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.

Long-Term Sequelae of severe COVID-19: outpatient assessment of radiological and pulmonary function tests Secuelas a largo plazo de la COVID-19 grave: valoración ambulatoria de pruebas radiológicas y de función pulmonar

Objective: Identify lung sequelae of COVID-19 through radiological and pulmonary function assessment. Design: Prospective, longitudinal, cohort study from March 2020 to March 2021. Setting: Intensive Care Units (ICU) in a tertiary hospital in Portugal. Patients: 254 patients with COVID-19 admitted to ICU due to respiratory illness. Interventions: A chest computed tomography (CT) scan and pulmonary function tests (PFT) were performed at 3 to 6 months. Main variables of interest: CT-scan;PFT;decreased diffusion capacity of carbon monoxide (DLCO). Results: All CT scans revealed improvement in the follow-up, with 72% of patients still showing abnormalities, 58% with ground glass opacities and 62% with evidence of fibrosis. PFT had abnormalities in 94 patients (46%): thirteen patients (7%) had an obstructive pattern, 35 (18%) had a restrictive pattern, and 58 (30%) had decreased DLCO. There was a statistically significant association between abnormalities in the follow-up CT scan and older age, more extended hospital and ICU stay, higher SAPS II and APACHE scores and invasive ventilation. Mechanical ventilation, especially with no lung protective parameters, was associated with abnormalities in PFT. Multivariate regression showed more abnormalities in lung function with more extended ICU hospitalization, chronic obstructive pulmonary disease (COPD), chronic kidney disease, invasive mechanical ventilation, and ventilation with higher plateau pressure, and more abnormalities in CT-scan with older age, more extended ICU stay, organ solid transplants and ventilation with higher positive end-expiratory pressure (PEEP). Conclusions: Most patients with severe COVID-19 still exhibit abnormalities in CT scans or lung function tests three to six months after discharge.

The PRINCOVID retrospective study - a predictive model of pressure injuries for critical COVID-19 patients.

OBJECTIVE: To characterize pressure injuries (PI), identify risk factors, and develop a predictive model for PI at intensive care unit (ICU) admission for critical COVID-19 patients. DESIGN: Retrospective analysis of a consecutive sample of patients admitted to ICU between May/2020 and September/2021. Inclusion criteria encompassed the diagnosis of Acute Respiratory Distress Syndrome due to SARS-CoV-2, requiring invasive mechanical ventilation >48 h. Several predictors were evaluated: socio-demographic characteristics, comorbidities, clinical and laboratory findings at ICU admission. The primary outcome was the presence of PI. RESULTS: 205 patients were included, mostly males (73%) with a mean age of 62 years old. PI prevalence was 58%. On multivariable analysis, male gender, hypertension, hemoglobin, and albumin at ICU admission were independently associated with PI, constituting the PRINCOVID model. The model reached an AUC-ROC of 0.71, surpassing the Braden Scale(p = 0.0015). The PRINCOVID score ranges from 0-15, with two risk groups: "at-risk"(≤7 points) and "high-risk"(>7 points). CONCLUSIONS: This study proposes PRINCOVID as a multivariable model for developing PI in critical COVID-19 patients. Based on four parameters (gender, hypertension, hemoglobin and albumin at ICU admission), this model fairly predicts the development of PI. The PRINCOVID score allows patients' classification into two groups, facilitating early identification of high-risk patients.

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. METHODS: Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. RESULTS: Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49-69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI - 0.1% [- 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (- 3.2% [- 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. CONCLUSION: This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 ).

Evaluation of urinary cysteinyl leukotrienes as biomarkers of severity and putative therapeutic targets in COVID-19 patients.

