a case–case study based on electronic health records

Funding Information: The acquisition of sequencing equipment and reagents used in this study by the Instituto Nacional de Saúde Doutor Ricardo Jorge was partially funded by the HERA project (grant no. 2021/PHF/23776), supported by the European Commission through the European Centre for Disease Control, and also partially funded by the Genome PT project (grant no. POCI‐01‐0145‐FEDER‐022184), supported by COMPETE 2020–Operational Programme for Competitiveness and Internationalisation, Lisboa Portugal Regional Operational Programme, Algarve Portugal Regional Operational, under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund, and by the Portuguese Science and Technology Foundation. The Algarve Biomedical Center Laboratory received public funding through the Project ALG‐D2‐2021‐06 Variants Screen in Southern Portugal–Monitoring Variants of Concern in Southern Portugal and the Portuguese Science and Technology Foundation national support through the Comprehensive Health Research Center (grant no. UIDP/04923/2020). Funding information Funding Information: The acquisition of sequencing equipment and reagents used in this study by the Instituto Nacional de Saúde Doutor Ricardo Jorge was partially funded by the HERA project (grant no. 2021/PHF/23776), supported by the European Commission through the European Centre for Disease Control, and also partially funded by the Genome PT project (grant no. POCI-01-0145-FEDER-022184), supported by COMPETE 2020–Operational Programme for Competitiveness and Internationalisation, Lisboa Portugal Regional Operational Programme, Algarve Portugal Regional Operational, under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund, and by the Portuguese Science and Technology Foundation. The Algarve Biomedical Center Laboratory received public funding through the Project ALG-D2-2021-06 Variants Screen in Southern Portugal–Monitoring Variants of Concern in Southern Portugal and the Portuguese Science and Technology Foundation national support through the Comprehensive Health Research Center (grant no. UIDP/04923/2020). Publisher Copyright: © 2023 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.Background: Information on vaccine effectiveness in a context of novel variants of concern (VOC) emergence is of key importance to inform public health policies. This study aimed to estimate a measure of comparative vaccine effectiveness between Omicron (BA.1) and Delta (B.1.617.2 and sub-lineages) VOC according to vaccination exposure (primary or booster). Methods: We developed a case–case study using data on RT-PCR SARS-CoV-2-positive cases notified in Portugal during Weeks 49–51, 2021. To obtain measure of comparative vaccine effectiveness, we compared the odds of vaccination in Omicron cases versus Delta using logistic regression adjusted for age group, sex, region, week of diagnosis, and laboratory of origin. Results: Higher odds of vaccination were observed in cases infected by Omicron VOC compared with Delta VOC cases for both complete primary vaccination (odds ratio [OR] = 2.1; 95% confidence interval [CI]: 1.8 to 2.4) and booster dose (OR = 5.2; 95% CI: 3.1 to 8.8), equivalent to reduction of vaccine effectiveness from 44.7% and 92.8%, observed against infection with Delta, to −6.0% (95% CI: 29.2% to 12.7%) and 62.7% (95% CI: 35.7% to 77.9%), observed against infection with Omicron, for complete primary vaccination and booster dose, respectively. Conclusion: Consistent reduction in vaccine-induced protection against infection with Omicron was observed. Complete primary vaccination may not be protective against SARS-CoV-2 infection in regions where Omicron variant is dominant.publishersversionpublishe

A proteomic survival predictor for COVID-19 patients in intensive care

© 2022 Demichev et al. This is an open access article distributed under the terms of the Creative Commons Attribution License. https://creativecommons.org/licenses/by/4.0/Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Additional tools are also needed to monitor treatment, including experimental therapies in clinical trials. Comprehensively capturing human physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index, and APACHE II score showed limited performance in predicting the COVID-19 outcome. Instead, the quantification of 321 plasma protein groups at 349 timepoints in 50 critically ill patients receiving invasive mechanical ventilation revealed 14 proteins that showed trajectories different between survivors and non-survivors. A predictor trained on proteomic measurements obtained at the first time point at maximum treatment level (i.e. WHO grade 7), which was weeks before the outcome, achieved accurate classification of survivors (AUROC 0.81). We tested the established predictor on an independent validation cohort (AUROC 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that plasma proteomics can give rise to prognostic predictors substantially outperforming current prognostic markers in intensive care.Peer reviewedFinal Published versio

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study.

