Therapeutic Impact of Tocilizumab in the Setting of Severe COVID-19; an Updated and Comprehensive Review on Current Evidence.

Introduction: The COVID-19 pandemic caused by SARS-CoV-2 has been the major health concern in 2019 globally. Considering the severity and phase of the disease, various pharmacotherapy schedules were proposed. Here, we set out to provide close-up insights on the clinical utility of Tocilizumab (TCZ), a biologic monoclonal antibody in this regard. Methods: In this comprehensive review, various databases, including Scopus, PubMed Central, Medline, Embase, Google Scholar, and preprint publishers (med/bioRxiv) were searched until January 30, 2024, according to the keywords and search criteria. Results: Besides the pros and cons, compelling evidence purported the safety and efficacy of TCZ and indicated that it exhibits great potential to reduce short-term and all-cause (28-30-day) mortality. TCZ significantly drops the adverse events if administered in the right time course (in the inflammatory phase) during critical/severe COVID-19 pneumonia. Despite contradictory results, the benefits of TCZ appear significant, especially in combination with add-on therapies, such as corticosteroids. Although the safety of TCZ is acceptable, solid data is lacking as to its benefits during pregnancy. There are limited data on TCZ combination therapies, such as hemoperfusion, intravenous immunoglobulin (IVIG), simple O2 therapy, vasopressor support, convalescent plasma therapy, and even in vaccinated patients and COVID-19 reinfection, especially in elderly persons. In addition, the impact of TCZ therapy on the long-lasting COVID-19 is unclear. Conclusion: Personalized medicine based on individual characteristics and pertinent clinical conditions must be considered in the clinicians' decision-making policy. Finally, to mitigate the risk-to-benefit ratio of TCZ, a treatment algorithm, based on available literature and updated national institute of health (NIH) and Infectious Diseases Society of America (IDSA) guidelines, is also proposed.

Calcifediol or Corticosteroids in the Treatment of COVID-19: An Observational Study.

Medical treatment of coronavirus 19 disease (COVID-19) is a therapeutic challenge. The available data strongly suggest that calcifediol treatment may reduce the severity of COVID-19, and corticosteroids are the treatment of choice worldwide for severe COVID-19. Both have a very similar action profile, and their combined use in patients may modify the contribution of each administered compound. OBJECTIVE: To evaluate how treatment with calcifediol and/or corticosteroids in medical practice modified the need for ICU admission, death, or poor prognosis of patients hospitalized with COVID-19 during the first outbreaks. DESIGN, PATIENTS AND SETTING: A retrospective observational cohort study of patients admitted for COVID-19 to the Pneumology Unit of the Hospital Universitario Reina Sofía (Córdoba, Spain). INTERVENTIONS: Patients were treated with calcifediol or/and corticosteroids with the best available therapy and standard care, according to clinical practice guidelines. MEASUREMENTS: Admission to the intensive care unit (ICU) or death during hospitalization and poor prognosis. RESULTS: Seven hundred and twenty-eight patients were included. According to the treatment received, they were included in four groups: calcifediol (n = 68), glucocorticoids (n = 112), both (n = 510), or neither (n = 38). Of the 578 patients treated with calcifediol, 88 were admitted to the ICU (15%), while of the 150 not treated with calcifediol, 39 required ICU admission (26%) (p < 0.01). Among the patients taking calcifediol without glucocorticoids, only 4 of 68 (5.8%) required ICU admission, compared to 84 of 510 (16.5%) treated with both (p = 0.022). Of the 595 patients who had a good prognosis, 568 (82.01%) had received treatment with calcifediol versus the 133 patients with a poor prognosis, of whom 90 (67.66%) had received calcifediol (p < 0.001). This difference was not found for corticosteroids. INTERPRETATION: The treatment of choice for hospitalized patients with moderate or mild COVID-19 could be calcifediol, not administering corticosteroids, until the natural history of the disease reaches a stage of hyperinflammation.

Efficacy and Safety of Ensitrelvir for Asymptomatic or Mild COVID-19: An Exploratory Analysis of a Multicenter, Randomized, Phase 2b/3 Clinical Trial.

BACKGROUND: This phase 2b/3, randomized, placebo-controlled trial explored the efficacy and evaluated the safety of ensitrelvir. This trial involved individuals with asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patients with mild symptoms of coronavirus disease 2019 (COVID-19). METHODS: The trial was conducted at 57 medical institutions in Japan, South Korea, and Vietnam (study period: January 6-August 14, 2022). Eligible participants were randomized (1:1:1) to the ensitrelvir 125-mg, ensitrelvir 250-mg, or placebo group, received the allocated intervention orally, and were followed up until Day 28. Participants self-rated the severity of 14 typical COVID-19 symptoms and recorded the data in an electronic diary. RESULTS: In total, 572 participants (194, 189, and 189 in the ensitrelvir 125-mg, ensitrelvir 250-mg, and placebo groups, respectively) were included in the intention-to-treat population. Ensitrelvir 125-mg group observed a 77% reduction in the risk of developing any of the 14 COVID-19 symptoms or fever and a 29% reduction in the risk of worsening of such symptoms or fever versus placebo (statistically nonsignificant). The viral RNA, viral titer, and time to infectious viral clearance observed a statistically significant decrease versus placebo. Most treatment-related adverse events (TEAEs) were mild to moderate in severity, and the most common TEAE observed across groups was a decrease in high-density lipoprotein. CONCLUSIONS: Our exploratory results suggest a potential reduction in the risk of development or worsening of COVID-19 symptoms with ensitrelvir. Ensitrelvir showed antiviral efficacy and was well tolerated. TRIAL REGISTRATION: Japan Registry of Clinical Trials identifier: jRCT2031210350.