BACKGROUND: Cysteinyl leukotrienes (CysLT) are potent inflammation-promoting mediators, but remain scarcely explored in COVID-19. We evaluated urinary CysLT (U-CysLT) relationship with disease severity and their usefulness for prognostication in hospitalized COVID-19 patients. The impact on U-CysLT of veno-venous extracorporeal membrane oxygenation (VV-ECMO) and of comorbidities such as hypertension and obesity was also assessed. METHODS: Blood and spot urine were collected in "severe" (n = 26), "critically ill" (n = 17) and "critically ill on VV-ECMO" (n = 17) patients with COVID-19 at days 1-2 (admission), 3-4, 5-8 and weekly thereafter, and in controls (n = 23) at a single time point. U-CysLT were measured by ELISA. Routine markers, prognostic scores and outcomes were also evaluated. RESULTS: U-CysLT did not differ between groups at admission, but significantly increased along hospitalization only in critical groups, being markedly higher in VV-ECMO patients, especially in hypertensives. U-CysLT values during the first week were positively associated with ICU and total hospital length of stay in critical groups and showed acceptable area under curve (AUC) for prediction of 30-day mortality (AUC: 0.734, p = 0.001) among all patients. CONCLUSIONS: U-CysLT increase during hospitalization in critical COVID-19 patients, especially in hypertensives on VV-ECMO. U-CysLT association with severe outcomes suggests their usefulness for prognostication and as therapeutic targets.

Critical COVID-19 and neurological dysfunction - a direct comparative analysis between SARS-CoV-2 and other infectious pathogens. / COVID-19 crítico e disfunção neurológica - uma análise comparativa direta entre o SARS-CoV-2 e outros agentes infecciosos.

OBJECTIVE: To evaluate whether critical SARS-CoV-2 infection is more frequently associated with signs of corticospinal tract dysfunction and other neurological signs, symptoms, and syndromes, than other infectious pathogens. METHODS: This was a prospective cohort study with consecutive inclusion of patients admitted to intensive care units due to primary infectious acute respiratory distress syndrome requiring invasive mechanical ventilation > 48 hours. Eligible patients were randomly assigned to three investigators for clinical evaluation, which encompassed the examination of signs of corticospinal tract dysfunction. Clinical data, including other neurological complications and possible predictors, were independently obtained from clinical records. RESULTS: We consecutively included 54 patients with acute respiratory distress syndrome, 27 due to SARS-CoV-2 and 27 due to other infectious pathogens. The groups were comparable in most characteristics. COVID-19 patients presented a significantly higher risk of neurological complications (RR = 1.98; 95%CI 1.23 - 3.26). Signs of corticospinal tract dysfunction tended to be more prevalent in COVID-19 patients (RR = 1.62; 95%CI 0.72 - 3.44). CONCLUSION: Our study is the first comparative analysis between SARS-CoV-2 and other infectious pathogens, in an intensive care unit setting, assessing neurological dysfunction. We report a significantly higher risk of neurological dysfunction among COVID-19 patients. As such, we suggest systematic screening for neurological complications in severe COVID-19 patients.

OBJETIVO: Avaliar se a infecção grave pelo SARS-CoV-2 está mais comumente associada a sinais de disfunção do trato corticoespinhal e outros sinais, sintomas e síndromes neurológicas, em comparação com outros agentes infecciosos. MÉTODOS: Este foi um estudo de coorte prospectivo com inclusão consecutiva de doentes admitidos a unidades de cuidados intensivos devido a síndrome do desconforto respiratório agudo infeccioso primário, com necessidade de ventilação mecânica invasiva por > 48 horas. Os doentes incluídos foram atribuídos aleatoriamente a três investigadores para a avaliação clínica, a qual incluía a pesquisa de sinais de disfunção do trato corticoespinhal. Os dados clínicos, incluindo outras complicações neurológicas e possíveis preditores, foram obtidos independentemente a partir dos registros clínicos. RESULTADOS: Foram incluídos consecutivamente 54 doentes com síndrome do desconforto respiratório agudo, 27 devido a SARS-CoV-2 e 27 devido a outros agentes infecciosos. Os grupos eram comparáveis na maioria das características. Os doentes com COVID-19 apresentavam risco significativamente superior de complicações neurológicas (RR = 1,98; IC95% 1,23 - 3,26). Os sinais de disfunção do trato corticoespinhal tendiam a ser mais prevalentes em doentes com COVID-19 (RR = 1,62; IC95% 0,72 - 3,44). CONCLUSÃO: Este estudo foi a primeira análise comparativa visando avaliar disfunção neurológica, entre doentes com infecção SARS-CoV-2 e outros agentes infecciosos, em um contexto de unidade de cuidados intensivos. Reportamos um risco significativamente superior de disfunção neurológica em doentes com COVID-19. Como tal, sugere-se o rastreio sistemático de complicações neurológicas em doentes com COVID-19 crítico.

