Complement cascade in severe forms of COVID-19: Recent advances in therapy

International audienceThe complement system is an essential component of the innate immune system. The three complement pathways (classical, lectin, alternative) are directly or indirectly activated by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). In the most severe forms of COVID-19, overactivation of the complement system may contribute to the cytokine storm, endothelial inflammation (endotheliitis) and thrombosis. No antiviral drug has yet been shown to be effective in COVID-19. Therefore, immunotherapies represent a promising therapeutic in the immunopathological phase (following the viral phase) of the disease. Complement blockade, mostly C5a-C5aR axis blockade, may prevent acute respiratory distress syndrome (ARDS) from worsening or progression to death. Clinical trials are underway

Implication de la cascade du complément dans les formes sévères de COVID-19

Le système du complément est un composant essentiel du système immunitaire inné. Son activation excessive au cours de la COVID-19 participe à l’orage cytokinique, à l’inflammation endothéliale (endothélite) et aux thromboses qui accompagnent la maladie. Bloquer le complément, notamment l’axe C5a-C5aR1, par des thérapies spécifiques représente un espoir thérapeutique dans les formes les plus sévères de la maladie

COVID-19—White matter and globus pallidum lesions

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Salivary Alpha Amylase Bronchial Measure for Early Aspiration Pneumonia Diagnosis in Patients Treated With Therapeutic Hypothermia After Out-of-hospital Cardiac Arrest

International audienceBackground Aspiration pneumonia is the most common respiratory complication following out-of-hospital cardiac arrests (OHCA). Alpha-amylase (α-amylase) in pulmonary secretions is a biomarker of interest in detecting inhalation. The main goal of this study is to evaluate the performance of bronchoalveolar levels of α-amylase in early diagnosis of aspiration pneumonia, in patients admitted to intensive care unit (ICU) after OHCA. Methods This is a prospective single-center trial, led during 5 years (July 2015 to September 2020). We included patients admitted to ICU after OHCA. A protected specimen bronchial brushing and a mini-bronchoalveolar lavage (mini-BAL) were collected during the first 6 h after admission. Dosage of bronchial α-amylase and standard bacterial analysis were performed. Investigators confirmed pneumonia diagnosis using clinical, radiological, and microbiological criteria. Every patient underwent targeted temperature management. Results 88 patients were included. The 34% (30 patients) developed aspiration pneumonia within 5 days following admission. The 55% (17) of pneumonias occurred during the first 48 h. The 57% of the patients received a prophylactic antibiotic treatment on their admission day. ICU mortality was 50%. Median value of bronchial α-amylase did not differ whether patients had aspiration pneumonia (15 [0–94]) or not (3 [0–61], p = 0,157). Values were significantly different concerning early-onset pneumonia (within 48 h) [19 (7–297) vs. 3 (0–82), p = 0,047]. If one or more microorganisms were detected in the initial mini-BAL, median value of α-amylase was significantly higher [25 (2–230)] than in sterile cultures (2 [0–43], p = 0,007). With an 8.5 IU/L cut-point, sensitivity and specificity of α-amylase value for predicting aspiration pneumonia during the first 2 days were respectively 74 and 62%. True positive and negative rates were respectively 44 and 86%. The area under the ROC curve was 0,654 (CI 95%; 0,524–0,785). Mechanical ventilation duration, length of ICU stay, and mortality were similar in both groups. Conclusion In our study, dosage of bronchial α-amylase was not useful in predicting aspiration pneumonia within the first 5 days after ICU admission for OHCA. Performance in predicting early-onset pneumonia was moderate

Lack of viral clearance by the combination of hydroxychloroquine and azithromycin or lopinavir and ritonavir in SARS-CoV-2-related acute respiratory distress syndrome

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Ventilator Acquired Pneumonia in COVID-19 ICU Patients: A Retrospective Cohort Study during Pandemia in France

Describe the characteristics of ventilation-acquired pneumonia (VAP) and potential risk factors in critically ill SARS-CoV-2 patients admitted in three French public hospitals during the first year of the COVID-19 pandemic. We conducted a monocentric retrospective study in seven Marseille intensive care units (ICUs) aiming to describe VAP characteristics and identify their risk factors. VAP patients were compared to a non-VAP control group. From March to November 2020, 161 patients admitted for viral-induced acute respiratory failure (ARF) requiring invasive mechanical ventilation (IMV) were included. This cohort was categorized in two groups according to the development or not of a VAP during their stay in ICU. 82 patients (51%) developed ventilation-acquired pneumonia. Most of them were men (77%) and 55% had hypertension. In the VAP population, 31 out of 82 patients (38%) had received dexamethasone and 47% were administered antibiotic course prior to ICU admission. An amount of 88% of respiratory infections were late VAPs with a median delay of 10 days from the onset of IMV. Gram negative bacteria were responsible for 62% of VAPs with Pseudomonas spp. being the most documented bacteria. Less than a third of the ICU-acquired infections were due to multidrug resistant (MDR) bacteria mainly displaying AmpC cephalosporin hyper production resistance phenotype. Multivariate analysis revealed that early Dexamethasone administration in ICU, male sex, older age and ROX score were risk factors for VAP whereas pre-ICU antimicrobial treatment and higher IGS 2 were protective factors. VAP is a frequent ICU-related complication affecting half of patients infected with SARS-CoV-2 and requiring IMV. It was responsible for increased morbidity due to a longer ICU and hospital stay. VAP risk factors included demographic factors such as age and sex. Dexamethasone was associated with a threefold greater risk of developing VAP during ICU stay. These results need to be comforted by large multi-centric studies before questioning the only available and effective treatment against SARS-CoV-2 in ICU patients