Impact of COVID-19 Treatment on Real-World Outcomes in Inflammatory Bowel Disease.

BACKGROUND: While there are multiple safe and effective agents for COVID-19 treatment, their impact in inflammatory bowel disease (IBD) remains uncertain. AIMS: Our objective was to assess the effects of these therapies on both IBD and COVID outcomes. METHODS: A single-center retrospective study of adult patients with IBD who contracted COVID-19 between 12/2020 and 11/2022 was performed. Patients were stratified by COVID-19 treatment (antivirals and/or intravenous antibodies) vs no therapy. The primary outcome was the development of severe COVID-19 infection, defined by need for supplemental oxygen, corticosteroids and/or antibiotics, or hospitalization. Secondary outcomes included rates of withholding advanced IBD therapy (defined as biologic agents or small molecules) and of post-COVID-19 IBD flare. RESULTS: Of 127 patients with COVID-19 infection, 70% were on advanced therapies, 35% received COVID-19 treatment, and 15% developed severe COVID-19. Those treated for COVID-19 were more likely to be on corticosteroids [odds ratio (OR) 4.61, 95% confidence interval (CI) 1.72-12.39, p = 0.002] or advanced IBD therapies (OR 2.78, 95% CI 1.04-7.43, p = 0.041). After adjusting for age, race, sex, corticosteroid use, obesity, COVID-19 vaccination status, and severe COVID-19 infection, those treated for COVID-19 were more likely to have IBD therapy held (OR 6.95, 95% CI 1.72-28.15, p = 0.007). There was no significant difference in rates of post-COVID-19 IBD flares or severe COVID-19 infection. There were no COVID-related deaths. CONCLUSIONS: Patients with IBD on advanced therapies were frequently treated for acute COVID-19. Although COVID-19 treatment was associated with temporary withholding of IBD therapy, it did not result in increased IBD flares.

[Health alerts for substandard, falsified, and unregistered medical products at the onset of the COVID-19 pandemic in the AmericasAlertas de saúde para produtos médicos abaixo do padrão, falsificados e não registrados no início da pandemia de COVID-19 nas Américas]. / Alertas sanitarias de productos médicos subestándares, falsificados y no registrados al inicio de la pandemia de COVID-19 en las Américas.

Objective: Identify and analyze incidents of substandard, falsified, unregistered, and stolen medical products at the onset of the COVID-19 pandemic. Methods: Detailed search of the websites of regulatory authorities in the Americas. Identification of incidents of substandard, falsified, unregistered, and stolen medicines and medical devices (including in vitro diagnostics). The types of products were determined, as were the stages in the supply chain where they were detected, and the actions taken by authorities. Results: A total of 1 273 incidents were identified in 15 countries (1 087 substandard, 44 falsified, 123 unregistered, and 19 stolen products). The largest number of incidents involved medical devices, disinfectants, and antiseptics. The most frequently reported point in the supply chain was online purchasing. The principal measures taken by the regulatory authorities were: alerts, prohibition of use, prohibition of advertising and manufacture, recall, and monitoring of adverse events. Conclusions: A substantial number of incidents involving substandard, falsified, unregistered, and stolen medical products at the onset of the COVID-19 pandemic were identified. Shortages of supplies, easing of regulatory requirements, and increased demand are factors that may have led to an increase in the number of incidents. The national regulatory authorities of reference reported more frequent detection of incidents and more frequent application of health measures. A regulatory strategy is needed in order to address online sales and ensure the safe distribution of medical products.