Different epidemiology of bloodstream infections in COVID-19 compared to non-COVID-19 critically ill patients: a descriptive analysis of the Eurobact II study.

BACKGROUND: The study aimed to describe the epidemiology and outcomes of hospital-acquired bloodstream infections (HABSIs) between COVID-19 and non-COVID-19 critically ill patients. METHODS: We used data from the Eurobact II study, a prospective observational multicontinental cohort study on HABSI treated in ICU. For the current analysis, we selected centers that included both COVID-19 and non-COVID-19 critically ill patients. We performed descriptive statistics between COVID-19 and non-COVID-19 in terms of patients' characteristics, source of infection and microorganism distribution. We studied the association between COVID-19 status and mortality using multivariable fragility Cox models. RESULTS: A total of 53 centers from 19 countries over the 5 continents were eligible. Overall, 829 patients (median age 65 years [IQR 55; 74]; male, n = 538 [64.9%]) were treated for a HABSI. Included patients comprised 252 (30.4%) COVID-19 and 577 (69.6%) non-COVID-19 patients. The time interval between hospital admission and HABSI was similar between both groups. Respiratory sources (40.1 vs. 26.0%, p < 0.0001) and primary HABSI (25.4% vs. 17.2%, p = 0.006) were more frequent in COVID-19 patients. COVID-19 patients had more often enterococcal (20.5% vs. 9%) and Acinetobacter spp. (18.8% vs. 13.6%) HABSIs. Bacteremic COVID-19 patients had an increased mortality hazard ratio (HR) versus non-COVID-19 patients (HR 1.91, 95% CI 1.49-2.45). CONCLUSIONS: We showed that the epidemiology of HABSI differed between COVID-19 and non-COVID-19 patients. Enterococcal HABSI predominated in COVID-19 patients. COVID-19 patients with HABSI had elevated risk of mortality. Trial registration ClinicalTrials.org number NCT03937245 . Registered 3 May 2019.

What is the impact of previous cerebrovascular disease on critical COVID-19 patients' mortality? A prospective cohort study.

OBJECTIVES: We aimed to evaluate the effect of previous cerebrovascular disease (CVD) on mortality rates of critically ill COVID-19 patients. MATERIALS & METHODS: A prospective cohort study was performed between May/2020 and May/2021, at a tertiary-care-center. We consecutively included adult patients admitted to intensive care units (ICU) having as primary diagnosis Acute Respiratory Distress Syndrome due to SARS-CoV-2, requiring invasive mechanical ventilation for >48 h. We considered as exposure the diagnosis of previous CVD and as main outcome the in-ICU mortality. RESULTS: The study sample included 178 patients: 74.2% were males, with a mean age of 63 ± 12.4 years-old(yo). Previous CVD was documented in 17 patients (9.6%). During the study period, the mortality rate at ICU was of 33.1% (n = 59). The proportion of mortality at ICU was higher in patients with prior CVD (58.8% vs 30.4%; p = 0.02). Also, older patients (66 ± 11.4 yo vs. 62 ± 12.7 yo, p = 0.04) and those with higher score at SAPSII at ICU admission (47.8 ± 15.4 vs. 40.7 ± 15.9; p = 0.01) had a higher ICU deathrate. Patients with previous CVD had a 2.70 (95%CI = 1.36-5.39) higher likelihood of dying compared to those who had no previous CVD. After adjustment (for gender, age, SAPSII and total length of stay), multivariate Cox analysis revealed that previous CVD remained a strong predictor for in-ICU death in critically ill COVID-19 patients (HR = 2.51; 95%CI = 1.15-5.51). CONCLUSIONS: Previous CVD was significantly associated to higher mortality in critical COVID-19 patients. We suggest that, in patients with previous CVD, prioritization of vaccination strategies should be implemented alongst with higher surveillance when infected with SARS-CoV-2.

