Neurologic manifestations associated with COVID-19: a multicentre registry.

OBJECTIVES: To provide an overview of the spectrum, characteristics and outcomes of neurologic manifestations associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We conducted a single-centre retrospective study during the French coronavirus disease 2019 (COVID-19) epidemic in March-April 2020. All COVID-19 patients with de novo neurologic manifestations were eligible. RESULTS: We included 222 COVID-19 patients with neurologic manifestations from 46 centres in France. Median (interquartile range, IQR) age was 65 (53-72) years and 136 patients (61.3%) were male. COVID-19 was severe or critical in 102 patients (45.2%). The most common neurologic diseases were COVID-19-associated encephalopathy (67/222, 30.2%), acute ischaemic cerebrovascular syndrome (57/222, 25.7%), encephalitis (21/222, 9.5%) and Guillain-Barré syndrome (15/222, 6.8%). Neurologic manifestations appeared after the first COVID-19 symptoms with a median (IQR) delay of 6 (3-8) days in COVID-19-associated encephalopathy, 7 (5-10) days in encephalitis, 12 (7-18) days in acute ischaemic cerebrovascular syndrome and 18 (15-28) days in Guillain-Barré syndrome. Brain imaging was performed in 192 patients (86.5%), including 157 magnetic resonance imaging (70.7%). Among patients with acute ischaemic cerebrovascular syndrome, 13 (22.8%) of 57 had multiterritory ischaemic strokes, with large vessel thrombosis in 16 (28.1%) of 57. Brain magnetic resonance imaging of encephalitis patients showed heterogeneous acute nonvascular lesions in 14 (66.7%) of 21. Cerebrospinal fluid of 97 patients (43.7%) was analysed, with pleocytosis found in 18 patients (18.6%) and a positive SARS-CoV-2 PCR result in two patients with encephalitis. The median (IQR) follow-up was 24 (17-34) days with a high short-term mortality rate (28/222, 12.6%). CONCLUSIONS: Clinical spectrum and outcomes of neurologic manifestations associated with SARS-CoV-2 infection were broad and heterogeneous, suggesting different underlying pathogenic processes.

Management of pharmacovigilance during the COVID-19 pandemic crisis by the safety department of an academic sponsor: Lessons learnt and challenges from the EU DisCoVeRy clinical trial.

The current COVID-19 pandemic was an exceptional health situation, including for drug use. As there was no known effective drug for COVID-19 at the beginning of the pandemic, different drug candidates were proposed. In this article, we present the challenges for an academic Safety Department to manage the global safety of a European trial during the pandemic. The National Institute for Health and Medical Research (Inserm) conducted a European multicenter, open-label, randomized, controlled trial involving three repurposed and one-in development drugs (lopinavir/ritonavir, IFN-ß1a, hydroxychloroquine, and remdesivir) in adults hospitalized with COVID-19. From 25 March 2020 to 29 May 2020, the Inserm Safety Department had to manage 585 Serious Adverse Events (SAEs) initial notification and 396 follow-up reports. The Inserm Safety Department's staff was mobilized to manage these SAEs and to report Expedited safety reports to the competent authorities within the legal timeframes. More than 500 queries were sent to the investigators due to a lack of or incoherent information on SAE forms. At the same time, the investigators were overwhelmed by the management of patients suffering from COVID-19 infection. These particular conditions of missing data and lack of accurate description of adverse events made evaluation of the SAEs very difficult, particularly the assessment of the causal role of each investigational medicinal product. In parallel, working difficulties were accentuated by the national lockdown, frequent IT tool dysfunctions, delayed implementation of monitoring and the absence of automatic alerts for SAE form modification. Although COVID-19 is a confounding factor per se, the delay in and quality of SAE form completion and the real-time medical analysis by the Inserm Safety Department were major issues in the quick identification of potential safety signals. To conduct a high-quality clinical trial and ensure patient safety, all stakeholders must take their roles and responsibilities.