Objetivo: Identificar e analisar incidentes de produtos médicos abaixo do padrão, falsificados, não registrados e roubados no início da pandemia de COVID-19. Métodos: Foi realizada uma busca detalhada nos sites das autoridades reguladoras das Américas. Foram identificados incidentes envolvendo medicamentos e dispositivos médicos (incluindo para diagnóstico in vitro) abaixo do padrão, falsificados, não registrados e roubados. Foram determinados os tipos de produtos, os estágios da cadeia de abastecimento em que foram detectados e as medidas tomadas pelas autoridades. Resultados: Foram identificados 1 273 incidentes em 15 países (1 087 produtos abaixo do padrão, 44 falsificados, 123 não registrados e 19 roubados). O maior número de incidentes estava relacionado a dispositivos médicos, desinfetantes e antissépticos. O ponto na cadeia de abastecimento com a maior frequência de relatos foi a de aquisição pela internet. As medidas tomadas pelas autoridades reguladoras foram principalmente alertas, proibições de uso, proibições de publicidade e fabricação, recolhimento de produtos do mercado e monitoramento de eventos adversos. Conclusões: Houve um número significativo de incidentes envolvendo produtos médicos abaixo do padrão falsificados, não registrados e roubados no início da pandemia de COVID-19. A escassez de insumos, a flexibilização das exigências regulatórias e o aumento da demanda são fatores que podem levar a um maior número de incidentes. As autoridades reguladoras nacionais de referência informaram um aumento na frequência de detecção de incidentes e implementação de medidas sanitárias. O canal de vendas pela internet precisa ser abordado com alguma estratégia regulatória para garantir a distribuição segura de produtos médicos.

Determining and Comparing the Real-World Effectiveness of Molnupiravir and Nirmatrelvir-Ritonavir in Patients Hospitalized With COVID-19.

BACKGROUND: Current guidelines recommend using nirmatrelvir-ritonavir for coronavirus disease 2019 (COVID-19) treatment, but its potential drug interactions and contraindications limit its applicability in certain categories of patients. The aim of the study was to evaluate the real-world effectiveness of molnupiravir and nirmatrelvir-ritonavir in managing COVID-19 among hospitalized patients. METHODS: We conducted a retrospective cohort study among hospitalized COVID-19 patients who received molnupiravir or nirmatrelvir-ritonavir and did not require baseline supplemental oxygen from February 2022 to January 2023. We compared the effectiveness of molnupiravir and nirmatrelvir-ritonavir with a focus on disease progression. RESULTS: The study included 401 high-risk, hospitalized adult COVID-19 patients who received molnupiravir or nirmatrelvir-ritonavir. No significant difference was found in disease progression, the composite outcome of disease progression (4.0% vs. 1.4%, P = 0.782), and O2 supplementation via nasal prong (21.8% vs. 14.8%, P = 0.115) between the patients treated with molnupiravir and those treated with nirmatrelvir-ritonavir. This finding was similar after 1:1 propensity-score matching. In the multivariate analysis, molnupiravir treatment was not significantly associated with progression to severe disease. CONCLUSION: In conclusion, our findings suggest that similar to nirmatrelvir-ritonavir, molnupiravir has a distinct potential role in COVID-19 treatment, transcending its current perceived status as only a secondary option.

Evaluating in vivo effectiveness of sotrovimab for the treatment of Omicron subvariant BA.2 versus BA.1: a multicentre, retrospective cohort study.

BACKGROUND: In vitro data suggested reduced neutralizing capacity of sotrovimab, a monoclonal antibody, against Omicron BA.2 subvariant. However, limited in vivo data exist regarding clinical effectiveness of sotrovimab for coronavirus disease 2019 (COVID-19) due to Omicron BA.2. METHODS: A multicentre, retrospective cohort study was conducted at three Canadian academic tertiary centres. Electronic medical records were reviewed for patients ≥ 18 years with mild COVID-19 (sequencing-confirmed Omicron BA.1 or BA.2) treated with sotrovimab between February 1 to April 1, 2022. Thirty-day co-primary outcomes included hospitalization due to moderate or severe COVID-19; all-cause intensive care unit (ICU) admission, and all-cause mortality. Risk differences (BA.2 minus BA.1 group) for co-primary outcomes were adjusted with propensity score matching (e.g., age, sex, vaccination, immunocompromised status). RESULTS: Eighty-five patients were included (15 BA.2, 70 BA.1) with similar baseline characteristics between groups. Adjusted risk differences were non-statistically significant between groups for 30-day hospitalization (- 14.3%; 95% confidence interval (CI): - 32.6 to 4.0%), ICU admission (- 7.1%; 95%CI: - 20.6 to 6.3%), and mortality (- 7.1%; 95%CI: - 20.6 to 6.3%). CONCLUSIONS: No differences were demonstrated in hospitalization, ICU admission, or mortality rates within 30 days between sotrovimab-treated patients with BA.1 versus BA.2 infection. More real-world data may be helpful to properly assess sotrovimab's effectiveness against infections due to specific emerging COVID-19 variants.

The effects of remdesivir on mortality and the requirement for mechanical ventilation in patients with COVID-19: a systematic review stratified by disease severity.