INTRODUCTION: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. METHODS: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. FINDINGS: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2-6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p5mg/L, OR 3·55 [1·23-11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. INTERPRETATION: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification. FUNDING: UK Research and Innovation and National Institute for Health Research

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3-and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection

The Your COVID-19 risk assessment tool and the accompanying open access data and materials repositories

In March 2020, the Your COVID-19 Risk tool was developed in response to the global spread of SARS-CoV-2. The tool is an online resource based on key behavioural evidence-based risk factors related to contracting and spreading SARS-CoV-2. This article describes the development of the tool, the produced resources, the associated open repository, and initial results. This tool was developed by a multidisciplinary research team consisting of more than 150 international experts. This project leverages knowledge obtained in behavioural science, aiming to promote behaviour change by assessing risk and supporting individuals completing the assessment tool to protect themselves and others from infection. To enable iterative improvements of the tool, tool users can optionally answer questions about behavioural determinants. The data and results are openly shared to support governments and health agencies developing behaviour change interventions. Over 60 000 users in more than 150 countries have assessed their risk and provided data.info:eu-repo/semantics/publishedVersio

Research priorities for Long Covid: refined through an international multi-stakeholder forum.

No Abstract available

Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection

Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified

Benefits of early aggressive immunomodulatory therapy (tocilizumab and methylprednisolone) in COVID-19: Single center cohort study of 685 patients

Introduction: A growing evidence suggests that immune dysregulation and thrombotic phenomena are key features in the pathophysiology of COVID-19. Apart from antivirals and respiratory support, anticoagulants, corticoids and immunomodulators are increasingly being prescribed, especially for more severe cases. We describe the clinical outcome of a large cohort of patients preferentially treated with glucocorticoids and interleukin inhibitors. Methods: Single center and retrospective case series. Adult patients admitted with COVID-19 related respiratory insufficiency were included. Patients who died within 2 days after admission and those testing positive but asymptomatic were excluded. We defined two study periods: from March 3rd to March 31 st, 2020 (beginning of epidemic until peak of incidence) and April 1 st to May 7 th, 2020 (second half of epidemic). The majority of patients received respiratory support, combinations of antimicrobials, anticoagulants, corticoids and interleukin inhibitors. Antivirals were preferentially given in the first period. The clinical outcome (death and ventilator dependency) of both periods was compared. Results: From March 3 rd to May 7 th, 685 patients were included for analysis (58.4% males, mean age 68.9 years). Patients in the first period (n = 408) were younger (66.6 vs 71.1 years, p = 0.003), presented lower mean P a O2/FiO2 ratio at admission (256.5 vs 270.4 mm Hg,p = 0.0563), higher ferritin (1520 vs 1221 ng/ml, p = 0.01), higher IL-6 (679 vs 194 pg/ml, p < 0.0001) and similar D-dimer levels (3.59 vs 3.39 mu g/mL, p = 0.65) compared to the second period (n = 277). Lopinavir/ritonavir and interferon were preferentially given in the first period (23.8% and 32% vs 1.8% and 11.9%, p < 0.0001). Use of corticoids (88.2% vs 87.4%, p = 0,74) and tocilizumab (26.29 vs 20.22% p = 0.06) were similarly administered in both periods. Patients in the second period needed less mechanical ventilation (4.9% vs 16.9%, p < 0.0001), fewer ICU admission (6.1% vs 20.1%,p < 0.0001) and showed similar mortality (17.7% vs 15.4%, p = 0.43). Infectious and thrombotic complications were comparable in both periods (both around 8%, with no statistical difference). Patients treated with tocilizumab (n = 163) had lower mortality rate compared to those untreated under the same indication (7.9% vs 24.2%, p < 0.0001). Conclusions: In this large retrospective COVID-19 in-hospital cohort, lopinavir/ritonavir and interferon showed no significant impact on survival. Extensive use of corticosteroids and tocilizumab resulted in good overall outcome and showed acceptable complication rates