Social representations of mask wearing in the general population during the COVID-19 pandemic.

Introduction: Although one of the most prominent interventions against COVID-19, face masks seem poorly adopted by the general population. A growing body of literature has found that using face masks has social meaning. This qualitative study assessed the perceptions, representations and practices of mask wearing in the general population. Methods: A qualitative survey by short semi-structured walking interviews was carried out from April to December 2021 in 11 cities in France's Pays de la Loire region. Study locations were selected for their varied geographical, social, and economic characteristics, with urbanized and rural areas. Four domains linked to perceptions of masks and wearing them were explored: (i) evolution in mask wearing, (ii) decision-making methods for wearing and not wearing; (iii) incorporating the mask into way of life; (iv) projecting into the future. Results: A total of 116 people were interviewed. Masks marked a shift from the ordinary world to the pandemic. Overall, interviewees considered masks an obstacle to breathing, communication, and social interactions, leading to establishing strategies circumventing the mask mandate. Poor attention was paid to their medical usefulness as an obligatory clothing accessory. Mask-wearing decisions were driven by social relations, common sense, and vulnerability. The greater the feeling of security (i.e., being with close relatives), the less it was worn or worn properly, with decreased attention to others and their health. Most participants did not remember learning to wear a mask. Some were convinced that mask-wearing could not be learned (experiential knowledge). Institutions (school and work) played a central role by facilitating incorporation of masks into daily life. Conclusions: This study emphasizes the need to reinforce the individual medical values of face masks to prevent COVID-19. Ambitious education and training programmes should be planned to learn how and when to wear masks. Institutions (work and school) may be critical for this purpose.

Adaptation and Response of a Major Parisian Referral Hospital to the COVID-19 Surge: A Qualitative Study.

Since the beginning of the COVID-19 pandemic, few studies have focused on crisis management of multiple services within one hospital over several waves of the pandemic. The purpose of this study was to provide an overview of the COVID-19 crisis response of a Parisian referral hospital which managed the first three COVID cases in France and to analyze its resilience capacities. Between March 2020 and June 2021, we conducted observations, semi-structured interviews, focus groups, and lessons learned workshops. Data analysis was supported by an original framework on health system resilience. Three configurations emerged from the empirical data: 1) reorganization of services and spaces; 2) management of professionals' and patients' contamination risk; and 3) mobilization of human resources and work adaptation. The hospital and its staff mitigated the effects of the pandemic by implementing multiple and varied strategies, which the staff perceived as having positive and/or negative consequences. We observed an unprecedented mobilization of the hospital and its staff to absorb the crisis. Often the mobilization fell on the shoulders of the professionals, adding to their exhaustion. Our study demonstrates the capacity of the hospital and its staff to absorb the COVID-19 shock by putting in place mechanisms for continuous adaptation. More time and insight will be needed to observe whether these strategies and adaptations will be sustainable over the coming months and years and to assess the overall transformative capacities of the hospital.

Time to negative PCR conversion amongst high-risk patients with mild-to-moderate Omicron BA.1 and BA.2 COVID-19 treated with sotrovimab or nirmatrelvir.

