) patients, respectively. The overall 28-day mortality was 18%. Age, pre-existing comorbidities, severity of respiratory failure and the absence of antiviral therapy on admission were identified as independent predictors of 28-day outcome. CONCLUSION: Severity of hypoxaemia on admission, older age (> 70 years), cardiovascular and renal comorbidities were associated with worse outcome in COVID-19 patients. Antiviral treatment on admission was identified as a protective factor for 28-day mortality. Ascertaining the outcomes of critically ill COVID-19 patients is crucial to optimise hospital and ICU resources and provide the appropriate intensity level of care.

Effect of the use of an endotracheal tube and stylet versus an endotracheal tube alone on first-attempt intubation success: a multicentre, randomised clinical trial in 999 patients.

PURPOSE: The effect of the routine use of a stylet during tracheal intubation on first-attempt intubation success is unclear. We hypothesised that the first-attempt intubation success rate would be higher with tracheal tube + stylet than with tracheal tube alone. METHODS: In this multicentre randomised controlled trial, conducted in 32 intensive care units, we randomly assigned patients to tracheal tube + stylet or tracheal tube alone (i.e. without stylet). The primary outcome was the proportion of patients with first-attempt intubation success. The secondary outcome was the proportion of patients with complications related to tracheal intubation. Serious adverse events, i.e., traumatic injuries related to tracheal intubation, were evaluated. RESULTS: A total of 999 patients were included in the modified intention-to-treat analysis: 501 (50%) to tracheal tube + stylet and 498 (50%) to tracheal tube alone. First-attempt intubation success occurred in 392 patients (78.2%) in the tracheal tube + stylet group and in 356 (71.5%) in the tracheal tube alone group (absolute risk difference, 6.7; 95%CI 1.4-12.1; relative risk, 1.10; 95%CI 1.02-1.18; P = 0.01). A total of 194 patients (38.7%) in the tracheal tube + stylet group had complications related to tracheal intubation, as compared with 200 patients (40.2%) in the tracheal tube alone group (absolute risk difference, - 1.5; 95%CI - 7.5 to 4.6; relative risk, 0.96; 95%CI 0.83-1.12; P = 0.64). The incidence of serious adverse events was 4.0% and 3.6%, respectively (absolute risk difference, 0.4; 95%CI, - 2.0 to 2.8; relative risk, 1.10; 95%CI 0.59-2.06. P = 0.76). CONCLUSIONS: Among critically ill adults undergoing tracheal intubation, using a stylet improves first-attempt intubation success.

Can Thoracic Ultrasound on Admission Predict the Outcome of Critically Ill Patients with SARS-CoV-2? A French Multi-Centric Ancillary Retrospective Study.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks have led to massive admissions to intensive care units (ICUs). An ultrasound examination of the thorax is widely performed on admission in these patients. The primary objective of our study was to assess the performance of the lung ultrasound score (LUS) on ICU admission to predict the 28-day mortality rate in patients with SARS-CoV-2. The secondary objective was to asses the performance of thoracic ultrasound and biological markers of cardiac injury to predict mortality. METHODS: This multicentre, retrospective, observational study was conducted in six ICUs of four university hospitals in France from 15 March to 3 May 2020. Patients admitted to ICUs because of SARS-CoV-2-related acute respiratory failure and those who received an LUS examination at admission were included. The area under the receiver-operating characteristics (ROC) curve was determined for the LUS score to predict the 28-day mortality rate. The same analysis was performed for the Simplified Acute Physiology Score, left ventricular ejection fraction, cardiac output, brain natriuretic peptide and ultra-sensitive troponin levels at admission. RESULTS: In 57 patients, the 28-day mortality rate was 21%. The area under the ROC curve of the LUS score value on ICU admission was 0.68 [95% CI 0.54-0.82; p = 0.05]. In non-intubated patients on ICU admission (n = 40), the area under the ROC curves was 0.84 [95% CI 0.70-0.97; p = 0.005]. The best cut-off of 22 corresponded to 85% specificity and 83% sensitivity. CONCLUSIONS: LUS scores on ICU admission for SARS-CoV-2 did not efficiently predict the 28-day mortality rate. Performance was better for non-intubated patients at admission. Performance of biological cardiac markers may be equivalent to the LUS score.

A national healthcare response to intensive care bed requirements during the COVID-19 outbreak in France.

BACKGROUND: Whereas 5415 Intensive Care Unit (ICU) beds were initially available, 7148 COVID-19 patients were hospitalised in the ICU at the peak of the outbreak. The present study reports how the French Health Care system created temporary ICU beds to avoid being overwhelmed. METHODS: All French ICUs were contacted for answering a questionnaire focusing on the available beds and health care providers before and during the outbreak. RESULTS: Among 336 institutions with ICUs before the outbreak, 315 (94%) participated, covering 5054/5531 (91%) ICU beds. During the outbreak, 4806 new ICU beds (+95% increase) were created from Acute Care Unit (ACU, 2283), Post Anaesthetic Care Unit and Operating Theatre (PACU & OT, 1522), other units (374) or real build-up of new ICU beds (627), respectively. At the peak of the outbreak, 9860, 1982 and 3089 ICU, ACU and PACU beds were made available. Before the outbreak, 3548 physicians (2224 critical care anaesthesiologists, 898 intensivists and 275 from other specialties, 151 paediatrics), 1785 residents, 11,023 nurses and 6763 nursing auxiliaries worked in established ICUs. During the outbreak, 2524 physicians, 715 residents, 7722 nurses and 3043 nursing auxiliaries supplemented the usual staff in all ICUs. A total number of 3212 new ventilators were added to the 5997 initially available in ICU. CONCLUSION: During the COVID-19 outbreak, the French Health Care system created 4806 ICU beds (+95% increase from baseline), essentially by transforming beds from ACUs and PACUs. Collaboration between intensivists, critical care anaesthesiologists, emergency physicians as well as the mobilisation of nursing staff were primordial in this context.

Guidelines: Anaesthesia in the context of COVID-19 pandemic.

OBJECTIVES: The world is currently facing an unprecedented healthcare crisis caused by the COVID-19 pandemic. The objective of these guidelines is to produce a framework to facilitate the partial and gradual resumption of intervention activity in the context of the COVID-19 pandemic. METHODS: The group has endeavoured to produce a minimum number of recommendations to highlight the strengths to be retained in the 7 predefined areas: (1) protection of staff and patients; (2) benefit/risk and patient information; (3) preoperative assessment and decision on intervention; (4) modalities of the preanaesthesia consultation; (5) specificity of anaesthesia and analgesia; (6) dedicated circuits and (7) containment exit type of interventions. RESULTS: The SFAR Guideline panel provides 51 statements on anaesthesia management in the context of COVID-19 pandemic. After one round of discussion and various amendments, a strong agreement was reached for 100% of the recommendations and algorithms. CONCLUSION: We present suggestions for how the risk of transmission by and to anaesthetists can be minimised and how personal protective equipment policies relate to COVID-19 pandemic context.