Imbalance of Circulating Innate Lymphoid Cell Subpopulations in Patients With Septic Shock

International audienceBackground: Septic shock, a major cause of death in critical care, is the clinical translation of a cytokine storm in response to infection. It can be complicated by sepsis-induced immunosuppression, exemplified by blood lymphopenia, an excess of circulating Treg lymphocytes, and decreased HLA-DR expression on circulating monocytes. Such immunosuppression is associated with secondary infections, and highermortality. The effect of these biologicalmodifications on circulating innate lymphoid cells (ILCs) has been little studied.Methods: We prospectively enrolled patients with septic shock (Sepsis-3 definition) in the intensive care unit (ICU) of Timone CHU Hospital. ICU controls (trauma, cardiac arrest, neurological dysfunction) were recruited at the same time (NCT03297203). We performed immunophenotyping of adaptive lymphocytes (CD3(+) T cells, CD19(+) B cells, CD4(+) CD25(+) FoxP3(+) Treg lymphocytes), ILCs (CD3(-)CD56(+) NK cells and helper ILCs - ILC1, ILC2, and ILC3), and monocytes by flow cytometry on fresh blood samples collected between 24 and 72 h after admission. Results: We investigated adaptive and innate circulating lymphoid cells in the peripheral blood of 18 patients in septic shock, 15 ICU controls, and 30 healthy subjects. As expected, the peripheral blood lymphocytes of all ICU patients showed lymphopenia, which was not specific to sepsis, whereas those of the healthy volunteers did not. Circulating CD3(+) T cells and CD3(-)CD56(+) NK cells were mainly concerned. There was a tendency toward fewer Treg lymphocytes and lower HLA-DR expression on monocytes in ICU patients with sepsis. Although the ILC1 count was higher in septic patients than healthy subjects, ILC2, and ILC3 counts were lower in both ICU groups. However, ILC3s within the total ILCs were overrepresented in patients with septic shock. The depression of immune responses has been correlated with the occurrence of secondary infections. We did not find any differences in ILC distribution according to this criterion.Conclusion: All ICU patients exhibit lymphopenia, regardless of the nature (septic or sterile) of the initial medical condition. Specific distribution of circulating ILCs, with an excess of ILC1, and a lack of ILC3, may characterize septic shock during the first 3 days of the disease

Identification of druggable inhibitory immune checkpoints on Natural Killer cells in COVID-19

International audienceInfection with SARS-COV-2 is the cause of COVID-19 and has generated an unprecedented health crisis worldwide. While most of the patients experience mild symptoms, around 20% develop severe disease, characterized by pneumonia and in the worst cases by acute respiratory distress syndrome (ARDS).1 The analysis and understanding of the immune responses arising in the course of SARS-COV-2 infection may help to propose therapeutic solutions. Due to the crucial role of Natural Killer (NK) cells in antiviral immune responses,2 we analyzed NK cells in blood from a cohort of 82 individuals: 10 healthy controls (HC), 10 paucisymptomatic COVID-19 patients (pauci), 34 patients with pneumonia (pneumo) and 28 patients with ARDS due to SARS-CoV-2 infection. The absolute numbers of peripheral blood NK cells, B, CD4+, and CD8+ T lymphocytes were lower in the pneumonia and ARDS groups than in healthy controls, consistent with previously published results3 (Fig. 1a). We investigated the NK cell subsets further and found that among CD45+CD3−CD56+ total NK cells the proportion of mature NK cells, a subset defined on the basis of its expression of the CD16 and CD57 cell surface receptors, was markedly lower in patients with ARDS (Fig. 1b). Given their role in viral infection, the loss of mature NK cells may contribute to the pulmonary complications occurring in the most severe cases of COVID-19. We then focused our analysis on molecular pathways likely to improve NK cell antiviral activity to promote SARS-CoV-2 clearance, and analyzed the expression of several immune checkpoints. Given the availability of therapeutic monoclonal antibodies blocking the immunosuppressive functions of PD-1,4 NKG2A,5 and CD396 initially developed for cancer therapies, we analyzed the expression of these molecules on NK cells in our cohort. PD-1 and NKG2A are cell surface receptors, and their engagement with their ligands, PD-L1 and HLA-E, respectively, inhibits the function of T and NK cells. CD39 is an ectoenzyme that cleaves extracellular ATP and ADP, which can be released from dead cells upon viral infection, leading to the generation of adenosine, which has strong immunosuppressive effects on T and NK cells

Combined Anakinra and Ruxolitinib treatment to rescue extremely ill COVID-19 patients: A pilot study.

International audienceNo abstract availabl