OBJECTIVES: Our aim was to compare the clinical and virological outcomes in Omicron BA.1- and BA.2-infected patients who received sotrovimab with those in patients who received nirmatrelvir for the prevention of severe COVID-19. METHODS: In this multi-centric, prospective ANRS 0003S CoCoPrev cohort study, patients at a high risk of progression of mild-to-moderate BA.1 or BA.2 COVID-19 who received sotrovimab or nirmatrelvir were included. The proportion of patients with progression to severe COVID-19, time between the start of treatment to negative PCR conversion, SARS-CoV-2 viral decay, and characterization of resistance variants were determined. A multi-variable Cox proportional hazard model was used to determine the time to negative PCR conversion and a mixed-effect model for the dynamics of viral decay. RESULTS: Amongst 255 included patients, 199 (80%) received ≥3 vaccine doses, 195 (76%) received sotrovimab, and 60 (24%) received nirmatrelvir. On day 28, new COVID-19-related hospitalization occurred in 4 of 193 (2%; 95% CI, 1-5%) sotrovimab-treated patients and 0 of 55 nirmatrelvir-treated patients (p 0.24). One out of the 55 nirmatrelvir-treated patients died (2%; 95% CI, 0-10%). The median time to negative PCR conversion was 11.5 days (95% CI, 10.5-13) in the sotrovimab-treated patients vs. 4 days (95% CI, 4-9) in the nirmatrelvir-treated patients (p < 0.001). Viral decay was faster in the patients who received nirmatrelvir (p < 0.001). In the multi-variable analysis, nirmatrelvir and nasopharyngeal PCR cycle threshold values were independently associated with faster conversion to negative PCR (hazard ratio, 2.35; 95% CI, 1.56-3.56; p < 0.0001 and hazard ratio, 1.05; 95% CI, 1.01-1.08; p 0.01, respectively). CONCLUSIONS: Early administration of nirmatrelvir in high-risk patients compared with that of sotrovimab was associated with faster viral clearance. This may participate to decrease transmission and prevent viral resistance.

Contributions and challenges of community pharmacists during the COVID-19 pandemic: a qualitative study.

BACKGROUND: Healthcare services across the world have been deeply impacted by the COVID-19 pandemic. In primary care, community pharmacists have had an important role in the frontline healthcare response to the pandemic. OBJECTIVES: This study aimed to explore the experiences, contributions and perceived challenges of community pharmacists regarding the provision of healthcare services during the COVID-19 pandemic. METHODS: Semi-structured qualitative interviews were conducted with community pharmacists in France. Participants were recruited through a professional organization of pharmacists combined with a snowballing technique. Interviews were transcribed and then analyzed using thematic analysis. RESULTS: A total of 16 community pharmacists participated in the interviews. Study participants described providing a range of novel services in response to the pandemic on top of continuing their usual services. All participants described providing preventative services to reduce and mitigate the spread of SARS-CoV-2, such as education on hygiene and social distancing, delivery of face masks and hand sanitizer and adjusting pharmacy premises. Most respondents also described being involved in SARS-CoV-2 detection through screening and performing antigen testing in pharmacies. Participants reported being actively involved in COVID-19 vaccination by educating the general public about vaccines, facilitating their distribution to general practitioners as well as administering vaccines. Over half the respondents described rapidly changing guidelines and service users' anxiety as challenges to the provision of healthcare services during the pandemic. CONCLUSIONS: This study suggests that community pharmacists have significantly contributed to the response to the COVID-19 pandemic by ensuring continuity of pharmaceutical services and providing novel screening, testing and vaccination services. Their roles and responsibilities during the COVID-19 health crisis indicate that they can play an important role in the management of emerging infectious diseases.

Dual Monoclonal Antibodies on Sars-Cov-2 Alpha and Delta Variants: Clinical and Virological Efficacy.

Monoclonal antibodies (MAbs) targeting the Spike glycoprotein of SARS-CoV-2 is a key strategy to prevent severe COVID-19. Here, the efficacy of two monoclonal antibody bitherapies against SARS-CoV-2 was assessed on 92 patients at high risk of severe COVID-19 between March and October 2021 (Bichat-Claude Bernard Hospital, Paris, France). Nine patients died despite appropriate management. From 14 days following treatment initiation, we observed a slower viral load decay for patients treated with the bitherapy Bamlanivimab/Etsevimab compared to the Casirivimab/Imdevimab association therapy (P = 0.045). The emergence of several mutations on the Spike protein known to diminish antiviral efficacy was observed from 1 to 3 weeks after infusion. The Q493R mutation was frequently selected, located in a region of joint structural overlap by Bamlanivimab/Etsevimab antibodies. Despite that this study was done on former SARS-CoV-2 variants (Alpha and Delta), the results provide new insights into resistance mechanisms in SARS-CoV-2 antibodies neutralization escape and should be considered for current and novel variants. IMPORTANCE Monoclonal antibody bitherapies (MAbs) are commonly prescribed to treat severe SARS-CoV-2-positive patients, and the rapid growth of resistance mutation emergence is alarming globally. To explore this issue, we conducted both clinical and genomic analyses of SARS-CoV-2 in a series of patients treated in 2021. We first noticed that the two dual therapies prescribed during the study had different kinetics of viral load decay. Rapidly after initiation of the treatments, resistance mutations emerged in the interface between the MAbs and the target Spike glycoprotein, demonstrating the importance to continuously screen the viral genome during treatment course. Taken together, the results highlight that viral mutations may emerge under selective pressure, conferring a putative competitive advantage, and could rapidly spread, as observed for the Omicron variant.

