Bronchial epithelia from adults and children: SARS-CoV-2 spread via syncytia formation and type III interferon infectivity restriction.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections initiate in the bronchi of the upper respiratory tract and are able to disseminate to the lower respiratory tract, where infections can cause an acute respiratory distress syndrome with a high degree of mortality in elderly patients. We used reconstituted primary bronchial epithelia from adult and child donors to follow the SARS-CoV-2 infection dynamics. We show that, in epithelia from adult donors, infections initiate in multiciliated cells and spread within 24 to 48 h throughout the whole epithelia. Syncytia formed of ciliated and basal cells appeared at the apical side of the epithelia within 3 to 4 d and were released into the apical lumen, where they contributed to the transmittable virus dose. A small number of reconstituted epithelia were intrinsically more resistant to virus infection, limiting virus spread to different degrees. This phenotype was more frequent in epithelia derived from children versus adults and correlated with an accelerated release of type III interferon. Treatment of permissive adult epithelia with exogenous type III interferon restricted infection, while type III interferon gene knockout promoted infection. Furthermore, a transcript analysis revealed that the inflammatory response was specifically attenuated in children. Taken together, our findings suggest that apical syncytia formation is an underappreciated source of virus propagation for tissue or environmental dissemination, whereas a robust type III interferon response such as commonly seen in young donors restricted SARS-CoV-2 infection. Thus, the combination of interferon restriction and attenuated inflammatory response in children might explain the epidemiological observation of age-related susceptibility to COVID-19.

Post-vaccination SARS-cov-2 infection in nursing home residents, Bordeaux, France.

OBJECTIVE: To describe COVID-19 breakthrough infections in two nursing homes (NHs) sites of active COVID-19 clusters despite optimal vaccination coverage. METHODS: A cross-sectional study was conducted in two NHs of south-western France, following the investigation of COVID-19 clusters (February-March 2021). SARS-CoV-2-confirmed infection was defined by positive RT-PCR. Antibodies neutralization capacities were tested in a subgroup of fully-vaccinated and seropositive-residents. RESULTS: Of the 152 residents, 66% were female with median age 87 years (IQR: 80.0-90.2). Overall, 132 (87%) residents received 2 doses of vaccine, 14 (9%) one dose and 6 (4%) were unvaccinated. Forty-seven (31%) residents had confirmed infection (45 (98%) with variant 20I/501Y.V1). All 6 non-vaccinated residents, 4 /14 who had one dose and 37/132 that had two doses, were infected. Of the 39 residents reporting symptoms, 12 and 3 presented severe and critical disease, respectively. One resident with a confirmed infection died. Infected-residents had a median anti-S IgG titre of 19 116.0 (IQR: 3 028.0-39 681.8 AU/mL), 19 times higher than that of non-infected vaccinated persons (1,207.0; IQR: 494.0-2,782.0). In the subgroup of 19 residents tested for neutralizing antibodies, the neutralizing titre (50%) was strongly positively correlated with the anti-S IgG titre (correlation coefficient = 0.83), and 1.5 times higher for the infected than non-infected residents [5.9 (IQR: 5.3-6.9) vs. 3.6 (2.9-3.8)]. CONCLUSION: Institutionalized elderly persons who undergo breakthrough infection develop higher titres of anti-S IgGs, which are strongly correlated with the neutralizing capacity of the antibodies. These results advocate for additional vaccine doses in this population.

Inhaled ciclesonide for outpatient treatment of COVID-19 in adults at risk of adverse outcomes: a randomised controlled trial (COVERAGE).