BACKGROUND/AIMS: The effectiveness of remdesivir treatment in reducing mortality and the requirement for mechanical ventilation (MV) remains uncertain, as randomized controlled trials (RCTs) have produced conflicting results. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and other data resources to find RCTs published prior to April 10, 2023. The selection of studies, assessment of risk of bias, and meta-analysis were conducted according to PRISMA guidelines. The primary outcomes were all-cause mortality and the need to initiate MV. RESULTS: A total of 5,068 articles were screened, from eight RCTs comprising 11,945 patients. The meta-analysis found that, compared to standard care or placebo, remdesivir treatment provided no significant all-cause mortality benefit (pooled risk ratio [RR], 0.93; 95% confidence interval [CI], 0.85-1.02; 8 studies; high certainty evidence), while subgroup analyses revealed a trend towards reduced mortality among patients requiring oxygen but not MV (pooled RR, 0.88; 95% CI, 0.77-1.00; 6 studies; I2 = 4%). The need to initiate MV (pooled RR, 0.74; 95% CI, 0.59-0.94; 7 studies; moderate certainty evidence) in remdesivir-treated patients was also reduced compared to controls. Remdesivir significantly increased clinical improvement and discharge and significantly reduced serious adverse events. CONCLUSION: In this systematic review and meta-analysis of RCTs, it was found that remdesivir treatment did not show a substantial decrease in the risk of mortality. However, it was linked to a reduction in the necessity for additional ventilatory support, suggesting remdesivir could be beneficial for COVID-19 patients, particularly those who are not on MV.

Alertas sanitarias de productos médicos subestándares, falsificados y no registrados al inicio de la pandemia de COVID-19 en las Américas / Health alerts for substandard, falsified, and unregistered medical products at the onset of the COVID-19 pandemic in the Americas / Alertas de saúde para produtos médicos abaixo do padrão, falsificados e não registrados no início da pandemia de COVID-19 nas Américas

RESUMEN Objetivo. Identificar y analizar los incidentes de productos médicos subestándares, falsificados, no registrados y robados al inicio de la pandemia de COVID-19. Métodos. Búsqueda detallada en los sitios web de las autoridades reguladoras de las Américas. Identificación de los incidentes de medicamentos y dispositivos médicos (incluidos los de diagnóstico in vitro) subestándares falsificados, no registrados y robados. Se determinaron los tipos de productos, las etapas de la cadena de suministro en las que se detectaron y las medidas tomadas por las autoridades. Resultados. Se identificaron 1 273 incidentes en 15 países (1 087 productos subestándares, 44 falsificados, 123 no registrados y 19 robados). La mayor cantidad de incidentes corresponden a dispositivos médicos, desinfectantes y antisépticos. El punto en la cadena de suministro con mayor frecuencia de informes fue la adquisición a través de internet. Las medidas tomadas por las autoridades reguladoras corresponden en su mayoría a: alerta, prohibición de uso, prohibición de publicidad y fabricación, retiro del mercado y seguimiento de eventos adversos. Conclusiones. Se evidenció un número destacable de incidentes de productos médicos subestándares, falsificados, no registrados y robados al inicio de la pandemia por COVID-19. La escasez de insumos, la flexibilización en los requisitos regulatorios y el aumento de la demanda son factores que pueden favorecer el incremento del número de incidentes. Las autoridades reguladoras nacionales de referencia presentaron mayores frecuencias de detección de incidentes y de aplicación de medidas sanitarias. Se observó que se debe abordar el canal de venta por internet con alguna estrategia reguladora para garantizar la distribución segura de productos médicos.

ABSTRACT Objective. Identify and analyze incidents of substandard, falsified, unregistered, and stolen medical products at the onset of the COVID-19 pandemic. Methods. Detailed search of the websites of regulatory authorities in the Americas. Identification of incidents of substandard, falsified, unregistered, and stolen medicines and medical devices (including in vitro diagnostics). The types of products were determined, as were the stages in the supply chain where they were detected, and the actions taken by authorities. Results. A total of 1 273 incidents were identified in 15 countries (1 087 substandard, 44 falsified, 123 unregistered, and 19 stolen products). The largest number of incidents involved medical devices, disinfectants, and antiseptics. The most frequently reported point in the supply chain was online purchasing. The principal measures taken by the regulatory authorities were: alerts, prohibition of use, prohibition of advertising and manufacture, recall, and monitoring of adverse events. Conclusions. A substantial number of incidents involving substandard, falsified, unregistered, and stolen medical products at the onset of the COVID-19 pandemic were identified. Shortages of supplies, easing of regulatory requirements, and increased demand are factors that may have led to an increase in the number of incidents. The national regulatory authorities of reference reported more frequent detection of incidents and more frequent application of health measures. A regulatory strategy is needed in order to address online sales and ensure the safe distribution of medical products.