Association of intensity of ventilation with 28-day mortality in COVID-19 patients with acute respiratory failure: insights from the PRoVENT-COVID study

Background: The intensity of ventilation, reflected by driving pressure (ΔP) and mechanical power (MP), has an association with outcome in invasively ventilated patients with or without acute respiratory distress syndrome (ARDS). It is uncertain if a similar association exists in coronavirus disease 2019 (COVID-19) patients with acute respiratory failure. Methods: We aimed to investigate the impact of intensity of ventilation on patient outcome. The PRoVENT-COVID study is a national multicenter observational study in COVID-19 patients receiving invasive ventilation. Ventilator parameters were collected a fixed time points on the first calendar day of invasive ventilation. Mean dynamic ΔP and MP were calculated for individual patients at time points without evidence of spontaneous breathing. A Cox proportional hazard model, and a double stratification analysis adjusted for confounders were used to estimate the independent associations of ΔP and MP with outcome. The primary endpoint was 28-day mortality. Results: In 825 patients included in this analysis, 28-day mortality was 27.5%. ΔP was not independently associated with mortality (HR 1.02 [95% confidence interval 0.88–1.18]; P = 0.750). MP, however, was independently associated with 28-day mortality (HR 1.17 [95% CI 1.01–1.36]; P = 0.031), and increasing quartiles of MP, stratified on comparable levels of ΔP, had higher risks of 28-day mortality (HR 1.15 [95% CI 1.01–1.30]; P = 0.028). Conclusions: In this cohort of critically ill invasively ventilated COVID-19 patients with acute respiratory failure, we show an independent association of MP, but not ΔP with 28-day mortality. MP could serve as one prognostic biomarker in addition to ΔP in these patients. Efforts aiming at limiting both ΔP and MP could translate in a better outcome. Trial registration Clinicaltrials.gov (study identifier NCT04346342). [Figure not available: see fulltext.

Prognostication using SpO2/FiO2 in invasively ventilated ICU patients with ARDS due to COVID-19 - Insights from the PRoVENT-COVID study

BACKGROUND: The SpO2/FiO2 is a useful oxygenation parameter with prognostic capacity in patients with ARDS. We investigated the prognostic capacity of SpO2/FiO2 for mortality in patients with ARDS due to COVID-19. METHODS: This was a post-hoc analysis of a national multicenter cohort study in invasively ventilated patients with ARDS due to COVID-19. The primary endpoint was 28-day mortality. RESULTS: In 869 invasively ventilated patients, 28-day mortality was 30.1%. The SpO2/FiO2 on day 1 had no prognostic value. The SpO2/FiO2 on day 2 and day 3 had prognostic capacity for death, with the best cut-offs being 179 and 199, respectively. Both SpO2/FiO2 on day 2 (OR, 0.66 [95%-CI 0.46-0.96]) and on day 3 (OR, 0.70 [95%-CI 0.51-0.96]) were associated with 28-day mortality in a model corrected for age, pH, lactate levels and kidney dysfunction (AUROC 0.78 [0.76-0.79]). The measured PaO2/FiO2 and the PaO2/FiO2 calculated from SpO2/FiO2 were strongly correlated (Spearman's r = 0.79). CONCLUSIONS: In this cohort of patients with ARDS due to COVID-19, the SpO2/FiO2 on day 2 and day 3 are independently associated with and have prognostic capacity for 28-day mortality. The SpO2/FiO2 is a useful metric for risk stratification in invasively ventilated COVID-19 patients