The impact of severe COVID-19 on health-related quality of life and disability: an early follow-up perspective. / Impacto da COVID-19 grave na qualidade de vida relacionada com a saúde e a incapacidade: uma perspectiva de follow-up a curto-prazo.

OBJECTIVE: To assess early postdischarge health-related quality of life and disability of all survivors of critical COVID-19 admitted for more than 24 hours to na intensive care unit.. METHODS: Study carried out at the Intensive Care Medicine Department of Centro Hospitalar Universitário São João from 8th October 2020 to 16th February 2021. Approximately 1 month after hospital discharge, an intensive care-trained nurse performed a telephone consultation with 99 survivors already at home applying the EuroQol Five-Dimensional Five-Level questionnaire and the 12-item World Health Organization Disability Assessment Schedule 2.0. RESULTS: The mean age of the population studied was 63 ± 12 years, and 32.5% were submitted to invasive mechanical ventilation. Their mean Simplified Acute Physiologic Score was 35 ± 14, and the Charlson Comorbidity Index was 3 ± 2. Intensive care medicine and hospital lengths of stay were 13 ± 22 and 22 ± 25 days, respectively. The mean EuroQol Visual Analog Scale was 65% (± 21), and only 35.3% had no or slight problems performing their usual activities, most having some degree of pain/discomfort and anxiety/depression. The 12-item World Health Organization Disability Assessment Schedule 2.0 showed marked impairments in terms of reassuring usual work or community activities and mobility. The use of both tools suggested that their health status was worse than their perception of it. CONCLUSION: This early identification of sequelae may help define flows and priorities for rehabilitation and reinsertion after critical COVID-19.

OBJETIVO: Avaliar a qualidade de vida relacionada com a saúde e a incapacidade no primeiro mês após a alta para domicílio de todos os sobreviventes de COVID-19 grave internados por mais de 24 horas no Serviço de Medicina Intensiva. METÓDOS: Estudo realizado no Serviço de Medicina Intensiva do Centro Hospitalar Universitário São João, entre 8 de outubro de 2020 e 16 de fevereiro de 2021. Aproximadamente 1 mês após a alta para domicílio, uma enfermeira com experiência em medicina intensiva realizou uma consulta telefônica a 99 sobreviventes, aplicando os questionários EuroQol Five-Dimensional Five-Level e World Health Disability Assessment Schedule 2.0 - 12 itens. RESULTADOS: A média de idade da população estudada foi de 63 ± 12 anos, e 32,5% foram submetidos à ventilação mecânica invasiva. O Simplified Acute Physiology Score médio foi de 35 ± 14, e o Índice de Comorbilidades de Charlson foi de 3 ± 2. O tempo de internamento em medicina intensiva e no hospital foi de 13 ± 22 e 22 ± 25 dias, respectivamente. A média da Escala Visual Analógica da EuroQol foi de 65% (± 21), sendo que apenas 35,3% dos sobreviventes não apresentaram ou tiveram problemas ligeiros para realizar suas atividades habituais, a maioria com algum grau de dor/desconforto e ansiedade/depressão. O World Health Disability Assessment Schedule 2.0 - 12 itens, mostrou incapacidade marcada em retomar o trabalho habitual ou atividades comunitárias e na mobilidade. O uso de ambas as ferramentas sugeriu que o estado de saúde dos sobreviventes seria pior do que a sua percepção. CONCLUSÃO: A identificação precoce de sequelas pode ajudar a definir fluxos e prioridades para a reabilitação e reinserção após a COVID-19 grave.

Depressive and Anxiety Symptoms in Severe COVID-19 Survivors: A Prospective Cohort Study.