Feasibility of large-scale eOSCES: the simultaneous evaluation of 500 medical students during a mock examination.

The COVID-19 pandemic has led health schools to cancel many on-site training and exams. Teachers were looking for the best option to carry out online OSCEs, and Zoom was the obvious choice since many schools have used it to pursue education purposes. METHODS: We conducted a feasibility study during the 2020-2021 college year divided into six pilot phases and the large-scale eOSCEs on Zoom on June 30th, 2021. We developed a specific application allowing us to mass create Zoom meetings and built an entire organization, including a technical support system (an SOS room and catching-up rooms) and teachers' training sessions. We assessed satisfaction via an online survey. RESULTS: On June 30th, 531/794 fifth-year medical students (67%) participated in a large-scale mock exam distributed in 135 Zoom meeting rooms with the mobilization of 298 teachers who either participated in the Zoom meetings as standardized patients (N =135, 45%) or examiners (N =135, 45%) or as supervisors in the catching-up rooms (N =16, 6%) or the SOS room (N =12, 4%). In addition, 32/270 teachers (12%) experienced difficulties connecting to their Zoom meetings and sought the help of an SOS room member. Furthermore, 40/531 students (7%) were either late to their station or had technical difficulties and declared those issues online and were welcomed in one of the catching-up rooms to perform their eOSCE stations. Additionally, 518/531 students (98%) completed the entire circuit of three stations, and 225/531 students (42%) answered the online survey. Among them, 194/225 (86%) found eOSCES helpful for training and expressed their satisfaction with this experience. CONCLUSION: Organizing large-scale eOSCEs on Zoom is feasible with the appropriate tools. In addition, eOCSEs should be considered complementary to on-site OSCEs and to train medical students in telemedicine.

Role and perception of clinical microbiology and infectious diseases trainees during the COVID-19 crisis.

Aim: To evaluate the role and perceptions of trainees during the COVID-19 pandemic. Method: An online survey was designed to provide an insight into the significance of the COVID-19 pandemic on working conditions of infectious diseases and clinical microbiology trainees. Results: The main roles of trainees included management of patients hospitalized for COVID-19 (55%), research (53%) and diagnostic procedures (43%). The majority (82%) of trainees felt useful in managing the crisis. However, more than two-thirds felt more stressed and more tired compared with other rotations. Only 39% of the participants had access to psychological support. Conclusion: Due to the significant impact of the pandemic on infectious diseases and clinical microbiology trainees, further research should focus on their health and welfare in the post-pandemic period.

Effect of remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial.