RESUMO Objetivo. Identificar e analisar incidentes de produtos médicos abaixo do padrão, falsificados, não registrados e roubados no início da pandemia de COVID-19. Métodos. Foi realizada uma busca detalhada nos sites das autoridades reguladoras das Américas. Foram identificados incidentes envolvendo medicamentos e dispositivos médicos (incluindo para diagnóstico in vitro) abaixo do padrão, falsificados, não registrados e roubados. Foram determinados os tipos de produtos, os estágios da cadeia de abastecimento em que foram detectados e as medidas tomadas pelas autoridades. Resultados. Foram identificados 1 273 incidentes em 15 países (1 087 produtos abaixo do padrão, 44 falsificados, 123 não registrados e 19 roubados). O maior número de incidentes estava relacionado a dispositivos médicos, desinfetantes e antissépticos. O ponto na cadeia de abastecimento com a maior frequência de relatos foi a de aquisição pela internet. As medidas tomadas pelas autoridades reguladoras foram principalmente alertas, proibições de uso, proibições de publicidade e fabricação, recolhimento de produtos do mercado e monitoramento de eventos adversos. Conclusões. Houve um número significativo de incidentes envolvendo produtos médicos abaixo do padrão falsificados, não registrados e roubados no início da pandemia de COVID-19. A escassez de insumos, a flexibilização das exigências regulatórias e o aumento da demanda são fatores que podem levar a um maior número de incidentes. As autoridades reguladoras nacionais de referência informaram um aumento na frequência de detecção de incidentes e implementação de medidas sanitárias. O canal de vendas pela internet precisa ser abordado com alguma estratégia regulatória para garantir a distribuição segura de produtos médicos.

Análisis de las interacciones de nirmatrelvir/ritonavir en pacientes ambulatorios en atención primaria / Nirmatrelvir/ritonavir drug-drug interactions in primary care outpatients

Fundamento. Nirmatrelvir/ritonavir es un antiviral oral con un alto potencial de producir interacciones farmacológicas. La población candidata a recibirlo es mayoritariamente vulnerable, con enfermedades crónicas y polimedicada. El objetivo es evaluar la validación farmacéutica previa a la ad-ministración del antiviral.Material y métodos. Las interacciones farmacológicas entre nirmatrelvir/ritonavir y el tratamiento habitual se consulta-ron en fichas técnicas y las herramientas de interacciones de UpToDate® y Universidad de Liverpool®. Se incluyeron las prescripciones validadas por un farmacéutico de atención primaria (abril/2022-abril/2023). Resultados. Se incluyeron 159 pacientes; en 83 se detecta-ron 168 interacciones que podían suponer un cambio en su tratamiento. Las estatinas (25,6%), anticoagulantes (10,7%) y antihipertensivos (10,7%) fueron los grupos terapéuticos más frecuentemente implicados. La suspensión (53,0%) y reducción de dosis (22,6%) fueron los cambios de trata-miento más frecuentes. Conclusiones. La revisión de potenciales interacciones far-macológicas, los ajustes posológicos y las modificaciones del tratamiento habitual del paciente han evitado potenciales to-xicidades, mejorando la seguridad de nirmatrelvir/ritonavir (AU)

Background. The oral antiviral nirmatrelvir/ritonavir inter-acts with a range of drugs. Candidate patients to receive this antiviral agent are usually vulnerable, multipathological and polymedicated. The objective is to evaluate the phar-maceutical validation prior to the administration of the an-tiviral.Material and methods. Drug-drug interactions between nirmatrelvir/ritonavir and patients’ usual treatment medi-cations were checked in product information and in the Up-ToDate® and the University of Liverpool® interaction tools. We included validated prescriptions between April/2022 and April/2023 by a Primary Care pharmacist.Results. Of the 159 study patients, 168 interactions were found in 83 individuals, which may have led to changes of their usual treatment. Statins (25.6%), anticoagulants (10.7%), and antihypertensives (10.7%) were the most fre-quently implicated therapeutic groups. Discontinuation (53.0%) and dose reduction (22.6%) were the most common treatment changes. Conclusions. Our search of potential drug interactions and subsequent dose adjustments and modifications of the pa-tient’s usual treatment has helped avoid potential toxicities ensuring a safe use of nirmatrelvir/ritonavir (AU)

COVID-19 early curative treatments in kidney transplant recipients: is it really reasonable at the Omicron era?

Objective: Data about efficacy and safety of the latest COVID-19 treatments as nirmatrelvir/ritonavir (n/r) or Sotrovimab is scarce in solid organ transplant recipients in the Omicron era. This study aims at describing the outcome of kidney transplant recipients (KTRs) presenting Omicron infection according to their management: n/r, sotrovimab or no specific treatment. Patients and methods: We conducted a monocentric, retrospective observational study, including KTRs diagnosed Omicron infection between January and May 1st 2022 and compared their outcome (primary outcome defined as hospital admission for COVID-19 within a month after symptoms onset) according to early COVID-19 management. Results: Forty-five patients were included: 22 treated (12 n/r, 10 sotrovimab) and 23 with no specific treatment. The groups were statistically comparable. Two patients were admitted for COVID-19: one in each group, resulting in a non-different probability of the primary outcome at on month (p=0.9). Three patients presented tacrolimus overdose including two with acute kidney injury. Conclusions: There was no difference in outcome according to early therapeutic management: n/r, sotrovimab or no specific treatment. Our study both underlines a decreased severity of Omicron COVID-19 in KTRs (probably related to vaccinal immunity and decreased virulence of Omicron) and a potential severe adverse effects with n/r.