The coronavirus disease 2019 (COVID-19) has rapidly spread worldwide, leading to increased concerns about long-term patients' neuropsychiatric consequences. This study aims to describe the presence of depressive and anxiety symptoms in severe COVID-19 survivors and to identify associated baseline, in-hospital and post-discharge factors. This study is part of the MAPA longitudinal project conducted with severe COVID-19 patients admitted in Intensive Care Medicine Department (ICMD) of a University Hospital (CHUSJ) in Porto, Portugal. Patients with ICMD length of stay ≤ 24 h, terminal illness, major auditory loss or inability to communicate at follow-up assessment were excluded. All participants were assessed by telephone post-discharge (median = 101 days), with a comprehensive protocol assessing depressive and anxiety symptoms, cognition, Intensive Care Unit (ICU) memories recall and health-related quality of life. Out of a sample of 56 survivors (median age = 65; 68% males), 29% and 23% had depressive and anxiety symptoms, respectively. Depressive and anxiety symptoms were significantly more prevalent among younger survivors and were associated with cognitive complaints, emotional and delusions ICU memories and fear of having COVID-19 sequelae, sleep problems and pain after discharge (all p < 0.05). An important proportion of these survivors suffers from depression and anxiety symptoms post-discharge, namely younger ones and those who reported more cognitive complaints, ICU memories, fear of having COVID-19 sequelae, sleep problems and pain. These findings highlight the importance of psychological consequences assessment and planning of appropriate and multidisciplinary follow-up care after hospitalization due to COVID-19.

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.

Old critically ill COVID-19 survivors: Patient and in-hospital factors associated with cognitive dysfunction

Background Cognitive dysfunction (CD) commonly occurs in survivors of critical illness, namely in those with severe respiratory failure, invasive mechanical ventilation (IMV), deep sedation and delirium. Many critically ill patients with COVID-19 are also expected to have an increased risk of CD, which may be exacerbated by specific conditions of hospitalization during COVID-19 pandemic. This study aimed to estimate the frequency of post-discharge CD in first wave COVID-19 survivors and to identify baseline and in-hospital associated factors. Methods This study is part of a multidisciplinary longitudinal project (MAPA-Mental health in critically ill COVID-19 patients), that is being conducted in Intensive Care Medicine Department of a Portuguese University Hospital. Patients >60 years, admitted due to COVID-19-associated Pneumonia, were included. Exclusion criteria were: Intensive Care Unit (ICU) length of stay (LoS)≤24h, terminal illness, major sensory loss or inability to communicate at the time of follow-up. Participants were evaluated with Six-item Cognitive Impairment Test (6CIT) by telephone. Baseline demographic, clinical and in-hospital data were collected, including sedation, respiratory support, major complications and LoS. Patients with and without CD after-discharge were compared. Results Thirty-two patients were included, with a median age of 72(IQR:64-76) years, mostly were male (66%) and none had previous clinical registry of cognitive impairment or dementia. Nosocomial infection (75%) and difficult weaning from MV (63%) were the most frequent complications. Deep sedation was used in 81% of the patients (median=20 days;IQR:15-42). About 81% needed IMV and 13% were supported with Extracorporeal Membrane Oxygenation (ECMO). Median ICU and hospital LoS were 29(IQR:144-56) and 66(IQR:33-102) days, respectively. Follow-up assessment occurred 93.4 days (IQR:68-120) after-discharge. Based on 6CIT, 16% of survivors had CD. Comparing both groups, those with CD were older (73vs.64;p=0.020), had a higher duration of IMV (73vs.22;p=0.017) and mostly were supported with ECMO (75%vs.25%;p=0.008). Conclusion Data suggest that CD is more frequent among older COVID-19 survivors, and those who needed prolonged IMV and ECMO support. Despite full clarification of all mechanisms involved, these findings highlight the importance of a timely and organized post-intensive care response composed by multidisciplinary teams to optimize assistance to survivors of critical illness.