OBJECTIVES: To assess the efficacy of inhaled ciclesonide in reducing the risk of adverse outcomes in COVID-19 outpatients at risk of developing severe illness. METHODS: COVERAGE is an open-label, randomized controlled trial. Outpatients with documented COVID-19, risk factors for aggravation, symptoms for ≤7 days, and absence of criteria for hospitalization are randomly allocated to either a control arm or one of several experimental arms, including inhaled ciclesonide. The primary efficacy endpoint is COVID-19 worsening (hospitalization, oxygen therapy at home, or death) by Day 14. Other endpoints are adverse events, maximal follow-up score on the WHO Ordinal Scale for Clinical Improvement, sustained alleviation of symptoms, cure, and RT-PCR and blood parameter evolution at Day 7. The trial's Safety Monitoring Board reviewed the first interim analysis of the ciclesonide arm and recommended halting it for futility. The results of this analysis are reported here. RESULTS: The analysis involved 217 participants (control 107, ciclesonide 110), including 111 women and 106 men. Their median age was 63 years (interquartile range 59-68), and 157 of 217 (72.4%) had at least one comorbidity. The median time since first symptom was 4 days (interquartile range 3-5). During the 28-day follow-up, 2 participants died (control 2/107 [1.9%], ciclesonide 0), 4 received oxygen therapy at home and were not hospitalized (control 2/107 [1.9%], ciclesonide 2/110 [1.8%]), and 24 were hospitalized (control 10/107 [9.3%], ciclesonide 14/110 [12.7%]). In intent-to-treat analysis of observed data, 26 participants reached the composite primary endpoint by Day 14, including 12 of 106 (11.3%, 95% CI: 6.0%-18.9%) in the control arm and 14 of 106 (13.2%; 95% CI: 7.4-21.2%) in the ciclesonide arm. Secondary outcomes were similar for both arms. DISCUSSION: Our findings are consistent with the European Medicines Agency's COVID-19 task force statement that there is currently insufficient evidence that inhaled corticosteroids are beneficial for patients with COVID-19.

Faisabilité de la transfusion de plasma de donneurs convalescents pour COVID-19 en réanimation

La transfusion de plasma de donneurs convalescents (PDC) au cours de la COVID-19 est controversée. En France, hors essai clinique, elle est encadrée par un protocole à usage thérapeutique soumis à un avis multidisciplinaire (RCP) préalable. L'expérience de ce traitement en réanimation n'est pas décrite. Tous les patients admis dans une unité de réanimation d'un CHU pour un SDRA COVID-19 et ayant une PCR plasmatique SARS-CoV-2 positive au moins 10 jours après le début des symptômes ont reçu une transfusion de PDC après validation en RCP. L'objectif principal était d'évaluer la tolérance et la virémie 7 j après la transfusion (J7). Entre mai 2020 et avril 2021, 31 patients (27 hommes et 4 femmes, âge moyen = 69 ans) ont été inclus et ont reçu un volume médian de 836 mL de PDC sur 2 jours consécutifs. Tous présentaient au moins un facteur de risque de forme grave dont 15 une affection maligne évolutive et 14 avaient une sérologie SARS-CoV-2 négative à l'admission en réanimation. Les PDC ont été transfusés en moyenne 18 j après le début des symptômes et 8 j après l'admission en réanimation. À J7, 22/31 patients avaient une PCR plasmatique négative. Le délai médian de négativation de la PCR plasmatique était de 8 j. À J 7, le score de sévérité clinique OMS était stable pour 12/31 (39 %), en amélioration pour 14/31 (45 %) et détérioré pour 5/31 (16 %) patients. La mortalité à 28 jours était de 26 % (8/31 dont 3 dans les sept jours après PDC). Aucun évènement indésirable significatif lié à la transfusion n'a été rapporté. Notre étude confirme la faisabilité de la transfusion de PDC en réanimation, notamment en cas d'immunodépression humorale. (French) [ABSTRACT FROM AUTHOR] Copyright of Transfusion Clinique et Biologique is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A Simple and Fast Method to Sequence the Full-Length Spike Gene for SARS-CoV-2 Variant Identification from Patient Samples

Since the beginning of the pandemic, a race has been underway to detect SARS-CoV-2 virus infection (PCR screening, serological diagnostic kits), treat patients (drug repurposing, standard care) and develop a vaccine. After almost a year of active circulation worldwide, SARS-CoV-2 variants have appeared in different countries. Those variants include mutations in multiple regions of the genome, particularly in the spike gene. Because this surface protein is a key player in both the spread of the virus and the efficacy of vaccine strategies, the challenge is to efficiently monitor the appearance of spike mutations in the population. The present work describes a procedure based on the widely available Sanger technology to produce a full-length sequence of the spike gene from patient-derived samples.