Objectif: Les données sur l'efficacité et la sécurité des derniers traitements de la Covid-19 sont peu nombreuses à l'ère du variant Omicron. Cette étude avait pour objectif de décrire l'évolution des transplantés rénaux (TR) présentant une infection à Omicron selon le traitement précoce reçu : nirmatrelvir/ritonavir (n/r), sotrovimab, ou pas de traitement. Patients et méthodes: Il s'agissait d'une étude monocentrique rétrospective observationnelle incluant tous les TR présentant une infection confirmée à Omicron entre le 1er janvier 2022 et le 1er mai 2022 et comparant leur évolution (critère de jugement principal : admission hospitalière pour Covid-19 à un mois du début des symptômes) selon leur prise en charge. Résultats: Quarante-cinq patients ont été inclus : 22 traités (12 n/r et 10 sotrovimab) et 23 non traités. Les groupes étaient statistiquement comparables. Seulement deux patients ont présenté le critère de jugement principal : un n/r et un non traité, avec une probabilité à un mois non différente (p = 0,9). Trois patients sur 12 ont en revanche présenté des surdosages en tacrolimus dans le groupe n/r, dont deux avec une insuffisance rénale aiguë. Conclusions: Dans les limites d'un petit effectif, nous n'avons pas montré de bénéfice au traitement précoce par n/r ou sotrovimab. On peut évoquer un effet de l'immunité vaccinale et une baisse de virulence du SARS-CoV-2. En revanche, les effets secondaires du n/r ne sont pas anodins avec des surdosages sévères malgré des protocoles de service précis. La balance bénéfice-risque de ces traitements doit être rediscutée.

The Early Detection of Fraudulent COVID-19 Products From Twitter Chatter: Data Set and Baseline Approach Using Anomaly Detection.

Background: Social media has served as a lucrative platform for spreading misinformation and for promoting fraudulent products for the treatment, testing, and prevention of COVID-19. This has resulted in the issuance of many warning letters by the US Food and Drug Administration (FDA). While social media continues to serve as the primary platform for the promotion of such fraudulent products, it also presents the opportunity to identify these products early by using effective social media mining methods. Objective: Our objectives were to (1) create a data set of fraudulent COVID-19 products that can be used for future research and (2) propose a method using data from Twitter for automatically detecting heavily promoted COVID-19 products early. Methods: We created a data set from FDA-issued warnings during the early months of the COVID-19 pandemic. We used natural language processing and time-series anomaly detection methods for automatically detecting fraudulent COVID-19 products early from Twitter. Our approach is based on the intuition that increases in the popularity of fraudulent products lead to corresponding anomalous increases in the volume of chatter regarding them. We compared the anomaly signal generation date for each product with the corresponding FDA letter issuance date. We also performed a brief manual analysis of chatter associated with 2 products to characterize their contents. Results: FDA warning issue dates ranged from March 6, 2020, to June 22, 2021, and 44 key phrases representing fraudulent products were included. From 577,872,350 posts made between February 19 and December 31, 2020, which are all publicly available, our unsupervised approach detected 34 out of 44 (77.3%) signals about fraudulent products earlier than the FDA letter issuance dates, and an additional 6 (13.6%) within a week following the corresponding FDA letters. Content analysis revealed misinformation, information, political, and conspiracy theories to be prominent topics. Conclusions: Our proposed method is simple, effective, easy to deploy, and does not require high-performance computing machinery unlike deep neural network-based methods. The method can be easily extended to other types of signal detection from social media data. The data set may be used for future research and the development of more advanced methods.

Identification of Clinical Response Predictors of Tocilizumab Treatment in Patients with Severe COVID-19 Based on Single-Center Experience.

Hyperinflammation in COVID-19 plays a crucial role in pathogenesis and severity; thus, many immunomodulatory agents are applied in its treatment. We aimed to identify good clinical response predictors of tocilizumab (TCZ) treatment in severe COVID-19, among clinical, laboratory, and radiological variables. We conducted a prospective, observational study with 120 patients with severe COVID-19 not improving despite dexamethasone (DEX) treatment. We used parametric and non-parametric statistics, univariate logistic regression, receiver operating characteristic (ROC) curves, and nonlinear factors tertile analysis. In total, 86 (71.7%) patients achieved the primary outcome of a good clinical response to TCZ. We identified forty-nine predictive factors with potential utility in patient selection and treatment monitoring. The strongest included time from symptom onset between 9 and 12 days, less than 70% of estimated radiological lung involvement, and lower activity of lactate dehydrogenase. Additional predictors were associated with respiratory function, vitamin D concentration, comorbidities, and inflammatory/organ damage biomarkers. Adverse events analysis proved the safety of such a regimen. Our study confirmed that using TCZ early in the hyperinflammatory phase, before severe respiratory failure development, is most beneficial. Considering the described predictive factors, employing simple and widely available laboratory, radiological, and clinical tools can optimize patient selection for immunomodulatory treatment with TCZ.