Neuropsychiatric symptomatology after severe COVID-19 in older survivors

Background:The coronavirus disease 2019 (COVID-19) has rapidly spread worldwide, leading to increased concerns about long-term patients’ neuropsychiatric morbidity. Currently, there is still few data regarding mental health after hospital discharge of severe COVID-19 elderly patients. Considering this, the present study aims to characterize the neuropsychiatric morbidity in old severe COVID-19 patients.Methods:In the context of an ongoing multidisciplinary research project, this study analyzed a subsample of patients aged ≥60 years, admitted due to COVID-19, during the first wave, in the Intensive Care Medicine Department (ICMD) of a University Hospital in Porto, Portugal. ICMD length of stay (LoS) ≤24h, terminal illness, major auditory loss or inability to communicate at the time of follow- up were used as exclusion criteria. Participants were evaluated by telephone in average 99 (±32) days after being discharged from the hospital, with Six-item Cognitive Impairment Test, PatientHealth Questionnaire and Generalized Anxiety Disorder Scale. Sociodemographic and relevant clinicaldata were obtained from hospital electronic records and clinical interview.Results:A sample of 39 survivors with a mean age of 70 (±6.3) years old were assessed. The majority were male (62%), married (64%), retired (77%), with low educational level (59%), and 15% lived alone. The average number of comorbidities and the daily medications per patient were 4.7 (±1.7) and 5.5 (±3.5), respectively.During ICMD stay, 69% had nosocomial infections and 56% delirium. Deep sedation was used in 74% of the patients (mean=30 days) and 74% needed Invasive Mechanical Ventilation. ICMD mean LoS was33 (±28.3) days. Based on follow-up assessment, 18% of survivors had cognitive impairment, whereas23% and 15% had depressive and anxiety symptoms, respectively. A positive and high correlation between depression and anxiety was found (rs=0.792;p<0.001). No significant associations were observed with cognitive impairment.Conclusions:The presence of this symptomatology may hinder a successful recovery once the patient is discharged back home. This is particularly relevant accruing the strong relationship between depressive and anxious symptoms found in this sample. Therefore, early screening and timely multidisciplinary support interventions to minimize these neuropsychiatric symptoms after discharge should be considered in order to achieve positive health outcomes.

Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial.

BACKGROUND: The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support. METHODS: DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir-ritonavir, lopinavir-ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948. FINDINGS: Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 [15%] vs 79 [19%]); (7) death (21 [5%] vs 24 [6%]). The difference between treatment groups was not significant (odds ratio 0·98 [95% CI 0·77-1·25]; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs control, 130 [31%] of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome). INTERPRETATION: No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support. FUNDING: European Union Commission, French Ministry of Health, Domaine d'intérêt majeur One Health Île-de-France, REACTing, Fonds Erasme-COVID-Université Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Health-Related Quality of Life in Survivors of Severe COVID-19 of a University Hospital in Northern Portugal.

INTRODUCTION: Long-term health impairments are often experienced among survivors of critical illness, which may have a negative impact on their quality of life. The aim of this study was to characterize COVID-19 survivors of critical illness and to evaluate health-related quality of life and disability following hospital discharge. MATERIAL AND METHODS: This is a retrospective case-series study that included COVID-19 survivors admitted to the Intensive Care Medicine Department of a University Hospital. Follow-up evaluation was performed between the 30th and the 90th day after discharge. Quality of life was explored using the five-level version of the EQ-5D instrument (EQ-5D-5L) and functionality using the 12-question World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). RESULTS: Forty-five survivors were enrolled, 28 (62.2%) men, median age 63.0 years. The EQ-5D-5L questionnaire showed moderate to extreme problems in some dimension in 29 patients (64.4%): mobility in six (13.3%), self-care in seven (13.3%), usual activities in 23 (51.1%), pain/discomfort in 14 (31.1%) and anxiety/depression in 17 (37.8%). When using the 12-question WHODAS 2.0 questionnaire, moderate to extreme disability was reported in some question in 37 patients (82.2%): 19 (42.2%) in standing for long periods, 18 (40.0%) in long-distance walking; 14 (31.1%) on taking care of household responsibilities and 17 (37.8%) in their day-to-day work; 23 (51.1%) felt emotionally affected by their health problems. DISCUSSION: Based on COVID-19 survivors-reported outcomes after critical illness, mobility, pain/discomfort, and anxiety/depression were the main problems that persisted one to three months after hospital discharge. CONCLUSION: An organized follow-up structure is crucial to improve health-related quality of life in critical COVID-19 survivors.