Accuracy of COVID-19 rapid antigenic tests compared to RT-PCR in a student population: The StudyCov study.

OBJECTIVE: There is a lack of data evaluating performance of antigenic test (AT) for SARS-CoV-2 diagnosis (Ag-RDT) in clinical practice, especially in asymptomatic subjects. The main objective of this study was to evaluate the diagnostic performance of AT compared to Reverse Transcription Polymerase Chain Reaction (RT-PCR) for SARS-CoV-2 diagnosis. METHODS: StudyCov is a monocentric cross-sectional study. A SARS-CoV-2 screening facility was set up in the Bordeaux University health campus from October 28th to November 20th 2020. Students willing to have a RT-PCR test (ARGENE SARS-CoV-2 R-GENE, BioMérieux, France) for SARS-CoV-2 diagnosis were also offered the Abbott Panbio™ SARS-CoV-2 antigenic rapid test. All participants attending the screening facility with an AT in addition to RT-PCR and having signed an informed consent were included in the study. The main objective was to assess performance of AT as compared with RT-PCR in the recruited population. Secondary objectives dealt with the analysis of the main objective stratified by current symptoms and risk exposure. A sensitivity analysis with different RT-PCR cycle thresholds was included. RESULTS: RT-PCR and AT results were available for 692 subjects. Overall sensitivity and specificity of AT tests were respectively 63.5% (95% confidence interval (CI): 49.0 - 76.4) and 100% (95% CI: 99.4 - 100). In the asymptomatic sub-group, they were respectively 35.0% (95% CI: 15.4% - 59.2%) and 100% (95% CI: 99.3 - 100). CONCLUSIONS: This study shows the poor sensitivity of AT in asymptomatic subjects, specificity being however excellent. The performance results fall below the World Health Organization recommendation of 80% sensitivity and question using AT in general population, especially when asymptomatic.

Feasibility of convalescent plasma therapy in severe COVID-19 patients with persistent SARS-CoV-2 viremia.

This study aims to assess the efficacy and safety of convalescent plasma therapy (CPT) in COVID-19 critically ill patients with protracted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNAemia. A retrospective cohort study was conducted in intensive care unit (ICU). All patients with severe COVID-19 pneumonia for whom RNAemia remained positive more than 14 days after onset of the infection were included and given CPT. The primary objective was to evaluate SARS-CoV-2 RNAemia 7 days (D7) after CPT. A total of 14 patients were included and they received a median CPT volume of 828 ml (range: 817-960). CPT was administered in a median time of 14 days after ICU admission. At D7, 13/14 patients had negative SARS-CoV-2 blood PCR and one patient had negative blood PCR 11 days after CPT. At D7 and at D14, the clinical status was improved in 7/14 and 11/14 patients, respectively. The 28-day mortality rate was 14%. No CPT-related adverse effects had been reported. CPT is safe and may be efficient in patients with protracted RNAemia admitted in ICU for severe COVID-19 pneumonia. Randomized controlled trials are needed to confirm these results.

Screening around a COVID-19 cluster: Exploring its impact on a local virus outbreak.

OBJECTIVE: In March 2020, we implemented screening of the contacts of a COVID-19 cluster having occurred in the Lot-et-Garonne department, the first department of the Nouvelle-Aquitaine region to be affected by the active circulation of SARS-CoV-2. We aimed to describe the impact of this screening on the local SARS-CoV-2 outbreak. METHODS: All high-risk contacts, as well as the individuals living in their households, were screened. We detailed the evolution of the number of confirmed COVID-19 cases in the Lot-et-Garonne department and the rest of the Nouvelle-Aquitaine region. RESULTS: Among the 89 screened individuals, 10 new cases were confirmed, including 4 asymptomatic persons. In Lot-et-Garonne, the number of confirmed COVID-19 cases immediately decreased after this screening and no epidemic peak occurred, contrary to what was observed in the rest of the region. CONCLUSION: The early screening of high-risk contacts of COVID-19 cases and members of their household implemented a few days before the first lockdown probably helped to prevent the spread of the virus in the department.