Patients with moderate to severe COVID-19 outcomes on remdesivir according to baseline 4C mortality score.

BACKGROUND: Remdesivir was the first antiviral to show clinical benefit in patients with moderate-to-severe COVID-19. Previous trials demonstrated a faster time to recovery in hospitalized patients treated with remdesivir vs placebo. Current guidelines recommend treatment with remdesivir based on hospitalization status, oxygen requirements, and time from symptom onset. However, other factors may be evaluated to determine disease severity and risk for progression. The 4C mortality score is a validated, eight variable score that may be used to categorize patients by mortality risk at the time of hospital admission for COVID pneumonia. The objective of this study was to determine if the 4C mortality score may be used to predict which patients with moderate to severe COVID-19 would benefit the most from remdesivir at the time of hospital admission. METHODS: This was a single-center retrospective cohort study comparing time to recovery among hospitalized patients with moderate-to-severe COVID-19 who were treated with remdesivir compared to those who were treated with standard of care (SOC). The primary outcome was time to recovery, defined as discharge from the hospital or no longer requiring supplemental oxygen, stratified by the 4C mortality score risk group. Secondary outcomes included in-hospital mortality, hospital length of stay, and time to recovery in patients who were started on remdesivir within 7 days from symptom onset vs after 7 days from symptom onset. A survival analysis was used to analyze time to recovery outcomes. RESULTS: Data was collected and analyzed for a total of 300 patients, of which 200 received remdesivir and 100 received SOC. Patients in the remdesivir group had a longer time to recovery compared to patients in the SOC group (6 days vs 4 days). This finding was driven by patients who were categorized to the intermediate risk and high risk mortality groups. Additionally, patients who received remdesivir had a longer length of hospital stay compared to those who received SOC (12 days vs 9 days). Remdesivir was not associated with an increased rate of adverse events. CONCLUSIONS: This study of patients admitted with moderate-to-severe COVID-19 found that patients who were treated with remdesivir had a longer time to recovery and a longer length of stay compared to those who received SOC. These findings add to the body of evidence questioning the benefit of remdesivir therapy among patients hospitalized with COVID-19.

The Therapy of SARS-CoV-2 Infection in Children.

The impact of SARS-CoV-2 infections in children has fortunately been lower than what has been seen in adults. However, even previously healthy children have developed severe disease, sometimes with subsequent mortality, and those who are infants or adolescents, are from racial and ethnic minority groups, or have certain chronic conditions are at higher risk of these outcomes. During the pandemic, extensive studies of therapeutic agents, including antivirals and immunomodulators, were conducted in adults. Few trials included children, and most were in older children and adolescents. Thus, the potential benefits of therapies in children must be extrapolated from adult evidence. Despite these limitations, advisory committees of the National Institute of Health (NIH), the Infectious Disease Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS) were constituted, and expert consensus guidelines were developed. This review provides a synthesis of those comprehensive recommendations for therapy in children. These address treatment during the early infectious period with antiviral agents, including remdesivir and nirmatrelvir/ritonavir, as well as treatment in the later period of immune dysregulation with corticosteroids and immunomodulators. In addition, the therapeutic approach for multisystem inflammatory syndrome in children (MIS-C), also referred to as Pediatric Inflammatory Multisystem Syndrome temporally associated with SARS-CoV-2 (PIMS-TS), is also provided.

Thromboprophylaxis with standard-dose vs. flexible-dose heparin for hospitalized COVID-19 patients: a target trial emulation.

OBJECTIVES: To compare mortality of hospitalized COVID-19 patients under two low-molecular weight heparin (LMWH) thromboprophylaxis strategies: standard dose and variable dose (standard dose increased to intermediate dose in the presence of laboratory abnormalities indicating an increased thrombosis risk). STUDY DESIGN AND SETTING: Target trial emulation using observational data from 2,613 adults admitted with a COVID-19 diagnosis in Madrid, Spain between March 16 and April 15, 2020. RESULTS: A total of 1,284 patients were eligible. Among 503 patients without increased baseline thrombotic risk, 28-day mortality risk (95% confidence interval [CI]) was 9.0% (6.6, 11.7) under the standard dose strategy and 5.6% (3.3, 8.3) under the variable dose strategy; risk difference 3.4% (95% CI: -0.24, 6.9); mortality hazard ratio 1.61 (95% CI: 0.97, 2.89). Among 781 patients with increased baseline thrombotic risk, the 28-day mortality risk was 25.8% (22.7, 29.0) under the standard dose strategy and 18.1% (9.3, 28.9) under the intermediate dose strategy; risk difference 7.7% (95% CI: -3.5, 17.2); mortality hazard ratio 1.45 (95% CI: 0.81, 3.17). Major bleeding and LMWH-induced coagulopathy were rare under all strategies. CONCLUSION: Escalating anticoagulation intensity after signs of thrombosis risk may increase the survival of hospitalized COVID-19 patients. However, effect estimates were imprecise and additional studies are warranted.