Introdução: Os sobreviventes de doença crítica apresentam frequentemente sequelas a longo prazo. O objetivo deste estudo foi caracterizar os sobreviventes da COVID-19 grave e avaliar a qualidade de vida após a alta hospitalar. Material e Métodos: Série de casos que inclui sobreviventes COVID-19 admitidos no Serviço de Medicina Intensiva de um Hospital Universitário. A consulta de seguimento foi realizada entre o 30º e o 90º dia após alta hospitalar. A qualidade de vida foi avaliada através do questionário EQ-5D com cinco níveis (EQ-5D-5L) e a funcionalidade através do instrumento World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) de 12 questões. Resultados: Foram incluídos 45 sobreviventes, 28 homens (62,2%), idade mediana de 63,0 anos. No questionário EQ-5D-5L 29 sobreviventes (64,4%) mostraram problemas moderados a extremos em alguma dimensão: seis (13,3%) na mobilidade, sete (13,3%) nos cuidados pessoais, 23 (51,1%) nas atividades habituais, 14 (31,1%) na dor/desconforto e 17 (37,8%) na ansiedade/depressão. No WHODAS 2.0 37 sobreviventes (82,2%) revelaram alterações funcionais moderadas a extremas em alguma questão: 19 (42,2%) em permanecer de pé por longos períodos, 18 (40,0%) em percorrer longas distâncias, 14 (31,1%) em cuidar das responsabilidades domésticas e 17 (37,8%) no dia-a-dia no trabalho; 23 (51,1%) mostraram-se emocionalmente afetados pelos seus problemas de saúde. Discussão: A avaliação dos sobreviventes COVID-19 após a doença crítica demonstra que a mobilidade, a dor/desconforto e a ansiedade/depressão são os principais problemas que persistem um a três meses após a alta hospitalar. Conclusão: O acompanhamento estruturado após alta poderá ter impacto significativo na qualidade de vida destes doentes.

Increase of Antimicrobial Consumption in a Tertiary Care Hospital during the First Phase of the COVID-19 Pandemic.

Background: The COVID-19 pandemic poses novel challenges in antimicrobial consumption metrics and stewardship strategies. COVID-19 patients became the major cause of hospital admission during the first wave of the pandemic, often leading to an antimicrobial prescription upon admission or treatment for superinfections. The aim of this study was to understand how antimicrobial consumption was impacted at the beginning of the pandemic in a tertiary care hospital, a reference center for COVID-19. Materials and Methods: A retrospective before-and-after study was done. Descriptive statistics of discharges, patient-days, and antimicrobial use indicators (defined daily doses (DDD)/100 discharges, DDD/100 patient-days) for various groups were calculated for the first three months of the pandemic (March, April, and May 2020) as a quarterly value, and for each year in 2011-2019, and their annual percentage changes were used to estimate 95% confidence intervals. The indicators were compared to patient type (medical/surgical), type of admission (urgent/elective), and age groups using Spearman's correlation coefficient. Results: Statistically significant increases occurred in 2020 for total antibacterials, macrolides, cephalosporins, amoxicillin/clavulanic acid, carbapenems, meropenem, and third-generation cephalosporins, while a reduction was seen in cefazolin/cefoxitin. A correlation was found between antibacterial consumption and patient or admission type. In 2020, unlike in pre-pandemic years, there was a different impact in DDD/100 discharges and DDD/100 patient-days due to increased lengths-of-stay and longer antimicrobial therapy. Conclusions: The COVID-19 pandemic led to an increase in antimicrobial consumption with a different impact in DDD/100 discharges and DDD/100 patient-days. This highlights the need to use both indicators simultaneously to better understand the causes of antimicrobial consumption variation and improve the design of effective antimicrobial stewardship interventions.

Recommendations from the Sociedade Portuguesa de Cuidados Intensivos and Infection & Sepsis Group for intensive care approach to COVID-19. / Recomendações da Sociedade Portuguesa de Cuidados Intensivos e Grupo de Infeção e Sépsis para a abordagem do COVID-19 em medicina intensiva.

Current COVID-19 epidemics was declared on December 31, 2019 at the Wuhan city seafood market, rapidly spreading throughout China, and later reaching several countries (mainly South Korea, Japan, Italy and Iran) and, since March 1, reaching Portugal. Most of the infected patients present with mild symptoms, not requiring hospitalization. Among those admitted to the hospital, 6% to 10% require admission to the intensive care unit. These recommendations are aimed to support the organization of intensive care services to respond COVID-19, providing optimized care to the patient and protection for healthcare professionals.