Autophagy and Mitophagy-Related Pathways at the Crossroads of Genetic Pathways Involved in Familial Sarcoidosis and Host-Pathogen Interactions Induced by Coronaviruses.

Sarcoidosis is a multisystem disease characterized by the development and accumulation of granulomas, the hallmark of an inflammatory process induced by environmental and/or infectious and or genetic factors. This auto-inflammatory disease mainly affects the lungs, the gateway to environmental aggressions and viral infections. We have shown previously that genetic predisposition to sarcoidosis occurring in familial cases is related to a large spectrum of pathogenic variants with, however, a clustering around mTOR (mammalian Target Of Rapamycin)-related pathways and autophagy regulation. The context of the COVID-19 pandemic led us to evaluate whether such genetic defects may increase the risk of a severe course of SARS-CoV2 infection in patients with sarcoidosis. We extended a whole exome screening to 13 families predisposed to sarcoidosis and crossed the genes sharing mutations with the list of genes involved in the SARS-CoV2 host-pathogen protein-protein interactome. A similar analysis protocol was applied to a series of 100 healthy individuals. Using ENRICH.R, a comprehensive gene set enrichment web server, we identified the functional pathways represented in the set of genes carrying deleterious mutations and confirmed the overrepresentation of autophagy- and mitophagy-related functions in familial cases of sarcoidosis. The same protocol was applied to the set of genes common to sarcoidosis and the SARS-CoV2-host interactome and found a significant enrichment of genes related to mitochondrial factors involved in autophagy, mitophagy, and RIG-I-like (Retinoic Acid Inducible Gene 1) Receptor antiviral response signaling. From these results, we discuss the hypothesis according to which sarcoidosis is a model for studying genetic abnormalities associated with host response to viral infections as a consequence of defects in autophagy and mitophagy processes.

Study of Thoracic CT in COVID-19: The STOIC Project.

Background There are conflicting data regarding the diagnostic performance of chest CT for COVID-19 pneumonia. Disease extent at CT has been reported to influence prognosis. Purpose To create a large publicly available data set and assess the diagnostic and prognostic value of CT in COVID-19 pneumonia. Materials and Methods This multicenter, observational, retrospective cohort study involved 20 French university hospitals. Eligible patients presented at the emergency departments of the hospitals involved between March 1 and April 30th, 2020, and underwent both thoracic CT and reverse transcription-polymerase chain reaction (RT-PCR) testing for suspected COVID-19 pneumonia. CT images were read blinded to initial reports, RT-PCR, demographic characteristics, clinical symptoms, and outcome. Readers classified CT scans as either positive or negative for COVID-19 based on criteria published by the French Society of Radiology. Multivariable logistic regression was used to develop a model predicting severe outcome (intubation or death) at 1-month follow-up in patients positive for both RT-PCR and CT, using clinical and radiologic features. Results Among 10 930 patients screened for eligibility, 10 735 (median age, 65 years; interquartile range, 51-77 years; 6147 men) were included and 6448 (60%) had a positive RT-PCR result. With RT-PCR as reference, the sensitivity and specificity of CT were 80.2% (95% CI: 79.3, 81.2) and 79.7% (95% CI: 78.5, 80.9), respectively, with strong agreement between junior and senior radiologists (Gwet AC1 coefficient, 0.79). Of all the variables analyzed, the extent of pneumonia at CT (odds ratio, 3.25; 95% CI: 2.71, 3.89) was the best predictor of severe outcome at 1 month. A score based solely on clinical variables predicted a severe outcome with an area under the curve of 0.64 (95% CI: 0.62, 0.66), improving to 0.69 (95% CI: 0.6, 0.71) when it also included the extent of pneumonia and coronary calcium score at CT. Conclusion Using predefined criteria, CT reading is not influenced by reader's experience and helps predict the outcome at 1 month. ClinicalTrials.gov identifier: NCT04355507 Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Rubin in this issue.

The Affinity of Hemoglobin for Oxygen Is Not Altered During COVID-19.