Brazilian guidelines for the treatment of outpatients with suspected or confirmed COVID-19. A joint guideline of the Brazilian Association of Emergency Medicine (ABRAMEDE), Brazilian Medical Association (AMB), Brazilian Society of Angiology and Vascular Surgery (SBACV), Brazilian Society of Geriatrics and Gerontology (SBGG), Brazilian Society of Infectious Diseases (SBI), Brazilian Society of Family and Community Medicine (SBFMC), and Brazilian Thoracic Society (SBPT).

BACKGROUND: Several therapies have been used or proposed for the treatment of COVID-19, although their effectiveness and safety have not been properly evaluated. The purpose of this document is to provide recommendations to support decisions about the drug treatment of outpatients with COVID-19 in Brazil. METHODS: A panel consisting of experts from different clinical fields, representatives of the Brazilian Ministry of Health, and methodologists (37 members in total) was responsible for preparing these guidelines. A rapid guideline development method was used, based on the adoption and/or adaptation of recommendations from existing international guidelines combined with additional structured searches for primary studies and new recommendations whenever necessary (GRADE-ADOLOPMENT). The rating of quality of evidence and the drafting of recommendations followed the GRADE method. RESULTS: Ten technologies were evaluated, and 10 recommendations were prepared. Recommendations were made against the use of anticoagulants, azithromycin, budesonide, colchicine, corticosteroids, hydroxychloroquine/chloroquine alone or combined with azithromycin, ivermectin, nitazoxanide, and convalescent plasma. It was not possible to make a recommendation regarding the use of monoclonal antibodies in outpatients, as their benefit is uncertain and their cost is high, with limitations of availability and implementation. CONCLUSION: To date, few therapies have demonstrated effectiveness in the treatment of outpatients with COVID-19. Recommendations are restricted to what should not be used, in order to provide the best treatment according to the principles of evidence-based medicine and to promote resource savings by aboiding ineffective treatments.

Recomendaciones para el manejo de los pacientes críticos con COVID-19 en las Unidades de Cuidados Intensivos / Recommendations for the management of critically ill patients with COVID-19 in Intensive Care Units

The COVID-19 pandemic has led to the admission of a high number of patients to the ICU, generally due to severe respiratory failure. Since the appearance of the first cases of SARS-CoV-2 infection, at the end of 2019, in China, a huge number of treatment recommendations for this entity have been published, not always supported by sufficient scientific evidence or with methodological rigor necessary. Thanks to the efforts of different groups of researchers, we currently have the results of clinical trials, and other types of studies, of higher quality. We consider it necessary to create a document that includes recommendations that collect this evidence regarding the diagnosis and treatment of COVID-19, but also aspects that other guidelines have not considered and that we consider essential in the management of critical patients with COVID-19. For this, a drafting committee has been created, made up of members of the SEMICYUC Working Groups more directly related to different specific aspects of the management of these patients (AU)

La pandemia por COVID-19 ha provocado el ingreso de un elevado número de pacientes en UCI, generalmente por insuficiencia respiratoria severa. Desde la aparición de los primeros casos de infección por SARS-CoV-2, a finales de 2019, en China, se ha publicado una cantidad ingente de recomendaciones de tratamiento de esta entidad, no siempre respaldadas por evidencia científica suficiente ni con el rigor metodológico necesario. Gracias al esfuerzo de distintos grupos de investigadores, actualmente disponemos de resultados de ensayos clínicos, y otro tipo de estudios, de mayor calidad. Consideramos necesario realizar un documento que incluya recomendaciones que recojan estas evidencias en cuanto al diagnóstico y el tratamiento de COVID-19, pero también aspectos que otras guías no han contemplado y que consideramos fundamentales en el manejo del paciente crítico con COVID-19. Para ello se ha creado un comité redactor, conformado por miembros de los Grupos de Trabajo de SEMICYUC más directamente relacionados con diferentes aspectos específicos del manejo de estos pacientes (AU)

[Recommendations for the management of critically ill patients with COVID-19 in Intensive Care Units]. / Recomendaciones para el manejo de los pacientes críticos con COVID-19 en las Unidades de Cuidados Intensivos.

The COVID-19 pandemic has led to the admission of a high number of patients to the ICU, generally due to severe respiratory failure. Since the appearance of the first cases of SARS-CoV-2 infection, at the end of 2019, in China, a huge number of treatment recommendations for this entity have been published, not always supported by sufficient scientific evidence or with methodological rigor necessary. Thanks to the efforts of different groups of researchers, we currently have the results of clinical trials, and other types of studies, of higher quality. We consider it necessary to create a document that includes recommendations that collect this evidence regarding the diagnosis and treatment of COVID-19, but also aspects that other guidelines have not considered and that we consider essential in the management of critical patients with COVID-19. For this, a drafting committee has been created, made up of members of the SEMICYUC Working Groups more directly related to different specific aspects of the management of these patients.