BACKGROUND: The antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. OBJECTIVES: To estimate the effect of remdesivir in blocking viral replication. METHODS: We analysed nasopharyngeal normalized viral loads from 665 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020-000936-23), randomized to either standard of care (SoC) or SoC + remdesivir. We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in blocking viral replication. Additional analyses were conducted stratified on time of treatment initiation (≤7 or >7 days since symptom onset) or viral load at randomization (< or ≥3.5 log10 copies/104 cells). RESULTS: In our model, remdesivir reduced viral production by infected cells by 2-fold on average (95% CI: 1.5-3.2-fold). Model-based simulations predict that remdesivir reduced time to viral clearance by 0.7 days compared with SoC, with large inter-individual variabilities (IQR: 0.0-1.3 days). Remdesivir had a larger impact in patients with high viral load at randomization, reducing viral production by 5-fold on average (95% CI: 2.8-25-fold) and the median time to viral clearance by 2.4 days (IQR: 0.9-4.5 days). CONCLUSIONS: Remdesivir halved viral production, leading to a median reduction of 0.7 days in the time to viral clearance compared with SoC. The efficacy was larger in patients with high viral load at randomization.

COVID-19 : les thérapeutiques Therapeutic options for COVID-19 patients

Les thérapeutiques en cours d’évaluation pour la COVID-19 interviennent à différents stades de la maladie. Alors que la prophylaxie à large échelle en population générale fait désormais appel à la vaccination, des molécules antivirales sont en cours d’évaluation pour la prophylaxie post-exposition, dont les anticorps monoclonaux, notamment chez les patients à haut risque d’évolution vers une forme sévère de COVID-19. La phase précoce de la maladie, symptomatique ou non, pourrait bénéficier d'une stimulation de l'immunité antivirale naturelle, comme les interférons de type 1 ou de l'administration de traitements antiviraux, et notamment les anticorps monoclonaux. À une phase plus avancée de la maladie, la corticothérapie a montré un bénéfice sur la mortalité chez des patients en hospitalisation conventionnelle ou en réanimation nécessitant un support en oxygène. Malgré de nombreux échecs de traitements antiviraux, des molécules antivirales ainsi que des thérapies ciblées anti-inflammatoires sont encore en cours d’évaluation.

COVID-19 : les thérapeutiques

Résumé Les thérapeutiques en cours d’évaluation pour la COVID-19 interviennent à différents stades de la maladie. Alors que la prophylaxie à large échelle en population générale fait désormais appel à la vaccination, des molécules antivirales sont en cours d’évaluation pour la prophylaxie post-exposition, dont les anticorps monoclonaux, notamment chez les patients à haut risque d’évolution vers une forme sévère de COVID-19. La phase précoce de la maladie, symptomatique ou non, pourrait bénéficier d'une stimulation de l'immunité antivirale naturelle, comme les interférons de type 1 ou de l'administration de traitements antiviraux, et notamment les anticorps monoclonaux. À une phase plus avancée de la maladie, la corticothérapie a montré un bénéfice sur la mortalité chez des patients en hospitalisation conventionnelle ou en réanimation nécessitant un support en oxygène. Malgré de nombreux échecs de traitements antiviraux, des molécules antivirales ainsi que des thérapies ciblées anti-inflammatoires sont encore en cours d’évaluation. There are different therapeutics options to treat COVID-19 at different stages of the disease. While large-scale prophylaxis in the general population now relies on vaccination, antiviral molecules such as monoclonal antibodies are being evaluated for post-exposure prophylaxis, particularly in patients at high risk of severe forms of COVID-19. The early phase of the disease, whether symptomatic or not, could benefit from stimulation of natural antiviral immunity such as type 1 interferons and/or from the administration of antiviral treatments including monoclonal antibodies. In more advanced stages of the disease, corticosteroid therapy has shown a benefit on mortality in hospitalized patients requiring oxygen support. Despite numerous disappointments of antiviral treatments, antiviral molecules are still being evaluated as well as targeted anti-inflammatory therapies.

Aims and challenges of building national trainee networks in clinical microbiology and infectious disease disciplines.

Trainees represent the medical practice of tomorrow. Interactions and collaborations at the early stage in career will strengthen the future of our specialties, clinical microbiology and infectious diseases. Trainee networks at the national level help access the best education and career opportunities. The aim of this collaborative white paper between the Trainee Association of European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and four national trainee networks is to discuss the motivation for building such networks and offer guidance for their creation and sustainability even during a health crisis.