Background: A computational proteomic analysis suggested that SARS-CoV-2 might bind to hemoglobin (Hb). The authors hypothesized that this phenomenon could result in a decreased oxygen (O2) binding and lead to hemolytic anemia as well. The aim of this work was to investigate whether the affinity of Hb for O2 was altered during COVID-19. Methods: In this retrospective, observational, single-center study, the blood gas analyses of 100 COVID-19 patients were compared to those of 100 non-COVID-19 patients. Fifty-five patients with carboxyhemoglobin (HbCO) ≥8% and 30 with sickle cell disease (SCD) were also included ("positive controls" with abnormal Hb affinity). P50 was corrected for body temperature, pH, and PCO2. Results: Patients did not differ statistically for age or sex ratio in COVID-19 and non-COVID-19 groups. Median P50 at baseline was 26 mmHg [25.2-26.8] vs. 25.9 mmHg [24-27.3], respectively (p = 0.42). As expected, P50 was 22.5 mmHg [21.6-23.8] in the high HbCO group and 29.3 mmHg [27-31.5] in the SCD group (p < 0.0001). Whatever the disease severity, samples from COVID-19 to non-COVID-19 groups were distributed on the standard O2-Hb dissociation curve. When considering the time-course of P50 between days 1 and 18 in both groups, no significant difference was observed. Median Hb concentration at baseline was 14 g.dl-1 [12.6-15.2] in the COVID-19 group vs. 13.2 g.dl-1 [11.4-14.7] in the non-COVID-19 group (p = 0.006). Among the 24 COVID-19 patients displaying anemia, none of them exhibited obvious biological hemolysis. Conclusion: There was no biological argument to support the hypothesis that SARS-CoV-2 could alter O2 binding to Hb.

Modeling Potential Autophagy Pathways in COVID-19 and Sarcoidosis.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mainly affects the lungs. Sarcoidosis is an autoinflammatory disease characterized by the diffusion of granulomas in the lungs and other organs. Here, we discuss how the two diseases might involve some common mechanistic cellular pathways around the regulation of autophagy.

Propositions Pour La Prise En Charge Des Troubles Du Sommeil Et De La Vigilance En Periode Epidemique Covid-19

RESUME Depuis mi-mars 2020, l’épidémie de COVID-19 a conduit à la suspension de la prise en charge des patients présentant des troubles du sommeil et de la vigilance. Bien qu’ayant rarement un caractère urgent, cette prise en charge ne peut être repoussée indéfiniment. Des propositions visant à établir les modalités de reprise progressive des activités de médecine du sommeil ont été élaborées grâce à la méthodologie CORE qui permet de dégager rapidement un consensus d’experts lorsque les données probantes sont insuffisantes. La réalisation d’explorations diagnostiques du sommeil et de la vigilance, doit être limitée aux patients pour lesquels la balance bénéfice-risque est favorable de manière indiscutable et lorsque les résultats sont susceptibles d’avoir un impact décisif sur une stratégie thérapeutique, en privilégiant la téléconsultation et les enregistrements ambulatoires. Le strict respect de la distanciation physique et des autres mesures barrière, le port d’équipement de protection par le personnel en fonction des tâches, l’utilisation de matériel à usage unique si possible, et des procédures rigoureuses de nettoyage et de désinfection de l’équipement et des locaux doit permettre de limiter les risques de transmission du SARS-CoV-2 entre le patient et les soignants. Les propositions du groupe d’experts sont valables au moment de leur publication mais seront bien entendu réévaluées et complétées très régulièrement en fonction de l’évolution des connaissances scientifiques et des recommandations des autorités de santé basées sur l’évolution de l’épidémie. SUMMARY Since mid-March 2020, the COVID-19 epidemic has led to the suspension of sleep clinic and sleep center operations. Although rarely urgent, sleep disorder management cannot be postponed indefinitely. Proposals to clarify the modalities for the gradual resumption of sleep medicine services have been developed using the CORE methodology, which allows for rapid expert consensus when the evidence-based data is weak. The performance of diagnostic sleep and alertness tests must be limited to patients for whom the benefit-risk balance is indisputably favorable and when the results are likely to have a decisive impact on a therapeutic strategy, with priority being given to teleconsultation and ambulatory recordings. Strict adherence to physical separation and other barrier measures, the use of protective equipment by staff and of single-use equipment whenever possible, and strict cleaning and disinfection procedures for equipment and premises should limit the risk of SARS-CoV-2 transmission between patient and staff members. The proposals of the expert group are valid at the time of their publication but will be re-evaluated and updated regularly according to the development of scientific knowledge and the recommendations of the health authorities based on the evolution of the epidemic.